Hybrid Quantum Mechanics/Molecular Mechanics Solvation Scheme for Computing Free Energies of Reactions at Metal-Water Interfaces.

PubMed

Faheem, Muhammad; Heyden, Andreas

2014-08-12

We report the development of a quantum mechanics/molecular mechanics free energy perturbation (QM/MM-FEP) method for modeling chemical reactions at metal-water interfaces. This novel solvation scheme combines planewave density function theory (DFT), periodic electrostatic embedded cluster method (PEECM) calculations using Gaussian-type orbitals, and classical molecular dynamics (MD) simulations to obtain a free energy description of a complex metal-water system. We derive a potential of mean force (PMF) of the reaction system within the QM/MM framework. A fixed-size, finite ensemble of MM conformations is used to permit precise evaluation of the PMF of QM coordinates and its gradient defined within this ensemble. Local conformations of adsorbed reaction moieties are optimized using sequential MD-sampling and QM-optimization steps. An approximate reaction coordinate is constructed using a number of interpolated states and the free energy difference between adjacent states is calculated using the QM/MM-FEP method. By avoiding on-the-fly QM calculations and by circumventing the challenges associated with statistical averaging during MD sampling, a computational speedup of multiple orders of magnitude is realized. The method is systematically validated against the results of ab initio QM calculations and demonstrated for C-C cleavage in double-dehydrogenated ethylene glycol on a Pt (111) model surface.

An adaptive quantum mechanics/molecular mechanics method for the infrared spectrum of water: incorporation of the quantum effect between solute and solvent.

PubMed

Watanabe, Hiroshi C; Banno, Misa; Sakurai, Minoru

2016-03-14

Quantum effects in solute-solvent interactions, such as the many-body effect and the dipole-induced dipole, are known to be critical factors influencing the infrared spectra of species in the liquid phase. For accurate spectrum evaluation, the surrounding solvent molecules, in addition to the solute of interest, should be treated using a quantum mechanical method. However, conventional quantum mechanics/molecular mechanics (QM/MM) methods cannot handle free QM solvent molecules during molecular dynamics (MD) simulation because of the diffusion problem. To deal with this problem, we have previously proposed an adaptive QM/MM "size-consistent multipartitioning (SCMP) method". In the present study, as the first application of the SCMP method, we demonstrate the reproduction of the infrared spectrum of liquid-phase water, and evaluate the quantum effect in comparison with conventional QM/MM simulations.

Efficient approach to obtain free energy gradient using QM/MM MD simulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Asada, Toshio; Koseki, Shiro; The Research Institute for Molecular Electronic Devices

2015-12-31

The efficient computational approach denoted as charge and atom dipole response kernel (CDRK) model to consider polarization effects of the quantum mechanical (QM) region is described using the charge response and the atom dipole response kernels for free energy gradient (FEG) calculations in the quantum mechanical/molecular mechanical (QM/MM) method. CDRK model can reasonably reproduce energies and also energy gradients of QM and MM atoms obtained by expensive QM/MM calculations in a drastically reduced computational time. This model is applied on the acylation reaction in hydrated trypsin-BPTI complex to optimize the reaction path on the free energy surface by means ofmore » FEG and the nudged elastic band (NEB) method.« less

Calculation of wave-functions with frozen orbitals in mixed quantum mechanics/molecular mechanics methods. Part I. Application of the Huzinaga equation.

PubMed

Ferenczy, György G

2013-04-05

Mixed quantum mechanics/quantum mechanics (QM/QM) and quantum mechanics/molecular mechanics (QM/MM) methods make computations feasible for extended chemical systems by separating them into subsystems that are treated at different level of sophistication. In many applications, the subsystems are covalently bound and the use of frozen localized orbitals at the boundary is a possible way to separate the subsystems and to ensure a sensible description of the electronic structure near to the boundary. A complication in these methods is that orthogonality between optimized and frozen orbitals has to be warranted and this is usually achieved by an explicit orthogonalization of the basis set to the frozen orbitals. An alternative to this approach is proposed by calculating the wave-function from the Huzinaga equation that guaranties orthogonality to the frozen orbitals without basis set orthogonalization. The theoretical background and the practical aspects of the application of the Huzinaga equation in mixed methods are discussed. Forces have been derived to perform geometry optimization with wave-functions from the Huzinaga equation. Various properties have been calculated by applying the Huzinaga equation for the central QM subsystem, representing the environment by point charges and using frozen strictly localized orbitals to connect the subsystems. It is shown that a two to three bond separation of the chemical or physical event from the frozen bonds allows a very good reproduction (typically around 1 kcal/mol) of standard Hartree-Fock-Roothaan results. The proposed scheme provides an appropriate framework for mixed QM/QM and QM/MM methods. Copyright © 2012 Wiley Periodicals, Inc.

Cation solvation with quantum chemical effects modeled by a size-consistent multi-partitioning quantum mechanics/molecular mechanics method.

PubMed

Watanabe, Hiroshi C; Kubillus, Maximilian; Kubař, Tomáš; Stach, Robert; Mizaikoff, Boris; Ishikita, Hiroshi

2017-07-21

In the condensed phase, quantum chemical properties such as many-body effects and intermolecular charge fluctuations are critical determinants of the solvation structure and dynamics. Thus, a quantum mechanical (QM) molecular description is required for both solute and solvent to incorporate these properties. However, it is challenging to conduct molecular dynamics (MD) simulations for condensed systems of sufficient scale when adapting QM potentials. To overcome this problem, we recently developed the size-consistent multi-partitioning (SCMP) quantum mechanics/molecular mechanics (QM/MM) method and realized stable and accurate MD simulations, using the QM potential to a benchmark system. In the present study, as the first application of the SCMP method, we have investigated the structures and dynamics of Na + , K + , and Ca 2+ solutions based on nanosecond-scale sampling, a sampling 100-times longer than that of conventional QM-based samplings. Furthermore, we have evaluated two dynamic properties, the diffusion coefficient and difference spectra, with high statistical certainty. Furthermore the calculation of these properties has not previously been possible within the conventional QM/MM framework. Based on our analysis, we have quantitatively evaluated the quantum chemical solvation effects, which show distinct differences between the cations.

Calculation of wave-functions with frozen orbitals in mixed quantum mechanics/molecular mechanics methods. II. Application of the local basis equation.

PubMed

Ferenczy, György G

2013-04-05

The application of the local basis equation (Ferenczy and Adams, J. Chem. Phys. 2009, 130, 134108) in mixed quantum mechanics/molecular mechanics (QM/MM) and quantum mechanics/quantum mechanics (QM/QM) methods is investigated. This equation is suitable to derive local basis nonorthogonal orbitals that minimize the energy of the system and it exhibits good convergence properties in a self-consistent field solution. These features make the equation appropriate to be used in mixed QM/MM and QM/QM methods to optimize orbitals in the field of frozen localized orbitals connecting the subsystems. Calculations performed for several properties in divers systems show that the method is robust with various choices of the frozen orbitals and frontier atom properties. With appropriate basis set assignment, it gives results equivalent with those of a related approach [G. G. Ferenczy previous paper in this issue] using the Huzinaga equation. Thus, the local basis equation can be used in mixed QM/MM methods with small size quantum subsystems to calculate properties in good agreement with reference Hartree-Fock-Roothaan results. It is shown that bond charges are not necessary when the local basis equation is applied, although they are required for the self-consistent field solution of the Huzinaga equation based method. Conversely, the deformation of the wave-function near to the boundary is observed without bond charges and this has a significant effect on deprotonation energies but a less pronounced effect when the total charge of the system is conserved. The local basis equation can also be used to define a two layer quantum system with nonorthogonal localized orbitals surrounding the central delocalized quantum subsystem. Copyright © 2013 Wiley Periodicals, Inc.

Parametrization of Combined Quantum Mechanical and Molecular Mechanical Methods: Bond-Tuned Link Atoms.

PubMed

Wu, Xin-Ping; Gagliardi, Laura; Truhlar, Donald G

2018-05-30

Combined quantum mechanical and molecular mechanical (QM/MM) methods are the most powerful available methods for high-level treatments of subsystems of very large systems. The treatment of the QM-MM boundary strongly affects the accuracy of QM/MM calculations. For QM/MM calculations having covalent bonds cut by the QM-MM boundary, it has been proposed previously to use a scheme with system-specific tuned fluorine link atoms. Here, we propose a broadly parametrized scheme where the parameters of the tuned F link atoms depend only on the type of bond being cut. In the proposed new scheme, the F link atom is tuned for systems with a certain type of cut bond at the QM-MM boundary instead of for a specific target system, and the resulting link atoms are call bond-tuned link atoms. In principle, the bond-tuned link atoms can be as convenient as the popular H link atoms, and they are especially well adapted for high-throughput and accurate QM/MM calculations. Here, we present the parameters for several kinds of cut bonds along with a set of validation calculations that confirm that the proposed bond-tuned link-atom scheme can be as accurate as the system-specific tuned F link-atom scheme.

Advances in quantum and molecular mechanical (QM/MM) simulations for organic and enzymatic reactions.

PubMed

Acevedo, Orlando; Jorgensen, William L

2010-01-19

Application of combined quantum and molecular mechanical (QM/MM) methods focuses on predicting activation barriers and the structures of stationary points for organic and enzymatic reactions. Characterization of the factors that stabilize transition structures in solution and in enzyme active sites provides a basis for design and optimization of catalysts. Continued technological advances allowed for expansion from prototypical cases to mechanistic studies featuring detailed enzyme and condensed-phase environments with full integration of the QM calculations and configurational sampling. This required improved algorithms featuring fast QM methods, advances in computing changes in free energies including free-energy perturbation (FEP) calculations, and enhanced configurational sampling. In particular, the present Account highlights development of the PDDG/PM3 semi-empirical QM method, computation of multi-dimensional potentials of mean force (PMF), incorporation of on-the-fly QM in Monte Carlo (MC) simulations, and a polynomial quadrature method for efficient modeling of proton-transfer reactions. The utility of this QM/MM/MC/FEP methodology is illustrated for a variety of organic reactions including substitution, decarboxylation, elimination, and pericyclic reactions. A comparison to experimental kinetic results on medium effects has verified the accuracy of the QM/MM approach in the full range of solvents from hydrocarbons to water to ionic liquids. Corresponding results from ab initio and density functional theory (DFT) methods with continuum-based treatments of solvation reveal deficiencies, particularly for protic solvents. Also summarized in this Account are three specific QM/MM applications to biomolecular systems: (1) a recent study that clarified the mechanism for the reaction of 2-pyrone derivatives catalyzed by macrophomate synthase as a tandem Michael-aldol sequence rather than a Diels-Alder reaction, (2) elucidation of the mechanism of action of fatty acid amide hydrolase (FAAH), an unusual Ser-Ser-Lys proteolytic enzyme, and (3) the construction of enzymes for Kemp elimination of 5-nitrobenzisoxazole that highlights the utility of QM/MM in the design of artificial enzymes.

Converging ligand-binding free energies obtained with free-energy perturbations at the quantum mechanical level.

PubMed

Olsson, Martin A; Söderhjelm, Pär; Ryde, Ulf

2016-06-30

In this article, the convergence of quantum mechanical (QM) free-energy simulations based on molecular dynamics simulations at the molecular mechanics (MM) level has been investigated. We have estimated relative free energies for the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavity host, including the host, the ligand, and all water molecules within 4.5 Å of the ligand in the QM calculations (158-224 atoms). We use single-step exponential averaging (ssEA) and the non-Boltzmann Bennett acceptance ratio (NBB) methods to estimate QM/MM free energy with the semi-empirical PM6-DH2X method, both based on interaction energies. We show that ssEA with cumulant expansion gives a better convergence and uses half as many QM calculations as NBB, although the two methods give consistent results. With 720,000 QM calculations per transformation, QM/MM free-energy estimates with a precision of 1 kJ/mol can be obtained for all eight relative energies with ssEA, showing that this approach can be used to calculate converged QM/MM binding free energies for realistic systems and large QM partitions. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.

Converging ligand‐binding free energies obtained with free‐energy perturbations at the quantum mechanical level

PubMed Central

Olsson, Martin A.; Söderhjelm, Pär

2016-01-01

In this article, the convergence of quantum mechanical (QM) free‐energy simulations based on molecular dynamics simulations at the molecular mechanics (MM) level has been investigated. We have estimated relative free energies for the binding of nine cyclic carboxylate ligands to the octa‐acid deep‐cavity host, including the host, the ligand, and all water molecules within 4.5 Å of the ligand in the QM calculations (158–224 atoms). We use single‐step exponential averaging (ssEA) and the non‐Boltzmann Bennett acceptance ratio (NBB) methods to estimate QM/MM free energy with the semi‐empirical PM6‐DH2X method, both based on interaction energies. We show that ssEA with cumulant expansion gives a better convergence and uses half as many QM calculations as NBB, although the two methods give consistent results. With 720,000 QM calculations per transformation, QM/MM free‐energy estimates with a precision of 1 kJ/mol can be obtained for all eight relative energies with ssEA, showing that this approach can be used to calculate converged QM/MM binding free energies for realistic systems and large QM partitions. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. PMID:27117350

Application of a BOSS-Gaussian interface for QM/MM simulations of Henry and methyl transfer reactions.

PubMed

Vilseck, Jonah Z; Kostal, Jakub; Tirado-Rives, Julian; Jorgensen, William L

2015-10-15

Hybrid quantum mechanics and molecular mechanics (QM/MM) computer simulations have become an indispensable tool for studying chemical and biological phenomena for systems too large to treat with QM alone. For several decades, semiempirical QM methods have been used in QM/MM simulations. However, with increased computational resources, the introduction of ab initio and density function methods into on-the-fly QM/MM simulations is being increasingly preferred. This adaptation can be accomplished with a program interface that tethers independent QM and MM software packages. This report introduces such an interface for the BOSS and Gaussian programs, featuring modification of BOSS to request QM energies and partial atomic charges from Gaussian. A customizable C-shell linker script facilitates the interprogram communication. The BOSS-Gaussian interface also provides convenient access to Charge Model 5 (CM5) partial atomic charges for multiple purposes including QM/MM studies of reactions. In this report, the BOSS-Gaussian interface is applied to a nitroaldol (Henry) reaction and two methyl transfer reactions in aqueous solution. Improved agreement with experiment is found by determining free-energy surfaces with MP2/CM5 QM/MM simulations than previously reported investigations using semiempirical methods. © 2015 Wiley Periodicals, Inc.

Theoretical Modeling of Hydrogen Bonding in omolecular Solutions: The Combination of Quantum Mechanics and Molecular Mechanics

NASA Astrophysics Data System (ADS)

Ma, Jing; Jiang, Nan; Li, Hui

Hydrogen bonding interaction takes an important position in solutions. The non-classic nature of hydrogen bonding requires the resource-demanding quantum mechanical (QM) calculations. The molecular mechanics (MM) method, with much lower computational load, is applicable to the large-sized system. The combination of QM and MM is an efficient way in the treatment of solution. Taking advantage of the low-cost energy-based fragmentation QM approach (in which the o-molecule is divided into several subsystems, and QM calculation is carried out on each subsystem that is embedded in the environment of background charges of distant parts), the fragmentation-based QM/MM and polarization models have been implemented for the modeling of o-molecule in aqueous solutions, respectively. Within the framework of the fragmentation-based QM/MM hybrid model, the solute is treated by the fragmentation QM calculation while the numerous solvent molecules are described by MM. In the polarization model, the polarizability is considered by allowing the partial charges and fragment-centered dipole moments to be variables, with values coming from the energy-based fragmentation QM calculations. Applications of these two methods to the solvated long oligomers and cyclic peptides have demonstrated that the hydrogen bonding interaction affects the dynamic change in chain conformations of backbone.

Use of Nonequilibrium Work Methods to Compute Free Energy Differences Between Molecular Mechanical and Quantum Mechanical Representations of Molecular Systems.

PubMed

Hudson, Phillip S; Woodcock, H Lee; Boresch, Stefan

2015-12-03

Carrying out free energy simulations (FES) using quantum mechanical (QM) Hamiltonians remains an attractive, albeit elusive goal. Renewed efforts in this area have focused on using "indirect" thermodynamic cycles to connect "low level" simulation results to "high level" free energies. The main obstacle to computing converged free energy results between molecular mechanical (MM) and QM (ΔA(MM→QM)), as recently demonstrated by us and others, is differences in the so-called "stiff" degrees of freedom (e.g., bond stretching) between the respective energy surfaces. Herein, we demonstrate that this problem can be efficiently circumvented using nonequilibrium work (NEW) techniques, i.e., Jarzynski's and Crooks' equations. Initial applications of computing ΔA(NEW)(MM→QM), for blocked amino acids alanine and serine as well as to generate butane's potentials of mean force via the indirect QM/MM FES method, showed marked improvement over traditional FES approaches.

Multiscale Free Energy Simulations: An Efficient Method for Connecting Classical MD Simulations to QM or QM/MM Free Energies Using Non-Boltzmann Bennett Reweighting Schemes

PubMed Central

2015-01-01

The reliability of free energy simulations (FES) is limited by two factors: (a) the need for correct sampling and (b) the accuracy of the computational method employed. Classical methods (e.g., force fields) are typically used for FES and present a myriad of challenges, with parametrization being a principle one. On the other hand, parameter-free quantum mechanical (QM) methods tend to be too computationally expensive for adequate sampling. One widely used approach is a combination of methods, where the free energy difference between the two end states is computed by, e.g., molecular mechanics (MM), and the end states are corrected by more accurate methods, such as QM or hybrid QM/MM techniques. Here we report two new approaches that significantly improve the aforementioned scheme; with a focus on how to compute corrections between, e.g., the MM and the more accurate QM calculations. First, a molecular dynamics trajectory that properly samples relevant conformational degrees of freedom is generated. Next, potential energies of each trajectory frame are generated with a QM or QM/MM Hamiltonian. Free energy differences are then calculated based on the QM or QM/MM energies using either a non-Boltzmann Bennett approach (QM-NBB) or non-Boltzmann free energy perturbation (NB-FEP). Both approaches are applied to calculate relative and absolute solvation free energies in explicit and implicit solvent environments. Solvation free energy differences (relative and absolute) between ethane and methanol in explicit solvent are used as the initial test case for QM-NBB. Next, implicit solvent methods are employed in conjunction with both QM-NBB and NB-FEP to compute absolute solvation free energies for 21 compounds. These compounds range from small molecules such as ethane and methanol to fairly large, flexible solutes, such as triacetyl glycerol. Several technical aspects were investigated. Ultimately some best practices are suggested for improving methods that seek to connect MM to QM (or QM/MM) levels of theory in FES. PMID:24803863

Multiscale Free Energy Simulations: An Efficient Method for Connecting Classical MD Simulations to QM or QM/MM Free Energies Using Non-Boltzmann Bennett Reweighting Schemes.

PubMed

König, Gerhard; Hudson, Phillip S; Boresch, Stefan; Woodcock, H Lee

2014-04-08

THE RELIABILITY OF FREE ENERGY SIMULATIONS (FES) IS LIMITED BY TWO FACTORS: (a) the need for correct sampling and (b) the accuracy of the computational method employed. Classical methods (e.g., force fields) are typically used for FES and present a myriad of challenges, with parametrization being a principle one. On the other hand, parameter-free quantum mechanical (QM) methods tend to be too computationally expensive for adequate sampling. One widely used approach is a combination of methods, where the free energy difference between the two end states is computed by, e.g., molecular mechanics (MM), and the end states are corrected by more accurate methods, such as QM or hybrid QM/MM techniques. Here we report two new approaches that significantly improve the aforementioned scheme; with a focus on how to compute corrections between, e.g., the MM and the more accurate QM calculations. First, a molecular dynamics trajectory that properly samples relevant conformational degrees of freedom is generated. Next, potential energies of each trajectory frame are generated with a QM or QM/MM Hamiltonian. Free energy differences are then calculated based on the QM or QM/MM energies using either a non-Boltzmann Bennett approach (QM-NBB) or non-Boltzmann free energy perturbation (NB-FEP). Both approaches are applied to calculate relative and absolute solvation free energies in explicit and implicit solvent environments. Solvation free energy differences (relative and absolute) between ethane and methanol in explicit solvent are used as the initial test case for QM-NBB. Next, implicit solvent methods are employed in conjunction with both QM-NBB and NB-FEP to compute absolute solvation free energies for 21 compounds. These compounds range from small molecules such as ethane and methanol to fairly large, flexible solutes, such as triacetyl glycerol. Several technical aspects were investigated. Ultimately some best practices are suggested for improving methods that seek to connect MM to QM (or QM/MM) levels of theory in FES.

Rapid Convergence of Energy and Free Energy Profiles with Quantum Mechanical Size in Quantum Mechanical-Molecular Mechanical Simulations of Proton Transfer in DNA.

PubMed

Das, Susanta; Nam, Kwangho; Major, Dan Thomas

2018-03-13

In recent years, a number of quantum mechanical-molecular mechanical (QM/MM) enzyme studies have investigated the dependence of reaction energetics on the size of the QM region using energy and free energy calculations. In this study, we revisit the question of QM region size dependence in QM/MM simulations within the context of energy and free energy calculations using a proton transfer in a DNA base pair as a test case. In the simulations, the QM region was treated with a dispersion-corrected AM1/d-PhoT Hamiltonian, which was developed to accurately describe phosphoryl and proton transfer reactions, in conjunction with an electrostatic embedding scheme using the particle-mesh Ewald summation method. With this rigorous QM/MM potential, we performed rather extensive QM/MM sampling, and found that the free energy reaction profiles converge rapidly with respect to the QM region size within ca. ±1 kcal/mol. This finding suggests that the strategy of QM/MM simulations with reasonably sized and selected QM regions, which has been employed for over four decades, is a valid approach for modeling complex biomolecular systems. We point to possible causes for the sensitivity of the energy and free energy calculations to the size of the QM region, and potential implications.

Combined quantum and molecular mechanics (QM/MM).

PubMed

Friesner, Richard A

2004-12-01

We describe the current state of the art of mixed quantum mechanics/molecular mechanics (QM/MM) methodology, with a particular focus on modeling of enzymatic reactions. Over the past decade, the effectiveness of these methods has increased dramatically, based on improved quantum chemical methods, advances in the description of the QM/MM interface, and reductions in the cost/performance of computing hardware. Two examples of pharmaceutically relevant applications, cytochrome P450 and class C β-lactamase, are presented.: © 2004 Elsevier Ltd . All rights reserved.

Multiconfiguration Molecular Mechanics Based on Combined Quantum Mechanical and Molecular Mechanical Calculations.

PubMed

Lin, Hai; Zhao, Yan; Tishchenko, Oksana; Truhlar, Donald G

2006-09-01

The multiconfiguration molecular mechanics (MCMM) method is a general algorithm for generating potential energy surfaces for chemical reactions by fitting high-level electronic structure data with the help of molecular mechanical (MM) potentials. It was previously developed as an extension of standard MM to reactive systems by inclusion of multidimensional resonance interactions between MM configurations corresponding to specific valence bonding patterns, with the resonance matrix element obtained from quantum mechanical (QM) electronic structure calculations. In particular, the resonance matrix element is obtained by multidimensional interpolation employing a finite number of geometries at which electronic-structure calculations of the energy, gradient, and Hessian are carried out. In this paper, we present a strategy for combining MCMM with hybrid quantum mechanical molecular mechanical (QM/MM) methods. In the new scheme, electronic-structure information for obtaining the resonance integral is obtained by means of hybrid QM/MM calculations instead of fully QM calculations. As such, the new strategy can be applied to the studies of very large reactive systems. The new MCMM scheme is tested for two hydrogen-transfer reactions. Very encouraging convergence is obtained for rate constants including tunneling, suggesting that the new MCMM method, called QM/MM-MCMM, is a very general, stable, and efficient procedure for generating potential energy surfaces for large reactive systems. The results are found to converge well with respect to the number of Hessians. The results are also compared to calculations in which the resonance integral data are obtained by pure QM, and this illustrates the sensitivity of reaction rate calculations to the treatment of the QM-MM border. For the smaller of the two systems, comparison is also made to direct dynamics calculations in which the potential energies are computed quantum mechanically on the fly.

Toward Determining ATPase Mechanism in ABC Transporters: Development of the Reaction Path–Force Matching QM/MM Method

PubMed Central

Zhou, Y.; Ojeda-May, P.; Nagaraju, M.; Pu, J.

2016-01-01

Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are ubiquitous ATP-dependent membrane proteins involved in translocations of a wide variety of substrates across cellular membranes. To understand the chemomechanical coupling mechanism as well as functional asymmetry in these systems, a quantitative description of how ABC transporters hydrolyze ATP is needed. Complementary to experimental approaches, computer simulations based on combined quantum mechanical and molecular mechanical (QM/MM) potentials have provided new insights into the catalytic mechanism in ABC transporters. Quantitatively reliable determination of the free energy requirement for enzymatic ATP hydrolysis, however, requires substantial statistical sampling on QM/MM potential. A case study shows that brute force sampling of ab initio QM/MM (AI/MM) potential energy surfaces is computationally impractical for enzyme simulations of ABC transporters. On the other hand, existing semiempirical QM/MM (SE/MM) methods, although affordable for free energy sampling, are unreliable for studying ATP hydrolysis. To close this gap, a multiscale QM/MM approach named reaction path–force matching (RP–FM) has been developed. In RP–FM, specific reaction parameters for a selected SE method are optimized against AI reference data along reaction paths by employing the force matching technique. The feasibility of the method is demonstrated for a proton transfer reaction in the gas phase and in solution. The RP–FM method may offer a general tool for simulating complex enzyme systems such as ABC transporters. PMID:27498639

A simple and effective solution to the constrained QM/MM simulations

NASA Astrophysics Data System (ADS)

Takahashi, Hideaki; Kambe, Hiroyuki; Morita, Akihiro

2018-04-01

It is a promising extension of the quantum mechanical/molecular mechanical (QM/MM) approach to incorporate the solvent molecules surrounding the QM solute into the QM region to ensure the adequate description of the electronic polarization of the solute. However, the solvent molecules in the QM region inevitably diffuse into the MM bulk during the QM/MM simulation. In this article, we developed a simple and efficient method, referred to as the "boundary constraint with correction (BCC)," to prevent the diffusion of the solvent water molecules by means of a constraint potential. The point of the BCC method is to compensate the error in a statistical property due to the bias potential by adding a correction term obtained through a set of QM/MM simulations. The BCC method is designed so that the effect of the bias potential completely vanishes when the QM solvent is identical with the MM solvent. Furthermore, the desirable conditions, that is, the continuities of energy and force and the conservations of energy and momentum, are fulfilled in principle. We applied the QM/MM-BCC method to a hydronium ion(H3O+) in aqueous solution to construct the radial distribution function (RDF) of the solvent around the solute. It was demonstrated that the correction term fairly compensated the error and led the RDF in good agreement with the result given by an ab initio molecular dynamics simulation.

A multiscale quantum mechanics/electromagnetics method for device simulations.

PubMed

Yam, ChiYung; Meng, Lingyi; Zhang, Yu; Chen, GuanHua

2015-04-07

Multiscale modeling has become a popular tool for research applying to different areas including materials science, microelectronics, biology, chemistry, etc. In this tutorial review, we describe a newly developed multiscale computational method, incorporating quantum mechanics into electronic device modeling with the electromagnetic environment included through classical electrodynamics. In the quantum mechanics/electromagnetics (QM/EM) method, the regions of the system where active electron scattering processes take place are treated quantum mechanically, while the surroundings are described by Maxwell's equations and a semiclassical drift-diffusion model. The QM model and the EM model are solved, respectively, in different regions of the system in a self-consistent manner. Potential distributions and current densities at the interface between QM and EM regions are employed as the boundary conditions for the quantum mechanical and electromagnetic simulations, respectively. The method is illustrated in the simulation of several realistic systems. In the case of junctionless field-effect transistors, transfer characteristics are obtained and a good agreement between experiments and simulations is achieved. Optical properties of a tandem photovoltaic cell are studied and the simulations demonstrate that multiple QM regions are coupled through the classical EM model. Finally, the study of a carbon nanotube-based molecular device shows the accuracy and efficiency of the QM/EM method.

Atomistic insight into the catalytic mechanism of glycosyltransferases by combined quantum mechanics/molecular mechanics (QM/MM) methods.

PubMed

Tvaroška, Igor

2015-02-11

Glycosyltransferases catalyze the formation of glycosidic bonds by assisting the transfer of a sugar residue from donors to specific acceptor molecules. Although structural and kinetic data have provided insight into mechanistic strategies employed by these enzymes, molecular modeling studies are essential for the understanding of glycosyltransferase catalyzed reactions at the atomistic level. For such modeling, combined quantum mechanics/molecular mechanics (QM/MM) methods have emerged as crucial. These methods allow the modeling of enzymatic reactions by using quantum mechanical methods for the calculation of the electronic structure of the active site models and treating the remaining enzyme environment by faster molecular mechanics methods. Herein, the application of QM/MM methods to glycosyltransferase catalyzed reactions is reviewed, and the insight from modeling of glycosyl transfer into the mechanisms and transition states structures of both inverting and retaining glycosyltransferases are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Improved QM Methods and Their Application in QM/MM Studies of Enzymatic Reactions

NASA Astrophysics Data System (ADS)

Jorgensen, William L.

2007-03-01

Quantum mechanics (QM) and Monte Carlo statistical mechanics (MC) simulations have been used by us since the early 1980s to study reaction mechanisms and the origin of solvent effects on reaction rates. A goal was always to perform the QM and MC/MM calculations simultaneously in order to obtain free-energy surfaces in solution with no geometrical restrictions. This was achieved by 2002 and complete free-energy profiles and surfaces with full sampling of solute and solvent coordinates can now be obtained through one job submission using BOSS [JCC 2005, 26, 1689]. Speed and accuracy demands also led to development of the improved semiempirical QM method, PDDG-PM3 [JCC 1601 (2002); JCTC 817 (2005)]. The combined PDDG-PM3/MC/FEP methodology has provided excellent results for free energies of activation for many reactions in numerous solvents. Recent examples include Cope, Kemp and E1cb eliminations [JACS 8829 (2005), 6141 (2006); JOC 4896 (2006)], as well as enzymatic reactions catalyzed by the putative Diels-Alderase, macrophomate synthase, and fatty-acid amide hydrolase [JACS 3577 (2005); JACS (2006)]. The presentation will focus on the accuracy that is currently achievable in such QM/MM studies and the accuracy of the underlying QM methodology including extensive comparisons of results from PDDG-PM3 and ab initio DFT methods.

Multi-Paradigm Multi-Scale Simulations for Fuel Cell Catalysts and Membranes

DTIC Science & Technology

2006-01-01

transfer studies on model systems. . Applying newly developed density functionals QM ( X3LYP ) for estimating the thermodynamics and kinetic energy...Density functional theory methods We have used many QM methods to probe chemical reaction mechanisms and find that the B3LYP and X3LYP [6] flavors of DFT...carried out QM calculations on the surface reactivity of the Pt and PtRu anode catalysts. This QM uses a new ab initio DFT-GGA method ( X3LYP ) [6

Efficient Strategy for the Calculation of Solvation Free Energies in Water and Chloroform at the Quantum Mechanical/Molecular Mechanical Level.

PubMed

Wang, Meiting; Li, Pengfei; Jia, Xiangyu; Liu, Wei; Shao, Yihan; Hu, Wenxin; Zheng, Jun; Brooks, Bernard R; Mei, Ye

2017-10-23

The partitioning of solute molecules between immiscible solvents with significantly different polarities is of great importance. The polarization between the solute and solvent molecules plays an essential role in determining the solubility of the solute, which makes computational studies utilizing molecular mechanics (MM) rather difficult. In contrast, quantum mechanics (QM) can provide more reliable predictions. In this work, the partition coefficients of the side chain analogs of some amino acids between water and chloroform were computed. The QM solvation free energies were calculated indirectly via a series of MM states using the multistate Bennett acceptance ratio (MBAR) and the MM-to-QM corrections were applied at the two endpoints using thermodynamic perturbation (TP). Previously, it has been shown (Jia et al. J. Chem. Theory Comput. 2016, 12, 499-511) that this method provides the minimal variance in the results without running QM simulations. However, if there is insufficient overlap in phase space between the MM and QM Hamiltonians, this method fails. In this work, we propose, for the first time, a quantity termed the reweighting entropy that serves as a metric for the reliability of the TP calculations. If the reweighting entropy is below a certain threshold (0.65 for the solvation free energy calculations in this work), this MM-to-QM correction should be avoided and two alternative methods can be employed by either introducing a semiempirical state or conducting nonequilibrium simulations. However, the results show that the QM methods are not guaranteed to yield better results than the MM methods. Further improvement of the QM methods are imperative, especially the treatment of the van der Waals and the electrostatic interactions between the QM region and the MM region in the first shell. We also propose a scheme for the calculation of the van der Waals parameters for the solute molecules in nonaqueous solvent, which improves the quality of the computed thermodynamic properties. Furthermore, the force field parameters for the sulfur-containing molecules are also optimized.

Combined quantum mechanics/molecular mechanics (QM/MM) simulations for protein-ligand complexes: free energies of binding of water molecules in influenza neuraminidase.

PubMed

Woods, Christopher J; Shaw, Katherine E; Mulholland, Adrian J

2015-01-22

The applicability of combined quantum mechanics/molecular mechanics (QM/MM) methods for the calculation of absolute binding free energies of conserved water molecules in protein/ligand complexes is demonstrated. Here, we apply QM/MM Monte Carlo simulations to investigate binding of water molecules to influenza neuraminidase. We investigate five different complexes, including those with the drugs oseltamivir and peramivir. We investigate water molecules in two different environments, one more hydrophobic and one hydrophilic. We calculate the free-energy change for perturbation of a QM to MM representation of the bound water molecule. The calculations are performed at the BLYP/aVDZ (QM) and TIP4P (MM) levels of theory, which we have previously demonstrated to be consistent with one another for QM/MM modeling. The results show that the QM to MM perturbation is significant in both environments (greater than 1 kcal mol(-1)) and larger in the more hydrophilic site. Comparison with the same perturbation in bulk water shows that this makes a contribution to binding. The results quantify how electronic polarization differences in different environments affect binding affinity and also demonstrate that extensive, converged QM/MM free-energy simulations, with good levels of QM theory, are now practical for protein/ligand complexes.

Perspective: Quantum mechanical methods in biochemistry and biophysics.

PubMed

Cui, Qiang

2016-10-14

In this perspective article, I discuss several research topics relevant to quantum mechanical (QM) methods in biophysical and biochemical applications. Due to the immense complexity of biological problems, the key is to develop methods that are able to strike the proper balance of computational efficiency and accuracy for the problem of interest. Therefore, in addition to the development of novel ab initio and density functional theory based QM methods for the study of reactive events that involve complex motifs such as transition metal clusters in metalloenzymes, it is equally important to develop inexpensive QM methods and advanced classical or quantal force fields to describe different physicochemical properties of biomolecules and their behaviors in complex environments. Maintaining a solid connection of these more approximate methods with rigorous QM methods is essential to their transferability and robustness. Comparison to diverse experimental observables helps validate computational models and mechanistic hypotheses as well as driving further development of computational methodologies.

Quantum-Mechanics Methodologies in Drug Discovery: Applications of Docking and Scoring in Lead Optimization.

PubMed

Crespo, Alejandro; Rodriguez-Granillo, Agustina; Lim, Victoria T

2017-01-01

The development and application of quantum mechanics (QM) methodologies in computer- aided drug design have flourished in the last 10 years. Despite the natural advantage of QM methods to predict binding affinities with a higher level of theory than those methods based on molecular mechanics (MM), there are only a few examples where diverse sets of protein-ligand targets have been evaluated simultaneously. In this work, we review recent advances in QM docking and scoring for those cases in which a systematic analysis has been performed. In addition, we introduce and validate a simplified QM/MM expression to compute protein-ligand binding energies. Overall, QMbased scoring functions are generally better to predict ligand affinities than those based on classical mechanics. However, the agreement between experimental activities and calculated binding energies is highly dependent on the specific chemical series considered. The advantage of more accurate QM methods is evident in cases where charge transfer and polarization effects are important, for example when metals are involved in the binding process or when dispersion forces play a significant role as in the case of hydrophobic or stacking interactions. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Mixed QM/MM molecular electrostatic potentials.

PubMed

Hernández, B; Luque, F J; Orozco, M

2000-05-01

A new method is presented for the calculation of the Molecular Electrostatic Potential (MEP) in large systems. Based on the mixed Quantum Mechanics/Molecular Mechanics (QM/MM) approach, the method assumes both a quantum and classical description for the molecule, and the calculation of the MEP in the space surrounding the molecule is made using this dual treatment. The MEP at points close to the molecule is computed using a full QM formalism, while a pure classical evaluation of the MEP is used for points located at large distances from the molecule. The algorithm allows the user to select the desired level of accuracy in the MEP, so that the definition of the regions where the MEP is computed at the classical or QM levels is adjusted automatically. The potential use of this QM/MM MEP in molecular modeling studies is discussed.

TINKTEP: A fully self-consistent, mutually polarizable QM/MM approach based on the AMOEBA force field

NASA Astrophysics Data System (ADS)

Dziedzic, Jacek; Mao, Yuezhi; Shao, Yihan; Ponder, Jay; Head-Gordon, Teresa; Head-Gordon, Martin; Skylaris, Chris-Kriton

2016-09-01

We present a novel quantum mechanical/molecular mechanics (QM/MM) approach in which a quantum subsystem is coupled to a classical subsystem described by the AMOEBA polarizable force field. Our approach permits mutual polarization between the QM and MM subsystems, effected through multipolar electrostatics. Self-consistency is achieved for both the QM and MM subsystems through a total energy minimization scheme. We provide an expression for the Hamiltonian of the coupled QM/MM system, which we minimize using gradient methods. The QM subsystem is described by the onetep linear-scaling DFT approach, which makes use of strictly localized orbitals expressed in a set of periodic sinc basis functions equivalent to plane waves. The MM subsystem is described by the multipolar, polarizable force field AMOEBA, as implemented in tinker. Distributed multipole analysis is used to obtain, on the fly, a classical representation of the QM subsystem in terms of atom-centered multipoles. This auxiliary representation is used for all polarization interactions between QM and MM, allowing us to treat them on the same footing as in AMOEBA. We validate our method in tests of solute-solvent interaction energies, for neutral and charged molecules, demonstrating the simultaneous optimization of the quantum and classical degrees of freedom. Encouragingly, we find that the inclusion of explicit polarization in the MM part of QM/MM improves the agreement with fully QM calculations.

Internal force corrections with machine learning for quantum mechanics/molecular mechanics simulations.

PubMed

Wu, Jingheng; Shen, Lin; Yang, Weitao

2017-10-28

Ab initio quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulation is a useful tool to calculate thermodynamic properties such as potential of mean force for chemical reactions but intensely time consuming. In this paper, we developed a new method using the internal force correction for low-level semiempirical QM/MM molecular dynamics samplings with a predefined reaction coordinate. As a correction term, the internal force was predicted with a machine learning scheme, which provides a sophisticated force field, and added to the atomic forces on the reaction coordinate related atoms at each integration step. We applied this method to two reactions in aqueous solution and reproduced potentials of mean force at the ab initio QM/MM level. The saving in computational cost is about 2 orders of magnitude. The present work reveals great potentials for machine learning in QM/MM simulations to study complex chemical processes.

QM/MM free energy simulations: recent progress and challenges

PubMed Central

Lu, Xiya; Fang, Dong; Ito, Shingo; Okamoto, Yuko; Ovchinnikov, Victor

2016-01-01

Due to the higher computational cost relative to pure molecular mechanical (MM) simulations, hybrid quantum mechanical/molecular mechanical (QM/MM) free energy simulations particularly require a careful consideration of balancing computational cost and accuracy. Here we review several recent developments in free energy methods most relevant to QM/MM simulations and discuss several topics motivated by these developments using simple but informative examples that involve processes in water. For chemical reactions, we highlight the value of invoking enhanced sampling technique (e.g., replica-exchange) in umbrella sampling calculations and the value of including collective environmental variables (e.g., hydration level) in metadynamics simulations; we also illustrate the sensitivity of string calculations, especially free energy along the path, to various parameters in the computation. Alchemical free energy simulations with a specific thermodynamic cycle are used to probe the effect of including the first solvation shell into the QM region when computing solvation free energies. For cases where high-level QM/MM potential functions are needed, we analyze two different approaches: the QM/MM-MFEP method of Yang and co-workers and perturbative correction to low-level QM/MM free energy results. For the examples analyzed here, both approaches seem productive although care needs to be exercised when analyzing the perturbative corrections. PMID:27563170

A QM/MM Metadynamics Study of the Direct Decarboxylation Mechanism for Orotidine-5'-monophosphate Decarboxylase using Two Different QM Regions: Acceleration too Small to Explain Rate of Enzyme Catalysis

PubMed Central

Stanton, Courtney; Kuo, I-Feng W.; Mundy, Christopher J.; Laino, Teodoro; Houk, K. N.

2011-01-01

Despite decades of study, the mechanism by which orotidine-5'-monophosphate decarboxylase (ODCase) catalyzes the decarboxylation of orotidine monophosphate remains unresolved. A computational investigation of the direct decarboxylation mechanism has been performed using mixed quantum mechanical/molecular mechanical (QM/MM) dynamics simulations. The study was performed with the program CP2K that integrates classical dynamics and ab initio dynamics based on the Born-Oppenheimer approach. Two different QM regions were explored. The free energy barriers for decarboxylation of orotidine-5'-monophosphate (OMP) in solution and in the enzyme (using the larger QM region) were determined with the metadynamics method to be 40 kcal/mol and 33 kcal/mol, respectively. The calculated change in activation free energy (ΔΔG±) on going from solution to the enzyme is therefore −7 kcal/mol, far less than the experimental change of −23 kcal/mol (for kcat/kuncat Radzicka, A.; Wolfenden, R., Science. 1995, 267, 90–92). These results do not support the direct decarboxylation mechanism that has been proposed for the enzyme. However, in the context of QM/MM calculations, it was found that the size of the QM region has a dramatic effect on the calculated reaction barrier. PMID:17927240

Construction of exchange repulsion in terms of the wave functions at QM/MM boundary region

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takahashi, Hideaki, E-mail: hideaki@m.tohoku.ac.jp; Umino, Satoru; Morita, Akihiro

2015-08-28

We developed a simple method to calculate exchange repulsion between a quantum mechanical (QM) solute and a molecular mechanical (MM) molecule in the QM/MM approach. In our method, the size parameter in the Buckingham type potential for the QM solute is directly determined in terms of the one-electron wave functions of the solute. The point of the method lies in the introduction of the exchange core function (ECF) defined as a Slater function which mimics the behavior of the exterior electron density at the QM/MM boundary region. In the present paper, the ECF was constructed in terms of the Becke-Rousselmore » (BR) exchange hole function. It was demonstrated that the ECF yielded by the BR procedure can faithfully reproduce the radial behavior of the electron density of a QM solute. The size parameter of the solute as well as the exchange repulsion are, then, obtained using the overlap model without any fitting procedure. To examine the efficiency of the method, it was applied to calculation of the exchange repulsions for minimal QM/MM systems, hydrogen-bonded water dimer, and H{sub 3}O{sup +}–H{sub 2}O. We found that our approach is able to reproduce the potential energy curves for these systems showing reasonable agreements with those given by accurate full quantum chemical calculations.« less

Simple and exact approach to the electronic polarization effect on the solvation free energy: formulation for quantum-mechanical/molecular-mechanical system and its applications to aqueous solutions.

PubMed

Takahashi, Hideaki; Omi, Atsushi; Morita, Akihiro; Matubayasi, Nobuyuki

2012-06-07

We present a simple and exact numerical approach to compute the free energy contribution δμ in solvation due to the electron density polarization and fluctuation of a quantum-mechanical solute in the quantum-mechanical/molecular-mechanical (QM/MM) simulation combined with the theory of the energy representation (QM/MM-ER). Since the electron density fluctuation is responsible for the many-body QM-MM interactions, the standard version of the energy representation method cannot be applied directly. Instead of decomposing the QM-MM polarization energy into the pairwise additive and non-additive contributions, we take sum of the polarization energies in the QM-MM interaction and adopt it as a new energy coordinate for the method of energy representation. Then, it is demonstrated that the free energy δμ can be exactly formulated in terms of the energy distribution functions for the solution and reference systems with respect to this energy coordinate. The benchmark tests were performed to examine the numerical efficiency of the method with respect to the changes in the individual properties of the solvent and the solute. Explicitly, we computed the solvation free energy of a QM water molecule in ambient and supercritical water, and also the free-energy change associated with the isomerization reaction of glycine from neutral to zwitterionic structure in aqueous solution. In all the systems examined, it was demonstrated that the computed free energy δμ agrees with the experimental value, irrespective of the choice of the reference electron density of the QM solute. The present method was also applied to a prototype reaction of adenosine 5'-triphosphate hydrolysis where the effect of the electron density fluctuation is substantial due to the excess charge. It was demonstrated that the experimental free energy of the reaction has been accurately reproduced with the present approach.

A new smoothing function to introduce long-range electrostatic effects in QM/MM calculations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fang, Dong; Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706; Duke, Robert E.

2015-07-28

A new method to account for long range electrostatic contributions is proposed and implemented for quantum mechanics/molecular mechanics long range electrostatic correction (QM/MM-LREC) calculations. This method involves the use of the minimum image convention under periodic boundary conditions and a new smoothing function for energies and forces at the cutoff boundary for the Coulomb interactions. Compared to conventional QM/MM calculations without long-range electrostatic corrections, the new method effectively includes effects on the MM environment in the primary image from its replicas in the neighborhood. QM/MM-LREC offers three useful features including the avoidance of calculations in reciprocal space (k-space), with themore » concomitant avoidance of having to reproduce (analytically or approximately) the QM charge density in k-space, and the straightforward availability of analytical Hessians. The new method is tested and compared with results from smooth particle mesh Ewald (PME) for three systems including a box of neat water, a double proton transfer reaction, and the geometry optimization of the critical point structures for the rate limiting step of the DNA dealkylase AlkB. As with other smoothing or shifting functions, relatively large cutoffs are necessary to achieve comparable accuracy with PME. For the double-proton transfer reaction, the use of a 22 Å cutoff shows a close reaction energy profile and geometries of stationary structures with QM/MM-LREC compared to conventional QM/MM with no truncation. Geometry optimization of stationary structures for the hydrogen abstraction step by AlkB shows some differences between QM/MM-LREC and the conventional QM/MM. These differences underscore the necessity of the inclusion of the long-range electrostatic contribution.« less

Efficient approach to include molecular polarizations using charge and atom dipole response kernels to calculate free energy gradients in the QM/MM scheme.

PubMed

Asada, Toshio; Ando, Kanta; Sakurai, Koji; Koseki, Shiro; Nagaoka, Masataka

2015-10-28

An efficient approach to evaluate free energy gradients (FEGs) within the quantum mechanical/molecular mechanical (QM/MM) framework has been proposed to clarify reaction processes on the free energy surface (FES) in molecular assemblies. The method is based on response kernel approximations denoted as the charge and the atom dipole response kernel (CDRK) model that include explicitly induced atom dipoles. The CDRK model was able to reproduce polarization effects for both electrostatic interactions between QM and MM regions and internal energies in the QM region obtained by conventional QM/MM methods. In contrast to charge response kernel (CRK) models, CDRK models could be applied to various kinds of molecules, even linear or planer molecules, without using imaginary interaction sites. Use of the CDRK model enabled us to obtain FEGs on QM atoms in significantly reduced computational time. It was also clearly demonstrated that the time development of QM forces of the solvated propylene carbonate radical cation (PC˙(+)) provided reliable results for 1 ns molecular dynamics (MD) simulation, which were quantitatively in good agreement with expensive QM/MM results. Using FEG and nudged elastic band (NEB) methods, we found two optimized reaction paths on the FES for decomposition reactions to generate CO2 molecules from PC˙(+), whose reaction is known as one of the degradation mechanisms in the lithium-ion battery. Two of these reactions proceed through an identical intermediate structure whose molecular dipole moment is larger than that of the reactant to be stabilized in the solvent, which has a high relative dielectric constant. Thus, in order to prevent decomposition reactions, PC˙(+) should be modified to have a smaller dipole moment along two reaction paths.

Evolution of Quantitative Measures in NMR: Quantum Mechanical qHNMR Advances Chemical Standardization of a Red Clover (Trifolium pratense) Extract

PubMed Central

2017-01-01

Chemical standardization, along with morphological and DNA analysis ensures the authenticity and advances the integrity evaluation of botanical preparations. Achievement of a more comprehensive, metabolomic standardization requires simultaneous quantitation of multiple marker compounds. Employing quantitative 1H NMR (qHNMR), this study determined the total isoflavone content (TIfCo; 34.5–36.5% w/w) via multimarker standardization and assessed the stability of a 10-year-old isoflavone-enriched red clover extract (RCE). Eleven markers (nine isoflavones, two flavonols) were targeted simultaneously, and outcomes were compared with LC-based standardization. Two advanced quantitative measures in qHNMR were applied to derive quantities from complex and/or overlapping resonances: a quantum mechanical (QM) method (QM-qHNMR) that employs 1H iterative full spin analysis, and a non-QM method that uses linear peak fitting algorithms (PF-qHNMR). A 10 min UHPLC-UV method provided auxiliary orthogonal quantitation. This is the first systematic evaluation of QM and non-QM deconvolution as qHNMR quantitation measures. It demonstrates that QM-qHNMR can account successfully for the complexity of 1H NMR spectra of individual analytes and how QM-qHNMR can be built for mixtures such as botanical extracts. The contents of the main bioactive markers were in good agreement with earlier HPLC-UV results, demonstrating the chemical stability of the RCE. QM-qHNMR advances chemical standardization by its inherent QM accuracy and the use of universal calibrants, avoiding the impractical need for identical reference materials. PMID:28067513

Sampling enhancement for the quantum mechanical potential based molecular dynamics simulations: a general algorithm and its extension for free energy calculation on rugged energy surface.

PubMed

Li, Hongzhi; Yang, Wei

2007-03-21

An approach is developed in the replica exchange framework to enhance conformational sampling for the quantum mechanical (QM) potential based molecular dynamics simulations. Importantly, with our enhanced sampling treatment, a decent convergence for electronic structure self-consistent-field calculation is robustly guaranteed, which is made possible in our replica exchange design by avoiding direct structure exchanges between the QM-related replicas and the activated (scaled by low scaling parameters or treated with high "effective temperatures") molecular mechanical (MM) replicas. Although the present approach represents one of the early efforts in the enhanced sampling developments specifically for quantum mechanical potentials, the QM-based simulations treated with the present technique can possess the similar sampling efficiency to the MM based simulations treated with the Hamiltonian replica exchange method (HREM). In the present paper, by combining this sampling method with one of our recent developments (the dual-topology alchemical HREM approach), we also introduce a method for the sampling enhanced QM-based free energy calculations.

Quantum chemical approaches in structure-based virtual screening and lead optimization

NASA Astrophysics Data System (ADS)

Cavasotto, Claudio N.; Adler, Natalia S.; Aucar, Maria G.

2018-05-01

Today computational chemistry is a consolidated tool in drug lead discovery endeavors. Due to methodological developments and to the enormous advance in computer hardware, methods based on quantum mechanics (QM) have gained great attention in the last 10 years, and calculations on biomacromolecules are becoming increasingly explored, aiming to provide better accuracy in the description of protein-ligand interactions and the prediction of binding affinities. In principle, the QM formulation includes all contributions to the energy, accounting for terms usually missing in molecular mechanics force-fields, such as electronic polarization effects, metal coordination, and covalent binding; moreover, QM methods are systematically improvable, and provide a greater degree of transferability. In this mini-review we present recent applications of explicit QM-based methods in small-molecule docking and scoring, and in the calculation of binding free-energy in protein-ligand systems. Although the routine use of QM-based approaches in an industrial drug lead discovery setting remains a formidable challenging task, it is likely they will increasingly become active players within the drug discovery pipeline.

Prediction of molecular crystal structures by a crystallographic QM/MM model with full space-group symmetry.

PubMed

Mörschel, Philipp; Schmidt, Martin U

2015-01-01

A crystallographic quantum-mechanical/molecular-mechanical model (c-QM/MM model) with full space-group symmetry has been developed for molecular crystals. The lattice energy was calculated by quantum-mechanical methods for short-range interactions and force-field methods for long-range interactions. The quantum-mechanical calculations covered the interactions within the molecule and the interactions of a reference molecule with each of the surrounding 12-15 molecules. The interactions with all other molecules were treated by force-field methods. In each optimization step the energies in the QM and MM shells were calculated separately as single-point energies; after adding both energy contributions, the crystal structure (including the lattice parameters) was optimized accordingly. The space-group symmetry was maintained throughout. Crystal structures with more than one molecule per asymmetric unit, e.g. structures with Z' = 2, hydrates and solvates, have been optimized as well. Test calculations with different quantum-mechanical methods on nine small organic molecules revealed that the density functional theory methods with dispersion correction using the B97-D functional with 6-31G* basis set in combination with the DREIDING force field reproduced the experimental crystal structures with good accuracy. Subsequently the c-QM/MM method was applied to nine compounds from the CCDC blind tests resulting in good energy rankings and excellent geometric accuracies.

Protonation States of Homocitrate and Nearby Residues in Nitrogenase Studied by Computational Methods and Quantum Refinement.

PubMed

Cao, Lili; Caldararu, Octav; Ryde, Ulf

2017-09-07

Nitrogenase is the only enzyme that can break the triple bond in N 2 to form two molecules of ammonia. The enzyme has been thoroughly studied with both experimental and computational methods, but there is still no consensus regarding the atomic details of the reaction mechanism. In the most common form, the active site is a MoFe 7 S 9 C(homocitrate) cluster. The homocitrate ligand contains one alcohol and three carboxylate groups. In water solution, the triply deprotonated form dominates, but because the alcohol (and one of the carboxylate groups) coordinate to the Mo ion, this may change in the enzyme. We have performed a series of computational calculations with molecular dynamics (MD), quantum mechanical (QM) cluster, combined QM and molecular mechanics (QM/MM), QM/MM with Poisson-Boltzmann and surface area solvation, QM/MM thermodynamic cycle perturbations, and quantum refinement methods to settle the most probable protonation state of the homocitrate ligand in nitrogenase. The results quite conclusively point out a triply deprotonated form (net charge -3) with a proton shared between the alcohol and one of the carboxylate groups as the most stable at pH 7. Moreover, we have studied eight ionizable protein residues close to the active site with MD simulations and determined the most likely protonation states.

Assignment of absolute stereostructures through quantum mechanics electronic and vibrational circular dichroism calculations.

PubMed

Dai, Peng; Jiang, Nan; Tan, Ren-Xiang

2016-01-01

Elucidation of absolute configuration of chiral molecules including structurally complex natural products remains a challenging problem in organic chemistry. A reliable method for assigning the absolute stereostructure is to combine the experimental circular dichroism (CD) techniques such as electronic and vibrational CD (ECD and VCD), with quantum mechanics (QM) ECD and VCD calculations. The traditional QM methods as well as their continuing developments make them more applicable with accuracy. Taking some chiral natural products with diverse conformations as examples, this review describes the basic concepts and new developments of QM approaches for ECD and VCD calculations in solution and solid states.

On the Difference Between Additive and Subtractive QM/MM Calculations

PubMed Central

Cao, Lili; Ryde, Ulf

2018-01-01

The combined quantum mechanical (QM) and molecular mechanical (MM) approach (QM/MM) is a popular method to study reactions in biochemical macromolecules. Even if the general procedure of using QM for a small, but interesting part of the system and MM for the rest is common to all approaches, the details of the implementations vary extensively, especially the treatment of the interface between the two systems. For example, QM/MM can use either additive or subtractive schemes, of which the former is often said to be preferable, although the two schemes are often mixed up with mechanical and electrostatic embedding. In this article, we clarify the similarities and differences of the two approaches. We show that inherently, the two approaches should be identical and in practice require the same sets of parameters. However, the subtractive scheme provides an opportunity to correct errors introduced by the truncation of the QM system, i.e., the link atoms, but such corrections require additional MM parameters for the QM system. We describe and test three types of link-atom correction, viz. for van der Waals, electrostatic, and bonded interactions. The calculations show that electrostatic and bonded link-atom corrections often give rise to problems in the geometries and energies. The van der Waals link-atom corrections are quite small and give results similar to a pure additive QM/MM scheme. Therefore, both approaches can be recommended. PMID:29666794

On the difference between additive and subtractive QM/MM calculations

NASA Astrophysics Data System (ADS)

Cao, Lili; Ryde, Ulf

2018-04-01

The combined quantum mechanical (QM) and molecular mechanical (MM) approach (QM/MM) is a popular method to study reactions in biochemical macromolecules. Even if the general procedure of using QM for a small, but interesting part of the system and MM for the rest is common to all approaches, the details of the implementations vary extensively, especially the treatment of the interface between the two systems. For example, QM/MM can use either additive or subtractive schemes, of which the former is often said to be preferable, although the two schemes are often mixed up with mechanical and electrostatic embedding. In this article, we clarify the similarities and differences of the two approaches. We show that inherently, the two approaches should be identical and in practice require the same sets of parameters. However, the subtractive scheme provides an opportunity to correct errors introduced by the truncation of the QM system, i.e. the link atoms, but such corrections require additional MM parameters for the QM system. We describe and test three types of link-atom correction, viz. for van der Waals, electrostatic and bonded interactions. The calculations show that electrostatic and bonded link-atom corrections often give rise to problems in the geometries and energies. The van der Waals link-atom corrections are quite small and give results similar to a pure additive QM/MM scheme. Therefore, both approaches can be recommended.

Theoretical analysis of geometry and NMR isotope shift in hydrogen-bonding center of photoactive yellow protein by combination of multicomponent quantum mechanics and ONIOM scheme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kanematsu, Yusuke; Tachikawa, Masanori

2014-11-14

Multicomponent quantum mechanical (MC-QM) calculation has been extended with ONIOM (our own N-layered integrated molecular orbital + molecular mechanics) scheme [ONIOM(MC-QM:MM)] to take account of both the nuclear quantum effect and the surrounding environment effect. The authors have demonstrated the first implementation and application of ONIOM(MC-QM:MM) method for the analysis of the geometry and the isotope shift in hydrogen-bonding center of photoactive yellow protein. ONIOM(MC-QM:MM) calculation for a model with deprotonated Arg52 reproduced the elongation of O–H bond of Glu46 observed by neutron diffraction crystallography. Among the unique isotope shifts in different conditions, the model with protonated Arg52 with solventmore » effect reasonably provided the best agreement with the corresponding experimental values from liquid NMR measurement. Our results implied the availability of ONIOM(MC-QM:MM) to distinguish the local environment around hydrogen bonds in a biomolecule.« less

Determining polarizable force fields with electrostatic potentials from quantum mechanical linear response theory

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Hao; Yang, Weitao, E-mail: weitao.yang@duke.edu; Department of Physics, Duke University, Durham, North Carolina 27708

We developed a new method to calculate the atomic polarizabilities by fitting to the electrostatic potentials (ESPs) obtained from quantum mechanical (QM) calculations within the linear response theory. This parallels the conventional approach of fitting atomic charges based on electrostatic potentials from the electron density. Our ESP fitting is combined with the induced dipole model under the perturbation of uniform external electric fields of all orientations. QM calculations for the linear response to the external electric fields are used as input, fully consistent with the induced dipole model, which itself is a linear response model. The orientation of the uniformmore » external electric fields is integrated in all directions. The integration of orientation and QM linear response calculations together makes the fitting results independent of the orientations and magnitudes of the uniform external electric fields applied. Another advantage of our method is that QM calculation is only needed once, in contrast to the conventional approach, where many QM calculations are needed for many different applied electric fields. The molecular polarizabilities obtained from our method show comparable accuracy with those from fitting directly to the experimental or theoretical molecular polarizabilities. Since ESP is directly fitted, atomic polarizabilities obtained from our method are expected to reproduce the electrostatic interactions better. Our method was used to calculate both transferable atomic polarizabilities for polarizable molecular mechanics’ force fields and nontransferable molecule-specific atomic polarizabilities.« less

Quantum mechanical/molecular mechanical/continuum style solvation model: time-dependent density functional theory.

PubMed

Thellamurege, Nandun M; Cui, Fengchao; Li, Hui

2013-08-28

A combined quantum mechanical/molecular mechanical/continuum (QM/MMpol/C) style method is developed for time-dependent density functional theory (TDDFT, including long-range corrected TDDFT) method, induced dipole polarizable force field, and induced surface charge continuum model. Induced dipoles and induced charges are included in the TDDFT equations to solve for the transition energies, relaxed density, and transition density. Analytic gradient is derived and implemented for geometry optimization and molecular dynamics simulation. QM/MMpol/C style DFT and TDDFT methods are used to study the hydrogen bonding of the photoactive yellow protein chromopore in ground state and excited state.

Variational and perturbative formulations of quantum mechanical/molecular mechanical free energy with mean-field embedding and its analytical gradients.

PubMed

Yamamoto, Takeshi

2008-12-28

Conventional quantum chemical solvation theories are based on the mean-field embedding approximation. That is, the electronic wavefunction is calculated in the presence of the mean field of the environment. In this paper a direct quantum mechanical/molecular mechanical (QM/MM) analog of such a mean-field theory is formulated based on variational and perturbative frameworks. In the variational framework, an appropriate QM/MM free energy functional is defined and is minimized in terms of the trial wavefunction that best approximates the true QM wavefunction in a statistically averaged sense. Analytical free energy gradient is obtained, which takes the form of the gradient of effective QM energy calculated in the averaged MM potential. In the perturbative framework, the above variational procedure is shown to be equivalent to the first-order expansion of the QM energy (in the exact free energy expression) about the self-consistent reference field. This helps understand the relation between the variational procedure and the exact QM/MM free energy as well as existing QM/MM theories. Based on this, several ways are discussed for evaluating non-mean-field effects (i.e., statistical fluctuations of the QM wavefunction) that are neglected in the mean-field calculation. As an illustration, the method is applied to an S(N)2 Menshutkin reaction in water, NH(3)+CH(3)Cl-->NH(3)CH(3) (+)+Cl(-), for which free energy profiles are obtained at the Hartree-Fock, MP2, B3LYP, and BHHLYP levels by integrating the free energy gradient. Non-mean-field effects are evaluated to be <0.5 kcal/mol using a Gaussian fluctuation model for the environment, which suggests that those effects are rather small for the present reaction in water.

Insights into the Lactonase Mechanism of Serum Paraoxonase 1 (PON1): Experimental and Quantum Mechanics/Molecular Mechanics (QM/MM) Studies.

PubMed

Le, Quang Anh Tuan; Kim, Seonghoon; Chang, Rakwoo; Kim, Yong Hwan

2015-07-30

Serum paraoxonase 1 (PON1) is a versatile enzyme for the hydrolysis of various substrates (e.g., lactones, phosphotriesters) and for the formation of a promising chemical platform γ-valerolactone. Elucidation of the PON1-catalyzed lactonase reaction mechanism is very important for understanding the enzyme function and for engineering this enzyme for specific applications. Kinetic study and hybrid quantum mechanics/molecular mechanics (QM/MM) method were used to investigate the PON1-catalyzed lactonase reaction of γ-butyrolactone (GBL) and (R)-γ-valerolactone (GVL). The activation energies obtained from the QM/MM calculations were in good agreement with the experiments. Interestingly, the QM/MM energy barriers at MP2/3-21G(d,p) level for the lactonase of GVL and GBL were respectively 14.3-16.2 and 11.5-13.1 kcal/mol, consistent with the experimental values (15.57 and 14.73 kcal/mol derived from respective kcat values of 36.62 and 147.21 s(-1)). The QM/MM energy barriers at MP2/6-31G(d) and MP2/6-31G(d,p) levels were also in relatively good agreements with the experiments. Importantly, the difference in the QM/MM energy barriers at MP2 level with all investigated basis sets for the lactonase of GVL and GBL were in excellent agreement with the experiments (0.9-3.1 and 0.8 kcal/mol, respectively). A detailed mechanism for the PON1-catalyzed lactonase reaction was also proposed in this study.

First-principles modeling of biological systems and structure-based drug-design.

PubMed

Sgrignani, Jacopo; Magistrato, Alessandra

2013-03-01

Molecular modeling techniques play a relevant role in drug design providing detailed information at atomistic level on the structural, dynamical, mechanistic and electronic properties of biological systems involved in diseases' onset, integrating and supporting commonly used experimental approaches. These information are often not accessible to the experimental techniques taken singularly, but are of crucial importance for drug design. Due to the enormous increase of the computer power in the last decades, quantum mechanical (QM) or first-principles-based methods have become often used to address biological issues of pharmaceutical relevance, providing relevant information for drug design. Due to their complexity and their size, biological systems are often investigated by means of a mixed quantum-classical (QM/MM) approach, which treats at an accurate QM level a limited chemically relevant portion of the system and at the molecular mechanics (MM) level the remaining of the biomolecule and its environment. This method provides a good compromise between computational cost and accuracy, allowing to characterize the properties of the biological system and the (free) energy landscape of the process in study with the accuracy of a QM description. In this review, after a brief introduction of QM and QM/MM methods, we will discuss few representative examples, taken from our work, of the application of these methods in the study of metallo-enzymes of pharmaceutical interest, of metal-containing anticancer drugs targeting the DNA as well as of neurodegenerative diseases. The information obtained from these studies may provide the basis for a rationale structure-based drug design of new and more efficient inhibitors or drugs.

A quantum-mechanics molecular-mechanics scheme for extended systems

NASA Astrophysics Data System (ADS)

Hunt, Diego; Sanchez, Veronica M.; Scherlis, Damián A.

2016-08-01

We introduce and discuss a hybrid quantum-mechanics molecular-mechanics (QM-MM) approach for Car-Parrinello DFT simulations with pseudopotentials and planewaves basis, designed for the treatment of periodic systems. In this implementation the MM atoms are considered as additional QM ions having fractional charges of either sign, which provides conceptual and computational simplicity by exploiting the machinery already existing in planewave codes to deal with electrostatics in periodic boundary conditions. With this strategy, both the QM and MM regions are contained in the same supercell, which determines the periodicity for the whole system. Thus, while this method is not meant to compete with non-periodic QM-MM schemes able to handle extremely large but finite MM regions, it is shown that for periodic systems of a few hundred atoms, our approach provides substantial savings in computational times by treating classically a fraction of the particles. The performance and accuracy of the method is assessed through the study of energetic, structural, and dynamical aspects of the water dimer and of the aqueous bulk phase. Finally, the QM-MM scheme is applied to the computation of the vibrational spectra of water layers adsorbed at the TiO2 anatase (1 0 1) solid-liquid interface. This investigation suggests that the inclusion of a second monolayer of H2O molecules is sufficient to induce on the first adsorbed layer, a vibrational dynamics similar to that taking place in the presence of an aqueous environment. The present QM-MM scheme appears as a very interesting tool to efficiently perform molecular dynamics simulations of complex condensed matter systems, from solutions to nanoconfined fluids to different kind of interfaces.

A quantum-mechanics molecular-mechanics scheme for extended systems.

PubMed

Hunt, Diego; Sanchez, Veronica M; Scherlis, Damián A

2016-08-24

We introduce and discuss a hybrid quantum-mechanics molecular-mechanics (QM-MM) approach for Car-Parrinello DFT simulations with pseudopotentials and planewaves basis, designed for the treatment of periodic systems. In this implementation the MM atoms are considered as additional QM ions having fractional charges of either sign, which provides conceptual and computational simplicity by exploiting the machinery already existing in planewave codes to deal with electrostatics in periodic boundary conditions. With this strategy, both the QM and MM regions are contained in the same supercell, which determines the periodicity for the whole system. Thus, while this method is not meant to compete with non-periodic QM-MM schemes able to handle extremely large but finite MM regions, it is shown that for periodic systems of a few hundred atoms, our approach provides substantial savings in computational times by treating classically a fraction of the particles. The performance and accuracy of the method is assessed through the study of energetic, structural, and dynamical aspects of the water dimer and of the aqueous bulk phase. Finally, the QM-MM scheme is applied to the computation of the vibrational spectra of water layers adsorbed at the TiO2 anatase (1 0 1) solid-liquid interface. This investigation suggests that the inclusion of a second monolayer of H2O molecules is sufficient to induce on the first adsorbed layer, a vibrational dynamics similar to that taking place in the presence of an aqueous environment. The present QM-MM scheme appears as a very interesting tool to efficiently perform molecular dynamics simulations of complex condensed matter systems, from solutions to nanoconfined fluids to different kind of interfaces.

Free Energy Contribution Analysis Using Response Kernel Approximation: Insights into the Acylation Reaction of a Beta-Lactamase.

PubMed

Asada, Toshio; Ando, Kanta; Bandyopadhyay, Pradipta; Koseki, Shiro

2016-09-08

A widely applicable free energy contribution analysis (FECA) method based on the quantum mechanical/molecular mechanical (QM/MM) approximation using response kernel approaches has been proposed to investigate the influences of environmental residues and/or atoms in the QM region on the free energy profile. This method can evaluate atomic contributions to the free energy along the reaction path including polarization effects on the QM region within a dramatically reduced computational time. The rate-limiting step in the deactivation of the β-lactam antibiotic cefalotin (CLS) by β-lactamase was studied using this method. The experimentally observed activation barrier was successfully reproduced by free energy perturbation calculations along the optimized reaction path that involved activation by the carboxylate moiety in CLS. It was found that the free energy profile in the QM region was slightly higher than the isolated energy and that two residues, Lys67 and Lys315, as well as water molecules deeply influenced the QM atoms associated with the bond alternation reaction in the acyl-enzyme intermediate. These facts suggested that the surrounding residues are favorable for the reactant complex and prevent the intermediate from being too stabilized to proceed to the following deacylation reaction. We have demonstrated that the free energy contribution analysis should be a useful method to investigate enzyme catalysis and to facilitate intelligent molecular design.

Multiscale Modeling of Plasmon-Enhanced Power Conversion Efficiency in Nanostructured Solar Cells.

PubMed

Meng, Lingyi; Yam, ChiYung; Zhang, Yu; Wang, Rulin; Chen, GuanHua

2015-11-05

The unique optical properties of nanometallic structures can be exploited to confine light at subwavelength scales. This excellent light trapping is critical to improve light absorption efficiency in nanoscale photovoltaic devices. Here, we apply a multiscale quantum mechanics/electromagnetics (QM/EM) method to model the current-voltage characteristics and optical properties of plasmonic nanowire-based solar cells. The QM/EM method features a combination of first-principles quantum mechanical treatment of the photoactive component and classical description of electromagnetic environment. The coupled optical-electrical QM/EM simulations demonstrate a dramatic enhancement for power conversion efficiency of nanowire solar cells due to the surface plasmon effect of nanometallic structures. The improvement is attributed to the enhanced scattering of light into the photoactive layer. We further investigate the optimal configuration of the nanostructured solar cell. Our QM/EM simulation result demonstrates that a further increase of internal quantum efficiency can be achieved by scattering light into the n-doped region of the device.

Methods for Efficiently and Accurately Computing Quantum Mechanical Free Energies for Enzyme Catalysis.

PubMed

Kearns, F L; Hudson, P S; Boresch, S; Woodcock, H L

2016-01-01

Enzyme activity is inherently linked to free energies of transition states, ligand binding, protonation/deprotonation, etc.; these free energies, and thus enzyme function, can be affected by residue mutations, allosterically induced conformational changes, and much more. Therefore, being able to predict free energies associated with enzymatic processes is critical to understanding and predicting their function. Free energy simulation (FES) has historically been a computational challenge as it requires both the accurate description of inter- and intramolecular interactions and adequate sampling of all relevant conformational degrees of freedom. The hybrid quantum mechanical molecular mechanical (QM/MM) framework is the current tool of choice when accurate computations of macromolecular systems are essential. Unfortunately, robust and efficient approaches that employ the high levels of computational theory needed to accurately describe many reactive processes (ie, ab initio, DFT), while also including explicit solvation effects and accounting for extensive conformational sampling are essentially nonexistent. In this chapter, we will give a brief overview of two recently developed methods that mitigate several major challenges associated with QM/MM FES: the QM non-Boltzmann Bennett's acceptance ratio method and the QM nonequilibrium work method. We will also describe usage of these methods to calculate free energies associated with (1) relative properties and (2) along reaction paths, using simple test cases with relevance to enzymes examples. © 2016 Elsevier Inc. All rights reserved.

A hybrid method for solutes in complex solvents: Density functional theory combined with empirical force fields

NASA Astrophysics Data System (ADS)

Eichinger, M.; Tavan, P.; Hutter, J.; Parrinello, M.

1999-06-01

We present a hybrid method for molecular dynamics simulations of solutes in complex solvents as represented, for example, by substrates within enzymes. The method combines a quantum mechanical (QM) description of the solute with a molecular mechanics (MM) approach for the solvent. The QM fragment of a simulation system is treated by ab initio density functional theory (DFT) based on plane-wave expansions. Long-range Coulomb interactions within the MM fragment and between the QM and the MM fragment are treated by a computationally efficient fast multipole method. For the description of covalent bonds between the two fragments, we introduce the scaled position link atom method (SPLAM), which removes the shortcomings of related procedures. The various aspects of the hybrid method are scrutinized through test calculations on liquid water, the water dimer, ethane and a small molecule related to the retinal Schiff base. In particular, the extent to which vibrational spectra obtained by DFT for the solute can be spoiled by the lower quality force field of the solvent is checked, including cases in which the two fragments are covalently joined. The results demonstrate that our QM/MM hybrid method is especially well suited for the vibrational analysis of molecules in condensed phase.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Umino, Satoru; Takahashi, Hideaki, E-mail: hideaki@m.tohoku.ac.jp; Morita, Akihiro

In a recent work, we developed a method [H. Takahashi et al., J. Chem. Phys. 143, 084104 (2015)] referred to as exchange-core function (ECF) approach, to compute exchange repulsion E{sub ex} between solute and solvent in the framework of the quantum mechanical (QM)/molecular mechanical (MM) method. The ECF, represented with a Slater function, plays an essential role in determining E{sub ex} on the basis of the overlap model. In the work of Takahashi et al. [J. Chem. Phys. 143, 084104 (2015)], it was demonstrated that our approach is successful in computing the hydrogen bond energies of minimal QM/MM systems includingmore » a cationic QM solute. We provide in this paper the extension of the ECF approach to the free energy calculation in condensed phase QM/MM systems by combining the ECF and the QM/MM-ER approach [H. Takahashi et al., J. Chem. Phys. 121, 3989 (2004)]. By virtue of the theory of solutions in energy representation, the free energy contribution δμ{sub ex} from the exchange repulsion was naturally formulated. We found that the ECF approach in combination with QM/MM-ER gives a substantial improvement on the calculation of the hydration free energy of a hydronium ion. This can be attributed to the fact that the ECF reasonably realizes the contraction of the electron density of the cation due to the deficit of an electron.« less

Quantum mechanics implementation in drug-design workflows: does it really help?

PubMed

Arodola, Olayide A; Soliman, Mahmoud Es

2017-01-01

The pharmaceutical industry is progressively operating in an era where development costs are constantly under pressure, higher percentages of drugs are demanded, and the drug-discovery process is a trial-and-error run. The profit that flows in with the discovery of new drugs has always been the motivation for the industry to keep up the pace and keep abreast with the endless demand for medicines. The process of finding a molecule that binds to the target protein using in silico tools has made computational chemistry a valuable tool in drug discovery in both academic research and pharmaceutical industry. However, the complexity of many protein-ligand interactions challenges the accuracy and efficiency of the commonly used empirical methods. The usefulness of quantum mechanics (QM) in drug-protein interaction cannot be overemphasized; however, this approach has little significance in some empirical methods. In this review, we discuss recent developments in, and application of, QM to medically relevant biomolecules. We critically discuss the different types of QM-based methods and their proposed application to incorporating them into drug-design and -discovery workflows while trying to answer a critical question: are QM-based methods of real help in drug-design and -discovery research and industry?

Grid-Based Projector Augmented Wave (GPAW) Implementation of Quantum Mechanics/Molecular Mechanics (QM/MM) Electrostatic Embedding and Application to a Solvated Diplatinum Complex.

PubMed

Dohn, A O; Jónsson, E Ö; Levi, G; Mortensen, J J; Lopez-Acevedo, O; Thygesen, K S; Jacobsen, K W; Ulstrup, J; Henriksen, N E; Møller, K B; Jónsson, H

2017-12-12

A multiscale density functional theory-quantum mechanics/molecular mechanics (DFT-QM/MM) scheme is presented, based on an efficient electrostatic coupling between the electronic density obtained from a grid-based projector augmented wave (GPAW) implementation of density functional theory and a classical potential energy function. The scheme is implemented in a general fashion and can be used with various choices for the descriptions of the QM or MM regions. Tests on H 2 O clusters, ranging from dimer to decamer show that no systematic energy errors are introduced by the coupling that exceeds the differences in the QM and MM descriptions. Over 1 ns of liquid water, Born-Oppenheimer QM/MM molecular dynamics (MD) are sampled combining 10 parallel simulations, showing consistent liquid water structure over the QM/MM border. The method is applied in extensive parallel MD simulations of an aqueous solution of the diplatinum [Pt 2 (P 2 O 5 H 2 ) 4 ] 4- complex (PtPOP), spanning a total time period of roughly half a nanosecond. An average Pt-Pt distance deviating only 0.01 Å from experimental results, and a ground-state Pt-Pt oscillation frequency deviating by <2% from experimental results were obtained. The simulations highlight a remarkable harmonicity of the Pt-Pt oscillation, while also showing clear signs of Pt-H hydrogen bonding and directional coordination of water molecules along the Pt-Pt axis of the complex.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sudiarta, I. Wayan; Angraini, Lily Maysari, E-mail: lilyangraini@unram.ac.id

We have applied the finite difference time domain (FDTD) method with the supersymmetric quantum mechanics (SUSY-QM) procedure to determine excited energies of one dimensional quantum systems. The theoretical basis of FDTD, SUSY-QM, a numerical algorithm and an illustrative example for a particle in a one dimensional square-well potential were given in this paper. It was shown that the numerical results were in excellent agreement with theoretical results. Numerical errors produced by the SUSY-QM procedure was due to errors in estimations of superpotentials and supersymmetric partner potentials.

Convergence of QM/MM and Cluster Models for the Spectroscopic Properties of the Oxygen-Evolving Complex in Photosystem II.

PubMed

Retegan, Marius; Neese, Frank; Pantazis, Dimitrios A

2013-08-13

The latest crystal structure of photosystem II at 1.9 Å resolution, which resolves the topology of the Mn4CaO5 oxygen evolving complex (OEC) at atomistic detail, enables a better correlation between structural features and spectroscopic properties than ever before. Building on the refined crystallographic model of the OEC and the protein, we present combined quantum mechanical/molecular mechanical (QM/MM) studies of the spectroscopic properties of the natural catalyst embedded in the protein matrix. Focusing on the S2 state of the catalytic cycle, we examine the convergence of not only structural parameters but also of the intracluster magnetic interactions in terms of exchange coupling constants and of experimentally relevant (55)Mn, (17)O, and (14)N hyperfine coupling constants with respect to QM/MM partitioning using five QM regions of increasing size. This enables us to assess the performance of the method and to probe second sphere effects by identifying amino acid residues that principally affect the spectroscopic properties of the OEC. Comparison between QM-only and QM/MM treatments reveals that whereas QM/MM models converge quickly to stable values, the QM cluster models need to incorporate significantly larger parts of the second coordination sphere and surrounding water molecules to achieve convergence for certain properties. This is mainly due to the sensitivity of the QM-only models to fluctuations in the hydrogen bonding network and ligand acidity. Additionally, a hydrogen bond that is typically omitted in QM-only treatments is shown to determine the hyperfine coupling tensor of the unique Mn(III) ion by regulating the rotation plane of the ligated D1-His332 imidazole ring, the only N-donor ligand of the OEC.

Structures in solutions from joint experimental-computational analysis: applications to cyclic molecules and studies of noncovalent interactions.

PubMed

Aliev, Abil E; Mia, Zakirin A; Khaneja, Harmeet S; King, Frank D

2012-01-26

The potential of an approach combining nuclear magnetic resonance (NMR) spectroscopy, molecular dynamics (MD) simulations, and quantum mechanical (QM) calculations for full structural characterizations in solution is assessed using cyclic organic compounds, namely, benzazocinone derivatives 1-3 with fused five- and eight-membered aliphatic rings, camphoric anhydride 4, and bullvalene 5. Various MD simulations were considered, using force field and semiempirical QM treatments, implicit and explicit solvation, and high-temperature MD calculations for selecting plausible molecular geometries for subsequent QM geometry optimizations using mainly B3LYP, M062X, and MP2 methods. The QM-predicted values of NMR parameters were compared to their experimental values for verification of the final structures derived from the MD/QM analysis. From these comparisons, initial estimates of quality thresholds (calculated as rms deviations) were 0.7-0.9 Hz for (3)J(HH) couplings, 0.07-0.11 Å for interproton distances, 0.05-0.08 ppm for (1)H chemical shifts, and 1.0-2.1 ppm for (13)C chemical shifts. The obtained results suggest that the accuracy of the MD analysis in predicting geometries and relative conformational energies is not critical and that the final geometry refinements of the structures selected from the MD simulations using QM methods are sufficient for correcting for the expected inaccuracy of the MD analysis. A unique example of C(sp(3))-H···N(sp(3)) intramolecular noncovalent interaction is also identified using the NMR/MD/QM and the natural bond orbital analyses. As the NMR/MD/QM approach relies on the final QM geometry optimization, comparisons of geometric characteristics predicted by different QM methods and those from X-ray and neutron diffraction measurements were undertaken using rigid and flexible cyclic systems. The joint analysis shows that intermolecular noncovalent interactions present in the solid state alter molecular geometries significantly compared to the geometries of isolated molecules from QM calculations.

High-level QM/MM calculations support the concerted mechanism for Michael addition and covalent complex formation in thymidylate synthase.

PubMed

Kaiyawet, Nopporn; Lonsdale, Richard; Rungrotmongkol, Thanyada; Mulholland, Adrian J; Hannongbua, Supot

2015-02-10

Thymidylate synthase (TS) is a promising cancer target, due to its crucial function in thymine synthesis. It performs the reductive methylation of 2'-deoxyuridine-5'-phosphate (dUMP) to thymidine-5'-phosphate (dTMP), using N-5,10-methylene-5,6,7,8-tetrahydrofolate (mTHF) as a cofactor. After the formation of the dUMP/mTHF/TS noncovalent complex, and subsequent conformational activation, this complex has been proposed to react via nucleophilic attack (Michael addition) by Cys146, followed by methylene-bridge formation to generate the ternary covalent intermediate. Herein, QM/MM (B3LYP-D/6-31+G(d)-CHARMM27) methods are used to model the formation of the ternary covalent intermediate. A two-dimensional potential energy surface reveals that the methylene-bridged intermediate is formed via a concerted mechanism, as indicated by a single transition state on the minimum energy pathway and the absence of a stable enolate intermediate. A range of different QM methods (B3LYP, MP2 and SCS-MP2, and different basis sets) are tested for the calculation of the activation energy barrier for the formation of the methylene-bridged intermediate. We test convergence of the QM/MM results with respect to size of the QM region. Inclusion of Arg166, which interacts with the nucleophilic thiolate, in the QM region is important for reliable results; the MM model apparently does not reproduce energies for distortion of the guanidinium side chain correctly. The spin component scaled-Møller-Plessett perturbation theory (SCS-MP2) approach was shown to be in best agreement (within 1.1 kcal/mol) while the results obtained with MP2 and B3LYP also yielded acceptable values (deviating by less than 3 kcal/mol) compared with the barrier derived from experiment. Our results indicate that using a dispersion-corrected DFT method, or a QM method with an accurate treatment of electron correlation, increases the agreement between the calculated and experimental activation energy barriers, compared with the semiempirical AM1 method. These calculations provide important insight into the reaction mechanism of TS and may be useful in the design of new TS inhibitors.

Collaborative Simulation Grid: Multiscale Quantum-Mechanical/Classical Atomistic Simulations on Distributed PC Clusters in the US and Japan

NASA Technical Reports Server (NTRS)

Kikuchi, Hideaki; Kalia, Rajiv; Nakano, Aiichiro; Vashishta, Priya; Iyetomi, Hiroshi; Ogata, Shuji; Kouno, Takahisa; Shimojo, Fuyuki; Tsuruta, Kanji; Saini, Subhash;

Free-energy analysis of the electron-density fluctuation in the quantum-mechanical/molecular-mechanical simulation combined with the theory of energy representation.

PubMed

Matubayasi, Nobuyuki; Takahashi, Hideaki

2012-01-28

The relationship is investigated for QM/MM (quantum-mechanical/molecular-mechanical) systems between the fluctuations of the electronic state of the QM subsystem and of the solvation effect due to the QM-MM interaction. The free-energy change due to the electron-density fluctuation around its average is highlighted, and is evaluated through an approximate functional formulated in terms of distribution functions of the many-body coupling (pairwise non-additive) part of the QM-MM interaction energy. A set of QM/MM simulations are conducted in MM water solvent for QM water solute in ambient and supercritical conditions and for QM glycine solute in the neutral and zwitterionic forms. The variation of the electronic distortion energy of the QM solute in the course of QM/MM simulation is then shown to be compensated by the corresponding variation of the free energy of solvation. The solvation free energy conditioned by the electronic distortion energy is further analyzed with its components. It is found that the many-body contribution is essentially equal between the free energy and the average sum of solute-solvent interaction energy. © 2012 American Institute of Physics

Protonation states of intermediates in the reaction mechanism of [NiFe] hydrogenase studied by computational methods.

PubMed

Dong, Geng; Ryde, Ulf

2016-06-01

The [NiFe] hydrogenases catalyse the reversible conversion of H2 to protons and electrons. The active site consists of a Fe ion with one carbon monoxide, two cyanide, and two cysteine (Cys) ligands. The latter two bridge to a Ni ion, which has two additional terminal Cys ligands. It has been suggested that one of the Cys residues is protonated during the reaction mechanism. We have used combined quantum mechanical and molecular mechanics (QM/MM) geometry optimisations, large QM calculations with 817 atoms, and QM/MM free energy simulations, using the TPSS and B3LYP methods with basis sets extrapolated to the quadruple zeta level to determine which of the four Cys residues is more favourable to protonate for four putative states in the reaction mechanism, Ni-SIa, Ni-R, Ni-C, and Ni-L. The calculations show that for all states, the terminal Cys-546 residue is most easily protonated by 14-51 kJ/mol, owing to a more favourable hydrogen-bond pattern around this residue in the protein.

Synergies Between Quantum Mechanics and Machine Learning in Reaction Prediction.

PubMed

Sadowski, Peter; Fooshee, David; Subrahmanya, Niranjan; Baldi, Pierre

2016-11-28

Machine learning (ML) and quantum mechanical (QM) methods can be used in two-way synergy to build chemical reaction expert systems. The proposed ML approach identifies electron sources and sinks among reactants and then ranks all source-sink pairs. This addresses a bottleneck of QM calculations by providing a prioritized list of mechanistic reaction steps. QM modeling can then be used to compute the transition states and activation energies of the top-ranked reactions, providing additional or improved examples of ranked source-sink pairs. Retraining the ML model closes the loop, producing more accurate predictions from a larger training set. The approach is demonstrated in detail using a small set of organic radical reactions.

Quantum mechanical/molecular mechanical/continuum style solvation model: second order Møller-Plesset perturbation theory.

PubMed

Thellamurege, Nandun M; Si, Dejun; Cui, Fengchao; Li, Hui

2014-05-07

A combined quantum mechanical/molecular mechanical/continuum (QM/MM/C) style second order Møller-Plesset perturbation theory (MP2) method that incorporates induced dipole polarizable force field and induced surface charge continuum solvation model is established. The Z-vector method is modified to include induced dipoles and induced surface charges to determine the MP2 response density matrix, which can be used to evaluate MP2 properties. In particular, analytic nuclear gradient is derived and implemented for this method. Using the Assisted Model Building with Energy Refinement induced dipole polarizable protein force field, the QM/MM/C style MP2 method is used to study the hydrogen bonding distances and strengths of the photoactive yellow protein chromopore in the wild type and the Glu46Gln mutant.

A QM/MM Metadynamics Study of the Direct Decarboxylation Mechanism for Orotidine-5'-monophosphate Decarboxylase using Two Different QM Regions: Acceleration too Small to Explain Rate of Enzyme Catalysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stanton, Courtney; Kuo, I-F W.; Mundy, Christopher J.

2007-11-01

Despite decades of study, the mechanism of orotidine-5'-monophosphate decarboxylase (ODCase) remains unresolved. A computational investigation of the direct decarboxylation mechanism has been performed using mixed quantum mechanical/molecular mechanical (QM/MM) dynamics simulations. The study was performed with the program CP2K that integrates classical dynamics and ab initio dynamics based on the Born-Oppenheimer approach. Two different QM regions were explored. It was found that the size of the QM region has a dramatic effect on the calculated reaction barrier. The free energy barriers for decarboxylation of orotidine-5'-monophosphate (OMP) in solution and in the enzyme were determined with the metadynamics method to bemore » 40 kcal/mol and 33 kcal/mol, respectively. The calculated change in activation free energy (ΔΔG±) on going from solution to the enzyme is therefore -7 kcal/mol, far less than the experimental change of -23 kcal/mol (for kcat/kuncat Radzicka, A.; Wolfenden, R., Science. 1995, 267, 90-92). These results do not support the direct decarboxylation mechanism in the enzyme. Funding was provided by the University of California Lawrence Livermore National Laboratory (LLNL) and the National Institutes of Health (NIH). Part of this work was performed under the auspices of the U.S. Department of Energy by LLNL under contract No. W-7405-Eng-48. Computer resources were provided by Livermore Computing.« less

Toward Hamiltonian Adaptive QM/MM: Accurate Solvent Structures Using Many-Body Potentials.

PubMed

Boereboom, Jelle M; Potestio, Raffaello; Donadio, Davide; Bulo, Rosa E

2016-08-09

Adaptive quantum mechanical (QM)/molecular mechanical (MM) methods enable efficient molecular simulations of chemistry in solution. Reactive subregions are modeled with an accurate QM potential energy expression while the rest of the system is described in a more approximate manner (MM). As solvent molecules diffuse in and out of the reactive region, they are gradually included into (and excluded from) the QM expression. It would be desirable to model such a system with a single adaptive Hamiltonian, but thus far this has resulted in distorted structures at the boundary between the two regions. Solving this long outstanding problem will allow microcanonical adaptive QM/MM simulations that can be used to obtain vibrational spectra and dynamical properties. The difficulty lies in the complex QM potential energy expression, with a many-body expansion that contains higher order terms. Here, we outline a Hamiltonian adaptive multiscale scheme within the framework of many-body potentials. The adaptive expressions are entirely general, and complementary to all standard (nonadaptive) QM/MM embedding schemes available. We demonstrate the merit of our approach on a molecular system defined by two different MM potentials (MM/MM'). For the long-range interactions a numerical scheme is used (particle mesh Ewald), which yields energy expressions that are many-body in nature. Our Hamiltonian approach is the first to provide both energy conservation and the correct solvent structure everywhere in this system.

Hybrid Quantum Mechanics/Molecular Mechanics/Coarse Grained Modeling: A Triple-Resolution Approach for Biomolecular Systems.

PubMed

Sokkar, Pandian; Boulanger, Eliot; Thiel, Walter; Sanchez-Garcia, Elsa

2015-04-14

We present a hybrid quantum mechanics/molecular mechanics/coarse-grained (QM/MM/CG) multiresolution approach for solvated biomolecular systems. The chemically important active-site region is treated at the QM level. The biomolecular environment is described by an atomistic MM force field, and the solvent is modeled with the CG Martini force field using standard or polarizable (pol-CG) water. Interactions within the QM, MM, and CG regions, and between the QM and MM regions, are treated in the usual manner, whereas the CG-MM and CG-QM interactions are evaluated using the virtual sites approach. The accuracy and efficiency of our implementation is tested for two enzymes, chorismate mutase (CM) and p-hydroxybenzoate hydroxylase (PHBH). In CM, the QM/MM/CG potential energy scans along the reaction coordinate yield reaction energies that are too large, both for the standard and polarizable Martini CG water models, which can be attributed to adverse effects of using large CG water beads. The inclusion of an atomistic MM water layer (10 Å for uncharged CG water and 5 Å for polarizable CG water) around the QM region improves the energy profiles compared to the reference QM/MM calculations. In analogous QM/MM/CG calculations on PHBH, the use of the pol-CG description for the outer water does not affect the stabilization of the highly charged FADHOOH-pOHB transition state compared to the fully atomistic QM/MM calculations. Detailed performance analysis in a glycine-water model system indicates that computation times for QM energy and gradient evaluations at the density functional level are typically reduced by 40-70% for QM/MM/CG relative to fully atomistic QM/MM calculations.

Accuracy of buffered-force QM/MM simulations of silica

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peguiron, Anke; Moras, Gianpietro; Colombi Ciacchi, Lucio

2015-02-14

We report comparisons between energy-based quantum mechanics/molecular mechanics (QM/MM) and buffered force-based QM/MM simulations in silica. Local quantities—such as density of states, charges, forces, and geometries—calculated with both QM/MM approaches are compared to the results of full QM simulations. We find the length scale over which forces computed using a finite QM region converge to reference values obtained in full quantum-mechanical calculations is ∼10 Å rather than the ∼5 Å previously reported for covalent materials such as silicon. Electrostatic embedding of the QM region in the surrounding classical point charges gives only a minor contribution to the force convergence. Whilemore » the energy-based approach provides accurate results in geometry optimizations of point defects, we find that the removal of large force errors at the QM/MM boundary provided by the buffered force-based scheme is necessary for accurate constrained geometry optimizations where Si–O bonds are elongated and for finite-temperature molecular dynamics simulations of crack propagation. Moreover, the buffered approach allows for more flexibility, since special-purpose QM/MM coupling terms that link QM and MM atoms are not required and the region that is treated at the QM level can be adaptively redefined during the course of a dynamical simulation.« less

QM/MM hybrid calculation of biological macromolecules using a new interface program connecting QM and MM engines

NASA Astrophysics Data System (ADS)

Hagiwara, Yohsuke; Ohta, Takehiro; Tateno, Masaru

2009-02-01

An interface program connecting a quantum mechanics (QM) calculation engine, GAMESS, and a molecular mechanics (MM) calculation engine, AMBER, has been developed for QM/MM hybrid calculations. A protein-DNA complex is used as a test system to investigate the following two types of QM/MM schemes. In a 'subtractive' scheme, electrostatic interactions between QM/MM regions are truncated in QM calculations; in an 'additive' scheme, long-range electrostatic interactions within a cut-off distance from QM regions are introduced into one-electron integration terms of a QM Hamiltonian. In these calculations, 338 atoms are assigned as QM atoms using Hartree-Fock (HF)/density functional theory (DFT) hybrid all-electron calculations. By comparing the results of the additive and subtractive schemes, it is found that electronic structures are perturbed significantly by the introduction of MM partial charges surrounding QM regions, suggesting that biological processes occurring in functional sites are modulated by the surrounding structures. This also indicates that the effects of long-range electrostatic interactions involved in the QM Hamiltonian are crucial for accurate descriptions of electronic structures of biological macromolecules.

The Quality of the Embedding Potential Is Decisive for Minimal Quantum Region Size in Embedding Calculations: The Case of the Green Fluorescent Protein.

PubMed

Nåbo, Lina J; Olsen, Jógvan Magnus Haugaard; Martínez, Todd J; Kongsted, Jacob

2017-12-12

The calculation of spectral properties for photoactive proteins is challenging because of the large cost of electronic structure calculations on large systems. Mixed quantum mechanical (QM) and molecular mechanical (MM) methods are typically employed to make such calculations computationally tractable. This study addresses the connection between the minimal QM region size and the method used to model the MM region in the calculation of absorption properties-here exemplified for calculations on the green fluorescent protein. We find that polarizable embedding is necessary for a qualitatively correct description of the MM region, and that this enables the use of much smaller QM regions compared to fixed charge electrostatic embedding. Furthermore, absorption intensities converge very slowly with system size and inclusion of effective external field effects in the MM region through polarizabilities is therefore very important. Thus, this embedding scheme enables accurate prediction of intensities for systems that are too large to be treated fully quantum mechanically.

Computation of the free energy due to electron density fluctuation of a solute in solution: A QM/MM method with perturbation approach combined with a theory of solutions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suzuoka, Daiki; Takahashi, Hideaki, E-mail: hideaki@m.tohoku.ac.jp; Morita, Akihiro

2014-04-07

We developed a perturbation approach to compute solvation free energy Δμ within the framework of QM (quantum mechanical)/MM (molecular mechanical) method combined with a theory of energy representation (QM/MM-ER). The energy shift η of the whole system due to the electronic polarization of the solute is evaluated using the second-order perturbation theory (PT2), where the electric field formed by surrounding solvent molecules is treated as the perturbation to the electronic Hamiltonian of the isolated solute. The point of our approach is that the energy shift η, thus obtained, is to be adopted for a novel energy coordinate of the distributionmore » functions which serve as fundamental variables in the free energy functional developed in our previous work. The most time-consuming part in the QM/MM-ER simulation can be, thus, avoided without serious loss of accuracy. For our benchmark set of molecules, it is demonstrated that the PT2 approach coupled with QM/MM-ER gives hydration free energies in excellent agreements with those given by the conventional method utilizing the Kohn-Sham SCF procedure except for a few molecules in the benchmark set. A variant of the approach is also proposed to deal with such difficulties associated with the problematic systems. The present approach is also advantageous to parallel implementations. We examined the parallel efficiency of our PT2 code on multi-core processors and found that the speedup increases almost linearly with respect to the number of cores. Thus, it was demonstrated that QM/MM-ER coupled with PT2 deserves practical applications to systems of interest.« less

Predicting hydration free energies with a hybrid QM/MM approach

PubMed Central

König, Gerhard; Pickard, Frank C.; Mei, Ye; Brooks, Bernard R.

2014-01-01

The correct representation of solute-water interactions is essential for the accurate simulation of most biological phenomena. Several highly accurate quantum methods are available to deal with solvation by using both implicit and explicit solvents. So far, however, most evaluations of those methods were based on a single conformation, which neglects solute entropy. Here, we present the first test of a novel approach to determine hydration free energies that uses molecular mechanics (MM) to sample phase space and quantum mechanics (QM) to evaluate the potential energies. Free energies are determined by using re-weighting with the Non-Boltzmann Bennett (NBB) method. In this context, the method is referred to as QM-NBB. Based on snapshots from MM sampling and accounting for their correct Boltzmann weight, it is possible to obtain hydration free energies that incorporate the effect of solute entropy. We evaluate the performance of several QM implicit solvent models, as well as explicit solvent QM/MM for the blind subset of the SAMPL4 hydration free energy challenge. While classical free energy simulations with molecular dynamics give root mean square deviations (RMSD) of 2.8 and 2.3 kcal/mol, the hybrid approach yields an improved RMSD of 1.6 kcal/mol. By selecting an appropriate functional and basis set, the RMSD can be reduced to 1 kcal/mol for calculations based on a single conformation. Results for a selected set of challenging molecules imply that this RMSD can be further reduced by using NBB to reweight MM trajectories with the SMD implicit solvent model. PMID:24504703

Predicting hydration free energies with a hybrid QM/MM approach: an evaluation of implicit and explicit solvation models in SAMPL4

NASA Astrophysics Data System (ADS)

König, Gerhard; Pickard, Frank C.; Mei, Ye; Brooks, Bernard R.

2014-03-01

The correct representation of solute-water interactions is essential for the accurate simulation of most biological phenomena. Several highly accurate quantum methods are available to deal with solvation by using both implicit and explicit solvents. So far, however, most evaluations of those methods were based on a single conformation, which neglects solute entropy. Here, we present the first test of a novel approach to determine hydration free energies that uses molecular mechanics (MM) to sample phase space and quantum mechanics (QM) to evaluate the potential energies. Free energies are determined by using re-weighting with the Non-Boltzmann Bennett (NBB) method. In this context, the method is referred to as QM-NBB. Based on snapshots from MM sampling and accounting for their correct Boltzmann weight, it is possible to obtain hydration free energies that incorporate the effect of solute entropy. We evaluate the performance of several QM implicit solvent models, as well as explicit solvent QM/MM for the blind subset of the SAMPL4 hydration free energy challenge. While classical free energy simulations with molecular dynamics give root mean square deviations (RMSD) of 2.8 and 2.3 kcal/mol, the hybrid approach yields an improved RMSD of 1.6 kcal/mol. By selecting an appropriate functional and basis set, the RMSD can be reduced to 1 kcal/mol for calculations based on a single conformation. Results for a selected set of challenging molecules imply that this RMSD can be further reduced by using NBB to reweight MM trajectories with the SMD implicit solvent model.

Quantum mechanical/molecular mechanical/continuum style solvation model: Second order Møller-Plesset perturbation theory

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thellamurege, Nandun M.; Si, Dejun; Cui, Fengchao

A combined quantum mechanical/molecular mechanical/continuum (QM/MM/C) style second order Møller-Plesset perturbation theory (MP2) method that incorporates induced dipole polarizable force field and induced surface charge continuum solvation model is established. The Z-vector method is modified to include induced dipoles and induced surface charges to determine the MP2 response density matrix, which can be used to evaluate MP2 properties. In particular, analytic nuclear gradient is derived and implemented for this method. Using the Assisted Model Building with Energy Refinement induced dipole polarizable protein force field, the QM/MM/C style MP2 method is used to study the hydrogen bonding distances and strengths ofmore » the photoactive yellow protein chromopore in the wild type and the Glu46Gln mutant.« less

Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism: Mexiletine N-Hydroxylation by Cytochrome P450 1A2.

PubMed

Lonsdale, Richard; Fort, Rachel M; Rydberg, Patrik; Harvey, Jeremy N; Mulholland, Adrian J

2016-06-20

The mechanism of cytochrome P450(CYP)-catalyzed hydroxylation of primary amines is currently unclear and is relevant to drug metabolism; previous small model calculations have suggested two possible mechanisms: direct N-oxidation and H-abstraction/rebound. We have modeled the N-hydroxylation of (R)-mexiletine in CYP1A2 with hybrid quantum mechanics/molecular mechanics (QM/MM) methods, providing a more detailed and realistic model. Multiple reaction barriers have been calculated at the QM(B3LYP-D)/MM(CHARMM27) level for the direct N-oxidation and H-abstraction/rebound mechanisms. Our calculated barriers indicate that the direct N-oxidation mechanism is preferred and proceeds via the doublet spin state of Compound I. Molecular dynamics simulations indicate that the presence of an ordered water molecule in the active site assists in the binding of mexiletine in the active site, but this is not a prerequisite for reaction via either mechanism. Several active site residues play a role in the binding of mexiletine in the active site, including Thr124 and Phe226. This work reveals key details of the N-hydroxylation of mexiletine and further demonstrates that mechanistic studies using QM/MM methods are useful for understanding drug metabolism.

Solvent effects on the properties of hyperbranched polythiophenes.

PubMed

Torras, Juan; Zanuy, David; Aradilla, David; Alemán, Carlos

2016-09-21

The structural and electronic properties of all-thiophene dendrimers and dendrons in solution have been evaluated using very different theoretical approaches based on quantum mechanical (QM) and hybrid QM/molecular mechanics (MM) methodologies: (i) calculations on minimum energy conformations using an implicit solvation model in combination with density functional theory (DFT) or time-dependent DFT (TD-DFT) methods; (ii) hybrid QM/MM calculations, in which the solute and solvent molecules are represented at the DFT level as point charges, respectively, on snapshots extracted from classical molecular dynamics (MD) simulations using explicit solvent molecules, and (iii) QM/MM-MD trajectories in which the solute is described at the DFT or TD-DFT level and the explicit solvent molecules are represented using classical force-fields. Calculations have been performed in dichloromethane, tetrahydrofuran and dimethylformamide. A comparison of the results obtained using the different approaches with the available experimental data indicates that the incorporation of effects associated with both the conformational dynamics of the dendrimer and the explicit solvent molecules is strictly necessary to satisfactorily reproduce the properties of the investigated systems. Accordingly, QM/MM-MD simulations are able to capture such effects providing a reliable description of electronic properties-conformational flexibility relationships in all-Th dendrimers.

Application of high level wavefunction methods in quantum mechanics/molecular mechanics hybrid schemes.

PubMed

Mata, Ricardo A

2010-05-21

In this Perspective, several developments in the field of quantum mechanics/molecular mechanics (QM/MM) approaches are reviewed. Emphasis is placed on the use of correlated wavefunction theory and new state of the art methods for the treatment of large quantum systems. Until recently, computational chemistry approaches to large/complex chemical problems have seldom been considered as tools for quantitative predictions. However, due to the tremendous development of computational resources and new quantum chemical methods, it is nowadays possible to describe the electronic structure of biomolecules at levels of theory which a decade ago were only possible for system sizes of up to 20 atoms. These advances are here outlined in the context of QM/MM. The article concludes with a short outlook on upcoming developments and possible bottlenecks for future applications.

Replicating effective pedagogical approaches from introductory physics to improve student learning of quantum mechanics

NASA Astrophysics Data System (ADS)

Sayer, Ryan Thomas

Upper-level undergraduate students entering a quantum mechanics (QM) course are in many ways similar to students entering an introductory physics course. Numerous studies have investigated the difficulties that novices face in introductory physics as well as the pedagogical approaches that are effective in helping them overcome those difficulties. My research focuses on replicating effective approaches and instructional strategies used in introductory physics courses to help advanced students in an upper-level QM course. I have investigated the use of Just-in-time Teaching (JiTT) and peer discussion involving clicker questions in an upper-level quantum mechanics course. The JiTT approach including peer discussions was effective in helping students overcome their difficulties and improve their understanding of QM concepts. Learning tools, such as a Quantum Interactive Learning Tutorial (QuILT) based on the Doubleslit Experiment (DSE) which I helped develop, have been successful in helping upper-level undergraduate students improve their understanding of QM. Many students have also demonstrated the ability to transfer knowledge from a QuILT based on the Mach-Zehnder interferometer while working on the DSE QuILT. In addition, I have been involved in implementing research-based activities during our semester-long professional development course for teaching assistants (TAs). In one intervention, TAs were asked to grade student solutions to introductory physics problems first using their choice of method, then again using a rubric designed to promote effective problem-solving approaches, then once more at the end of the semester using their choice of method. This intervention found that many TAs have ingrained beliefs about the purposes of grading which include placing the burden of proof on the instructor as well as a belief that grading cannot serve as a formative assessment. I also compared TAs grading practices and considerations when grading student solutions to QM problems versus when grading student solutions to introductory physics. Many TAs penalized students for not explicating the problem solving process more often in the QM context than in the introductory physics context. The implications of these interventions for promoting student learning in QM are discussed.

Reaction mechanism of Ru(II) piano-stool complexes: umbrella sampling QM/MM MD study.

PubMed

Futera, Zdeněk; Burda, Jaroslav V

2014-07-15

Biologically relevant interactions of piano-stool ruthenium(II) complexes with ds-DNA are studied in this article by hybrid quantum mechanics-molecular mechanics (QM/MM) computational technique. The whole reaction mechanism is divided into three phases: (i) hydration of the [Ru(II) (η(6) -benzene)(en)Cl](+) complex, (ii) monoadduct formation between the resulting aqua-Ru(II) complex and N7 position of one of the guanines in the ds-DNA oligomer, and (iii) formation of the intrastrand Ru(II) bridge (cross-link) between two adjacent guanines. Free energy profiles of all the reactions are explored by QM/MM MD umbrella sampling approach where the Ru(II) complex and two guanines represent a quantum core, which is described by density functional theory methods. The combined QM/MM scheme is realized by our own software, which was developed to couple several quantum chemical programs (in this study Gaussian 09) and Amber 11 package. Calculated free energy barriers of the both ruthenium hydration and Ru(II)-N7(G) DNA binding process are in good agreement with experimentally measured rate constants. Then, this method was used to study the possibility of cross-link formation. One feasible pathway leading to Ru(II) guanine-guanine cross-link with synchronous releasing of the benzene ligand is predicted. The cross-linking is an exergonic process with the energy barrier lower than for the monoadduct reaction of Ru(II) complex with ds-DNA. Copyright © 2014 Wiley Periodicals, Inc.

QM/MM Geometry Optimization on Extensive Free-Energy Surfaces for Examination of Enzymatic Reactions and Design of Novel Functional Properties of Proteins.

PubMed

Hayashi, Shigehiko; Uchida, Yoshihiro; Hasegawa, Taisuke; Higashi, Masahiro; Kosugi, Takahiro; Kamiya, Motoshi

2017-05-05

Many remarkable molecular functions of proteins use their characteristic global and slow conformational dynamics through coupling of local chemical states in reaction centers with global conformational changes of proteins. To theoretically examine the functional processes of proteins in atomic detail, a methodology of quantum mechanical/molecular mechanical (QM/MM) free-energy geometry optimization is introduced. In the methodology, a geometry optimization of a local reaction center is performed with a quantum mechanical calculation on a free-energy surface constructed with conformational samples of the surrounding protein environment obtained by a molecular dynamics simulation with a molecular mechanics force field. Geometry optimizations on extensive free-energy surfaces by a QM/MM reweighting free-energy self-consistent field method designed to be variationally consistent and computationally efficient have enabled examinations of the multiscale molecular coupling of local chemical states with global protein conformational changes in functional processes and analysis and design of protein mutants with novel functional properties.

QM/MM Geometry Optimization on Extensive Free-Energy Surfaces for Examination of Enzymatic Reactions and Design of Novel Functional Properties of Proteins

NASA Astrophysics Data System (ADS)

Hayashi, Shigehiko; Uchida, Yoshihiro; Hasegawa, Taisuke; Higashi, Masahiro; Kosugi, Takahiro; Kamiya, Motoshi

2017-05-01

Many remarkable molecular functions of proteins use their characteristic global and slow conformational dynamics through coupling of local chemical states in reaction centers with global conformational changes of proteins. To theoretically examine the functional processes of proteins in atomic detail, a methodology of quantum mechanical/molecular mechanical (QM/MM) free-energy geometry optimization is introduced. In the methodology, a geometry optimization of a local reaction center is performed with a quantum mechanical calculation on a free-energy surface constructed with conformational samples of the surrounding protein environment obtained by a molecular dynamics simulation with a molecular mechanics force field. Geometry optimizations on extensive free-energy surfaces by a QM/MM reweighting free-energy self-consistent field method designed to be variationally consistent and computationally efficient have enabled examinations of the multiscale molecular coupling of local chemical states with global protein conformational changes in functional processes and analysis and design of protein mutants with novel functional properties.

The application of quantum mechanics in structure-based drug design.

PubMed

Mucs, Daniel; Bryce, Richard A

2013-03-01

Computational chemistry has become an established and valuable component in structure-based drug design. However the chemical complexity of many ligands and active sites challenges the accuracy of the empirical potentials commonly used to describe these systems. Consequently, there is a growing interest in utilizing electronic structure methods for addressing problems in protein-ligand recognition. In this review, the authors discuss recent progress in the development and application of quantum chemical approaches to modeling protein-ligand interactions. The authors specifically consider the development of quantum mechanics (QM) approaches for studying large molecular systems pertinent to biology, focusing on protein-ligand docking, protein-ligand binding affinities and ligand strain on binding. Although computation of binding energies remains a challenging and evolving area, current QM methods can underpin improved docking approaches and offer detailed insights into ligand strain and into the nature and relative strengths of complex active site interactions. The authors envisage that QM will become an increasingly routine and valued tool of the computational medicinal chemist.

[Interactions of DNA bases with individual water molecules. Molecular mechanics and quantum mechanics computation results vs. experimental data].

PubMed

Gonzalez, E; Lino, J; Deriabina, A; Herrera, J N F; Poltev, V I

2013-01-01

To elucidate details of the DNA-water interactions we performed the calculations and systemaitic search for minima of interaction energy of the systems consisting of one of DNA bases and one or two water molecules. The results of calculations using two force fields of molecular mechanics (MM) and correlated ab initio method MP2/6-31G(d, p) of quantum mechanics (QM) have been compared with one another and with experimental data. The calculations demonstrated a qualitative agreement between geometry characteristics of the most of local energy minima obtained via different methods. The deepest minima revealed by MM and QM methods correspond to water molecule position between two neighbor hydrophilic centers of the base and to the formation by water molecule of hydrogen bonds with them. Nevertheless, the relative depth of some minima and peculiarities of mutual water-base positions in' these minima depend on the method used. The analysis revealed insignificance of some differences in the results of calculations performed via different methods and the importance of other ones for the description of DNA hydration. The calculations via MM methods enable us to reproduce quantitatively all the experimental data on the enthalpies of complex formation of single water molecule with the set of mono-, di-, and trimethylated bases, as well as on water molecule locations near base hydrophilic atoms in the crystals of DNA duplex fragments, while some of these data cannot be rationalized by QM calculations.

Quantum Mechanics: Myths and Facts

NASA Astrophysics Data System (ADS)

Nikolić, Hrvoje

2007-11-01

A common understanding of quantum mechanics (QM) among students and practical users is often plagued by a number of “myths”, that is, widely accepted claims on which there is not really a general consensus among experts in foundations of QM. These myths include wave-particle duality, time-energy uncertainty relation, fundamental randomness, the absence of measurement-independent reality, locality of QM, nonlocality of QM, the existence of well-defined relativistic QM, the claims that quantum field theory (QFT) solves the problems of relativistic QM or that QFT is a theory of particles, as well as myths on black-hole entropy. The fact is that the existence of various theoretical and interpretational ambiguities underlying these myths does not yet allow us to accept them as proven facts. I review the main arguments and counterarguments lying behind these myths and conclude that QM is still a not-yet-completely-understood theory open to further fundamental research.

Exchange repulsive potential adaptable for electronic structure changes during chemical reactions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yokogawa, D., E-mail: d.yokogawa@chem.nagoya-u.ac.jp

2015-04-28

Hybrid methods combining quantum mechanical (QM) and classical calculations are becoming important tools in chemistry. The popular approach to calculate the interaction between QM and classical calculations employs interatomic potentials. In most cases, the interatomic potential is constructed of an electrostatic (ES) potential and a non-ES potential. Because QM treatment is employed in the calculation of the ES potential, the electronic change can be considered in this ES potential. However, QM treatment of the non-ES potential is difficult because of high computational cost. To overcome this difficulty of evaluating the non-ES potential, we proposed an exchange repulsive potential as themore » main part of the non-ES potential on the basis of a QM approach. This potential is independent of empirical parameters and adaptable for electronic structure. We combined this potential with the reference interaction site model self-consistent field explicitly including spatial electron density distribution and successfully applied it to the chemical reactions in aqueous phase.« less

Developments toward more accurate molecular modeling of liquids

NASA Astrophysics Data System (ADS)

Evans, Tom J.

2000-12-01

The general goal of this research has been to improve upon existing combined quantum mechanics/molecular mechanics (QM/MM) methodologies. Error weighting functions have been introduced into the perturbative Monte Carlo (PMC) method for use with QM/MM. The PMC approach, introduced earlier, provides a means to reduce the number of full self-consistent field (SCF) calculations in simulations using the QM/MM potential by evoking perturbation theory to calculate energy changes due to displacements of a MM molecule. This will allow the ab initio QM/MM approach to be applied to systems that require more advanced, computationally demanding treatments of the QM and/or MM regions. Efforts have also been made to improve the accuracy of the representation of the solvent molecules usually represented by MM force fields. Results from an investigation of the applicability of the embedded density functional theory (EDFT) for studying physical properties of solutions will be presented. In this approach, the solute wavefunction is solved self- consistently in the field of individually frozen electron-density solvent molecules. To test its accuracy, the potential curves for interactions between Li+, Cl- and H2O with a single frozen-density H 2O molecule in different orientations have been calculated. With the development of the more sophisticated effective fragment potential (EFP) representation of solvent molecules, a QM/EFP technique was created. This hybrid QM/EFP approach was used to investigate the solvation of Li + by small clusters of water, as a test case for larger ionic dusters. The EFP appears to provide an accurate representation of the strong interactions that exist between Li+ and H2O. With the QM/EFP methodology comes an increased computational expense, resulting in an even greater need to rely on the PMC approach. However, while including the PMC into the hybrid QM/EFP technique, it was discovered that the previous implementation of the PMC was done incorrectly, invalidating earlier test results. The PMC implementation was therefore reworked, and tests were performed to investigate the methods usefulness in reducing the computational load of these types of simulations. The results that were obtained while studying F-(H2O) and F-(H 2O)2 show that PMC can be used cautiously to increase computational efficiency.

Multiple environment single system quantum mechanical/molecular mechanical (MESS-QM/MM) calculations. 1. Estimation of polarization energies.

PubMed

Sodt, Alexander J; Mei, Ye; König, Gerhard; Tao, Peng; Steele, Ryan P; Brooks, Bernard R; Shao, Yihan

2015-03-05

In combined quantum mechanical/molecular mechanical (QM/MM) free energy calculations, it is often advantageous to have a frozen geometry for the quantum mechanical (QM) region. For such multiple-environment single-system (MESS) cases, two schemes are proposed here for estimating the polarization energy: the first scheme, termed MESS-E, involves a Roothaan step extrapolation of the self-consistent field (SCF) energy; whereas the other scheme, termed MESS-H, employs a Newton-Raphson correction using an approximate inverse electronic Hessian of the QM region (which is constructed only once). Both schemes are extremely efficient, because the expensive Fock updates and SCF iterations in standard QM/MM calculations are completely avoided at each configuration. They produce reasonably accurate QM/MM polarization energies: MESS-E can predict the polarization energy within 0.25 kcal/mol in terms of the mean signed error for two of our test cases, solvated methanol and solvated β-alanine, using the M06-2X or ωB97X-D functionals; MESS-H can reproduce the polarization energy within 0.2 kcal/mol for these two cases and for the oxyluciferin-luciferase complex, if the approximate inverse electronic Hessians are constructed with sufficient accuracy.

Computation of the free energy change associated with one-electron reduction of coenzyme immersed in water: a novel approach within the framework of the quantum mechanical/molecular mechanical method combined with the theory of energy representation.

PubMed

Takahashi, Hideaki; Ohno, Hajime; Kishi, Ryohei; Nakano, Masayoshi; Matubayasi, Nobuyuki

2008-11-28

The isoalloxazine ring (flavin ring) is a part of the coenzyme flavin adenine dinucleotide and acts as an active site in the oxidation of a substrate. We have computed the free energy change Deltamicro(red) associated with one-electron reduction of the flavin ring immersed in water by utilizing the quantum mechanical/molecular mechanical method combined with the theory of energy representation (QM/MM-ER method) recently developed. As a novel treatment in implementing the QM/MM-ER method, we have identified the excess charge to be attached on the flavin ring as a solute while the remaining molecules, i.e., flavin ring and surrounding water molecules, are treated as solvent species. Then, the reduction free energy can be decomposed into the contribution Deltamicro(red)(QM) due to the oxidant described quantum chemically and the free energy Deltamicro(red)(MM) due to the water molecules represented by a classical model. By the sum of these contributions, the total reduction free energy Deltamicro(red) has been given as -80.1 kcal/mol. To examine the accuracy and efficiency of this approach, we have also conducted the Deltamicro(red) calculation using the conventional scheme that Deltamicro(red) is constructed from the solvation free energies of the flavin rings at the oxidized and reduced states. The conventional scheme has been implemented with the QM/MM-ER method and the calculated Deltamicro(red) has been estimated as -81.0 kcal/mol, showing excellent agreement with the value given by the new approach. The present approach is efficient, in particular, to compute free energy change for the reaction occurring in a protein since it enables ones to circumvent the numerical problem brought about by subtracting the huge solvation free energies of the proteins in two states before and after the reduction.

Quantum Mechanics/Molecular Mechanics Modeling of Enzymatic Processes: Caveats and Breakthroughs.

PubMed

Quesne, Matthew G; Borowski, Tomasz; de Visser, Sam P

2016-02-18

Nature has developed large groups of enzymatic catalysts with the aim to transfer substrates into useful products, which enables biosystems to perform all their natural functions. As such, all biochemical processes in our body (we drink, we eat, we breath, we sleep, etc.) are governed by enzymes. One of the problems associated with research on biocatalysts is that they react so fast that details of their reaction mechanisms cannot be obtained with experimental work. In recent years, major advances in computational hardware and software have been made and now large (bio)chemical systems can be studied using accurate computational techniques. One such technique is the quantum mechanics/molecular mechanics (QM/MM) technique, which has gained major momentum in recent years. Unfortunately, it is not a black-box method that is easily applied, but requires careful set-up procedures. In this work we give an overview on the technical difficulties and caveats of QM/MM and discuss work-protocols developed in our groups for running successful QM/MM calculations. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Computing pKa Values with a Mixing Hamiltonian Quantum Mechanical/Molecular Mechanical Approach.

PubMed

Liu, Yang; Fan, Xiaoli; Jin, Yingdi; Hu, Xiangqian; Hu, Hao

2013-09-10

Accurate computation of the pKa value of a compound in solution is important but challenging. Here, a new mixing quantum mechanical/molecular mechanical (QM/MM) Hamiltonian method is developed to simulate the free-energy change associated with the protonation/deprotonation processes in solution. The mixing Hamiltonian method is designed for efficient quantum mechanical free-energy simulations by alchemically varying the nuclear potential, i.e., the nuclear charge of the transforming nucleus. In pKa calculation, the charge on the proton is varied in fraction between 0 and 1, corresponding to the fully deprotonated and protonated states, respectively. Inspired by the mixing potential QM/MM free energy simulation method developed previously [H. Hu and W. T. Yang, J. Chem. Phys. 2005, 123, 041102], this method succeeds many advantages of a large class of λ-coupled free-energy simulation methods and the linear combination of atomic potential approach. Theory and technique details of this method, along with the calculation results of the pKa of methanol and methanethiol molecules in aqueous solution, are reported. The results show satisfactory agreement with the experimental data.

A Comparison of Quantum and Molecular Mechanical Methods to Estimate Strain Energy in Druglike Fragments.

PubMed

Sellers, Benjamin D; James, Natalie C; Gobbi, Alberto

2017-06-26

Reducing internal strain energy in small molecules is critical for designing potent drugs. Quantum mechanical (QM) and molecular mechanical (MM) methods are often used to estimate these energies. In an effort to determine which methods offer an optimal balance in accuracy and performance, we have carried out torsion scan analyses on 62 fragments. We compared nine QM and four MM methods to reference energies calculated at a higher level of theory: CCSD(T)/CBS single point energies (coupled cluster with single, double, and perturbative triple excitations at the complete basis set limit) calculated on optimized geometries using MP2/6-311+G**. The results show that both the more recent MP2.X perturbation method as well as MP2/CBS perform quite well. In addition, combining a Hartree-Fock geometry optimization with a MP2/CBS single point energy calculation offers a fast and accurate compromise when dispersion is not a key energy component. Among MM methods, the OPLS3 force field accurately reproduces CCSD(T)/CBS torsion energies on more test cases than the MMFF94s or Amber12:EHT force fields, which struggle with aryl-amide and aryl-aryl torsions. Using experimental conformations from the Cambridge Structural Database, we highlight three example structures for which OPLS3 significantly overestimates the strain. The energies and conformations presented should enable scientists to estimate the expected error for the methods described and we hope will spur further research into QM and MM methods.

A Mixed QM/MM Scoring Function to Predict Protein-Ligand Binding Affinity

PubMed Central

Hayik, Seth A.; Dunbrack, Roland; Merz, Kenneth M.

2010-01-01

Computational methods for predicting protein-ligand binding free energy continue to be popular as a potential cost-cutting method in the drug discovery process. However, accurate predictions are often difficult to make as estimates must be made for certain electronic and entropic terms in conventional force field based scoring functions. Mixed quantum mechanics/molecular mechanics (QM/MM) methods allow electronic effects for a small region of the protein to be calculated, treating the remaining atoms as a fixed charge background for the active site. Such a semi-empirical QM/MM scoring function has been implemented in AMBER using DivCon and tested on a set of 23 metalloprotein-ligand complexes, where QM/MM methods provide a particular advantage in the modeling of the metal ion. The binding affinity of this set of proteins can be calculated with an R2 of 0.64 and a standard deviation of 1.88 kcal/mol without fitting and 0.71 and a standard deviation of 1.69 kcal/mol with fitted weighting of the individual scoring terms. In this study we explore using various methods to calculate terms in the binding free energy equation, including entropy estimates and minimization standards. From these studies we found that using the rotational bond estimate to ligand entropy results in a reasonable R2 of 0.63 without fitting. We also found that using the ESCF energy of the proteins without minimization resulted in an R2 of 0.57, when using the rotatable bond entropy estimate. PMID:21221417

Solvent effects on the ultrafast nonradiative deactivation mechanisms of thymine in aqueous solution: Excited-state QM/MM molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Nakayama, Akira; Arai, Gaku; Yamazaki, Shohei; Taketsugu, Tetsuya

2013-12-01

On-the-fly excited-state quantum mechanics/molecular mechanics molecular dynamics (QM/MM-MD) simulations of thymine in aqueous solution are performed to investigate the role of solvent water molecules on the nonradiative deactivation process. The complete active space second-order perturbation theory (CASPT2) method is employed for a thymine molecule as the QM part in order to provide a reliable description of the excited-state potential energies. It is found that, in addition to the previously reported deactivation pathway involving the twisting of the C-C double bond in the pyrimidine ring, another efficient deactivation pathway leading to conical intersections that accompanies the out-of-plane displacement of the carbonyl group is observed in aqueous solution. Decay through this pathway is not observed in the gas phase simulations, and our analysis indicates that the hydrogen bonds with solvent water molecules play a key role in stabilizing the potential energies of thymine in this additional decay pathway.

Accuracy of Protein Embedding Potentials: An Analysis in Terms of Electrostatic Potentials.

PubMed

Olsen, Jógvan Magnus Haugaard; List, Nanna Holmgaard; Kristensen, Kasper; Kongsted, Jacob

2015-04-14

Quantum-mechanical embedding methods have in recent years gained significant interest and may now be applied to predict a wide range of molecular properties calculated at different levels of theory. To reach a high level of accuracy in embedding methods, both the electronic structure model of the active region and the embedding potential need to be of sufficiently high quality. In fact, failures in quantum mechanics/molecular mechanics (QM/MM)-based embedding methods have often been associated with the QM/MM methodology itself; however, in many cases the reason for such failures is due to the use of an inaccurate embedding potential. In this paper, we investigate in detail the quality of the electronic component of embedding potentials designed for calculations on protein biostructures. We show that very accurate explicitly polarizable embedding potentials may be efficiently designed using fragmentation strategies combined with single-fragment ab initio calculations. In fact, due to the self-interaction error in Kohn-Sham density functional theory (KS-DFT), use of large full-structure quantum-mechanical calculations based on conventional (hybrid) functionals leads to less accurate embedding potentials than fragment-based approaches. We also find that standard protein force fields yield poor embedding potentials, and it is therefore not advisable to use such force fields in general QM/MM-type calculations of molecular properties other than energies and structures.

Exact and Optimal Quantum Mechanics/Molecular Mechanics Boundaries.

PubMed

Sun, Qiming; Chan, Garnet Kin-Lic

2014-09-09

Motivated by recent work in density matrix embedding theory, we define exact link orbitals that capture all quantum mechanical (QM) effects across arbitrary quantum mechanics/molecular mechanics (QM/MM) boundaries. Exact link orbitals are rigorously defined from the full QM solution, and their number is equal to the number of orbitals in the primary QM region. Truncating the exact set yields a smaller set of link orbitals optimal with respect to reproducing the primary region density matrix. We use the optimal link orbitals to obtain insight into the limits of QM/MM boundary treatments. We further analyze the popular general hybrid orbital (GHO) QM/MM boundary across a test suite of molecules. We find that GHOs are often good proxies for the most important optimal link orbital, although there is little detailed correlation between the detailed GHO composition and optimal link orbital valence weights. The optimal theory shows that anions and cations cannot be described by a single link orbital. However, expanding to include the second most important optimal link orbital in the boundary recovers an accurate description. The second optimal link orbital takes the chemically intuitive form of a donor or acceptor orbital for charge redistribution, suggesting that optimal link orbitals can be used as interpretative tools for electron transfer. We further find that two optimal link orbitals are also sufficient for boundaries that cut across double bonds. Finally, we suggest how to construct "approximately" optimal link orbitals for practical QM/MM calculations.

Stepwise Catalytic Mechanism via Short-Lived Intermediate Inferred from Combined QM/MM MERP and PES Calculations on Retaining Glycosyltransferase ppGalNAcT2

PubMed Central

Trnka, Tomáš; Kozmon, Stanislav; Tvaroška, Igor; Koča, Jaroslav

2015-01-01

The glycosylation of cell surface proteins plays a crucial role in a multitude of biological processes, such as cell adhesion and recognition. To understand the process of protein glycosylation, the reaction mechanisms of the participating enzymes need to be known. However, the reaction mechanism of retaining glycosyltransferases has not yet been sufficiently explained. Here we investigated the catalytic mechanism of human isoform 2 of the retaining glycosyltransferase polypeptide UDP-GalNAc transferase by coupling two different QM/MM-based approaches, namely a potential energy surface scan in two distance difference dimensions and a minimum energy reaction path optimisation using the Nudged Elastic Band method. Potential energy scan studies often suffer from inadequate sampling of reactive processes due to a predefined scan coordinate system. At the same time, path optimisation methods enable the sampling of a virtually unlimited number of dimensions, but their results cannot be unambiguously interpreted without knowledge of the potential energy surface. By combining these methods, we have been able to eliminate the most significant sources of potential errors inherent to each of these approaches. The structural model is based on the crystal structure of human isoform 2. In the QM/MM method, the QM region consists of 275 atoms, the remaining 5776 atoms were in the MM region. We found that ppGalNAcT2 catalyzes a same-face nucleophilic substitution with internal return (SNi). The optimized transition state for the reaction is 13.8 kcal/mol higher in energy than the reactant while the energy of the product complex is 6.7 kcal/mol lower. During the process of nucleophilic attack, a proton is synchronously transferred to the leaving phosphate. The presence of a short-lived metastable oxocarbenium intermediate is likely, as indicated by the reaction energy profiles obtained using high-level density functionals. PMID:25849117

Stepwise catalytic mechanism via short-lived intermediate inferred from combined QM/MM MERP and PES calculations on retaining glycosyltransferase ppGalNAcT2.

PubMed

Trnka, Tomáš; Kozmon, Stanislav; Tvaroška, Igor; Koča, Jaroslav

2015-04-01

The glycosylation of cell surface proteins plays a crucial role in a multitude of biological processes, such as cell adhesion and recognition. To understand the process of protein glycosylation, the reaction mechanisms of the participating enzymes need to be known. However, the reaction mechanism of retaining glycosyltransferases has not yet been sufficiently explained. Here we investigated the catalytic mechanism of human isoform 2 of the retaining glycosyltransferase polypeptide UDP-GalNAc transferase by coupling two different QM/MM-based approaches, namely a potential energy surface scan in two distance difference dimensions and a minimum energy reaction path optimisation using the Nudged Elastic Band method. Potential energy scan studies often suffer from inadequate sampling of reactive processes due to a predefined scan coordinate system. At the same time, path optimisation methods enable the sampling of a virtually unlimited number of dimensions, but their results cannot be unambiguously interpreted without knowledge of the potential energy surface. By combining these methods, we have been able to eliminate the most significant sources of potential errors inherent to each of these approaches. The structural model is based on the crystal structure of human isoform 2. In the QM/MM method, the QM region consists of 275 atoms, the remaining 5776 atoms were in the MM region. We found that ppGalNAcT2 catalyzes a same-face nucleophilic substitution with internal return (SNi). The optimized transition state for the reaction is 13.8 kcal/mol higher in energy than the reactant while the energy of the product complex is 6.7 kcal/mol lower. During the process of nucleophilic attack, a proton is synchronously transferred to the leaving phosphate. The presence of a short-lived metastable oxocarbenium intermediate is likely, as indicated by the reaction energy profiles obtained using high-level density functionals.

Multiple Environment Single System Quantum Mechanical/Molecular Mechanical (MESS-QM/MM) Calculations. 1. Estimation of Polarization Energies

PubMed Central

2015-01-01

In combined quantum mechanical/molecular mechanical (QM/MM) free energy calculations, it is often advantageous to have a frozen geometry for the quantum mechanical (QM) region. For such multiple-environment single-system (MESS) cases, two schemes are proposed here for estimating the polarization energy: the first scheme, termed MESS-E, involves a Roothaan step extrapolation of the self-consistent field (SCF) energy; whereas the other scheme, termed MESS-H, employs a Newton–Raphson correction using an approximate inverse electronic Hessian of the QM region (which is constructed only once). Both schemes are extremely efficient, because the expensive Fock updates and SCF iterations in standard QM/MM calculations are completely avoided at each configuration. They produce reasonably accurate QM/MM polarization energies: MESS-E can predict the polarization energy within 0.25 kcal/mol in terms of the mean signed error for two of our test cases, solvated methanol and solvated β-alanine, using the M06-2X or ωB97X-D functionals; MESS-H can reproduce the polarization energy within 0.2 kcal/mol for these two cases and for the oxyluciferin–luciferase complex, if the approximate inverse electronic Hessians are constructed with sufficient accuracy. PMID:25321186

Multiple environment single system quantum mechanical/molecular mechanical (MESS-QM/MM) calculations. 1. Estimation of polarization energies

DOE PAGES

Sodt, Alexander J.; Mei, Ye; Konig, Gerhard; ...

2014-10-16

In combined quantum mechanical/molecular mechanical (QM/MM) free energy calculations, it is often advantageous to have a frozen geometry for the quantum mechanical (QM) region. For such multiple-environment single-system (MESS) cases, two schemes are proposed here for estimating the polarization energy: the first scheme, termed MESS-E, involves a Roothaan step extrapolation of the self-consistent field (SCF) energy; whereas the other scheme, termed MESS-H, employs a Newton–Raphson correction using an approximate inverse electronic Hessian of the QM region (which is constructed only once). Both schemes are extremely efficient, because the expensive Fock updates and SCF iterations in standard QM/MM calculations are completelymore » avoided at each configuration. Here, they produce reasonably accurate QM/MM polarization energies: MESS-E can predict the polarization energy within 0.25 kcal/mol in terms of the mean signed error for two of our test cases, solvated methanol and solvated β-alanine, using the M06-2X or ωB97X-D functionals; MESS-H can reproduce the polarization energy within 0.2 kcal/mol for these two cases and for the oxyluciferin–luciferase complex, if the approximate inverse electronic Hessians are constructed with sufficient accuracy.« less

Quantum mechanics capacitance molecular mechanics modeling of core-electron binding energies of methanol and methyl nitrite on Ag(111) surface.

PubMed

Löytynoja, T; Li, X; Jänkälä, K; Rinkevicius, Z; Ågren, H

2016-07-14

We study a newly devised quantum mechanics capacitance molecular mechanics (QMCMM) method for the calculation of core-electron binding energies in the case of molecules adsorbed on metal surfaces. This yet untested methodology is applied to systems with monolayer of methanol/methyl nitrite on an Ag(111) surface at 100 K temperature. It was found out that the studied C, N, and O 1s core-hole energies converge very slowly as a function of the radius of the metallic cluster, which was ascribed to build up of positive charge on the edge of the Ag slab. Further analysis revealed that an extrapolation process can be used to obtain binding energies that deviated less than 0.5 eV against experiments, except in the case of methanol O 1s where the difference was as large as 1.8 eV. Additional QM-cluster calculations suggest that the latter error can be connected to the lack of charge transfer over the QM-CMM boundary. Thus, the results indicate that the QMCMM and QM-cluster methods can complement each other in a holistic picture of molecule-adsorbate core-ionization studies, where all types of intermolecular interactions are considered.

Quantum mechanics capacitance molecular mechanics modeling of core-electron binding energies of methanol and methyl nitrite on Ag(111) surface

NASA Astrophysics Data System (ADS)

Löytynoja, T.; Li, X.; Jänkälä, K.; Rinkevicius, Z.; Ågren, H.

2016-07-01

We study a newly devised quantum mechanics capacitance molecular mechanics (QMCMM) method for the calculation of core-electron binding energies in the case of molecules adsorbed on metal surfaces. This yet untested methodology is applied to systems with monolayer of methanol/methyl nitrite on an Ag(111) surface at 100 K temperature. It was found out that the studied C, N, and O 1s core-hole energies converge very slowly as a function of the radius of the metallic cluster, which was ascribed to build up of positive charge on the edge of the Ag slab. Further analysis revealed that an extrapolation process can be used to obtain binding energies that deviated less than 0.5 eV against experiments, except in the case of methanol O 1s where the difference was as large as 1.8 eV. Additional QM-cluster calculations suggest that the latter error can be connected to the lack of charge transfer over the QM-CMM boundary. Thus, the results indicate that the QMCMM and QM-cluster methods can complement each other in a holistic picture of molecule-adsorbate core-ionization studies, where all types of intermolecular interactions are considered.

An Estimation of Hybrid Quantum Mechanical Molecular Mechanical Polarization Energies for Small Molecules Using Polarizable Force-Field Approaches

DOE PAGES

Huang, Jing; Mei, Ye; König, Gerhard; ...

2017-01-24

Here in this work, we report two polarizable molecular mechanics (polMM) force field models for estimating the polarization energy in hybrid quantum mechanical molecular mechanical (QM/MM) calculations. These two models, named the potential of atomic charges (PAC) and potential of atomic dipoles (PAD), are formulated from the ab initio quantum mechanical (QM) response kernels for the prediction of the QM density response to an external molecular mechanical (MM) environment (as described by external point charges). The PAC model is similar to fluctuating charge (FQ) models because the energy depends on external electrostatic potential values at QM atomic sites; the PADmore » energy depends on external electrostatic field values at QM atomic sites, resembling induced dipole (ID) models. To demonstrate their uses, we apply the PAC and PAD models to 12 small molecules, which are solvated by TIP3P water. The PAC model reproduces the QM/MM polarization energy with a R 2 value of 0.71 for aniline (in 10,000 TIP3P water configurations) and 0.87 or higher for other eleven solute molecules, while the PAD model has a much better performance with R 2 values of 0.98 or higher. The PAC model reproduces reference QM/MM hydration free energies for 12 solute molecules with a RMSD of 0.59 kcal/mol. The PAD model is even more accurate, with a much smaller RMSD of 0.12 kcal/mol, with respect to the reference. Lastly, this suggests that polarization effects, including both local charge distortion and intramolecular charge transfer, can be well captured by induced dipole type models with proper parametrization.« less

An Estimation of Hybrid Quantum Mechanical Molecular Mechanical Polarization Energies for Small Molecules Using Polarizable Force-Field Approaches.

PubMed

Huang, Jing; Mei, Ye; König, Gerhard; Simmonett, Andrew C; Pickard, Frank C; Wu, Qin; Wang, Lee-Ping; MacKerell, Alexander D; Brooks, Bernard R; Shao, Yihan

2017-02-14

In this work, we report two polarizable molecular mechanics (polMM) force field models for estimating the polarization energy in hybrid quantum mechanical molecular mechanical (QM/MM) calculations. These two models, named the potential of atomic charges (PAC) and potential of atomic dipoles (PAD), are formulated from the ab initio quantum mechanical (QM) response kernels for the prediction of the QM density response to an external molecular mechanical (MM) environment (as described by external point charges). The PAC model is similar to fluctuating charge (FQ) models because the energy depends on external electrostatic potential values at QM atomic sites; the PAD energy depends on external electrostatic field values at QM atomic sites, resembling induced dipole (ID) models. To demonstrate their uses, we apply the PAC and PAD models to 12 small molecules, which are solvated by TIP3P water. The PAC model reproduces the QM/MM polarization energy with a R 2 value of 0.71 for aniline (in 10,000 TIP3P water configurations) and 0.87 or higher for other 11 solute molecules, while the PAD model has a much better performance with R 2 values of 0.98 or higher. The PAC model reproduces reference QM/MM hydration free energies for 12 solute molecules with a RMSD of 0.59 kcal/mol. The PAD model is even more accurate, with a much smaller RMSD of 0.12 kcal/mol, with respect to the reference. This suggests that polarization effects, including both local charge distortion and intramolecular charge transfer, can be well captured by induced dipole type models with proper parametrization.

An Estimation of Hybrid Quantum Mechanical Molecular Mechanical Polarization Energies for Small Molecules Using Polarizable Force-Field Approaches

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Jing; Mei, Ye; König, Gerhard

Here in this work, we report two polarizable molecular mechanics (polMM) force field models for estimating the polarization energy in hybrid quantum mechanical molecular mechanical (QM/MM) calculations. These two models, named the potential of atomic charges (PAC) and potential of atomic dipoles (PAD), are formulated from the ab initio quantum mechanical (QM) response kernels for the prediction of the QM density response to an external molecular mechanical (MM) environment (as described by external point charges). The PAC model is similar to fluctuating charge (FQ) models because the energy depends on external electrostatic potential values at QM atomic sites; the PADmore » energy depends on external electrostatic field values at QM atomic sites, resembling induced dipole (ID) models. To demonstrate their uses, we apply the PAC and PAD models to 12 small molecules, which are solvated by TIP3P water. The PAC model reproduces the QM/MM polarization energy with a R 2 value of 0.71 for aniline (in 10,000 TIP3P water configurations) and 0.87 or higher for other eleven solute molecules, while the PAD model has a much better performance with R 2 values of 0.98 or higher. The PAC model reproduces reference QM/MM hydration free energies for 12 solute molecules with a RMSD of 0.59 kcal/mol. The PAD model is even more accurate, with a much smaller RMSD of 0.12 kcal/mol, with respect to the reference. Lastly, this suggests that polarization effects, including both local charge distortion and intramolecular charge transfer, can be well captured by induced dipole type models with proper parametrization.« less

Simulation with quantum mechanics/molecular mechanics for drug discovery.

PubMed

Barbault, Florent; Maurel, François

2015-10-01

Biological macromolecules, such as proteins or nucleic acids, are (still) molecules and thus they follow the same chemical rules that any simple molecule follows, even if their size generally renders accurate studies unhelpful. However, in the context of drug discovery, a detailed analysis of ligand association is required for understanding or predicting their interactions and hybrid quantum mechanics/molecular mechanics (QM/MM) computations are relevant tools to help elucidate this process. In this review, the authors explore the use of QM/MM for drug discovery. After a brief description of the molecular mechanics (MM) technique, the authors describe the subtractive and additive techniques for QM/MM computations. The authors then present several application cases in topics involved in drug discovery. QM/MM have been widely employed during the last decades to study chemical processes such as enzyme-inhibitor interactions. However, despite the enthusiasm around this area, plain MM simulations may be more meaningful than QM/MM. To obtain reliable results, the authors suggest fixing several keystone parameters according to the underlying chemistry of each studied system.

Simulation with quantum mechanics/molecular mechanics for drug discovery.

PubMed

Barbault, Florent; Maurel, François

2015-08-08

Biological macromolecules, such as proteins or nucleic acids, are (still) molecules and thus they follow the same chemical rules that any simple molecule follows, even if their size generally renders accurate studies unhelpful. However, in the context of drug discovery, a detailed analysis of ligand association is required for understanding or predicting their interactions and hybrid quantum mechanics/molecular mechanics (QM/MM) computations are relevant tools to help elucidate this process. Areas covered: In this review, the authors explore the use of QM/MM for drug discovery. After a brief description of the molecular mechanics (MM) technique, the authors describe the subtractive and additive techniques for QM/MM computations. The authors then present several application cases in topics involved in drug discovery. Expert opinion: QM/MM have been widely employed during the last decades to study chemical processes such as enzyme-inhibitor interactions. However, despite the enthusiasm around this area, plain MM simulations may be more meaningful than QM/MM. To obtain reliable results, the authors suggest fixing several keystone parameters according to the underlying chemistry of each studied system.

Optimization and benchmarking of a perturbative Metropolis Monte Carlo quantum mechanics/molecular mechanics program

NASA Astrophysics Data System (ADS)

Feldt, Jonas; Miranda, Sebastião; Pratas, Frederico; Roma, Nuno; Tomás, Pedro; Mata, Ricardo A.

2017-12-01

In this work, we present an optimized perturbative quantum mechanics/molecular mechanics (QM/MM) method for use in Metropolis Monte Carlo simulations. The model adopted is particularly tailored for the simulation of molecular systems in solution but can be readily extended to other applications, such as catalysis in enzymatic environments. The electrostatic coupling between the QM and MM systems is simplified by applying perturbation theory to estimate the energy changes caused by a movement in the MM system. This approximation, together with the effective use of GPU acceleration, leads to a negligible added computational cost for the sampling of the environment. Benchmark calculations are carried out to evaluate the impact of the approximations applied and the overall computational performance.

Optimization and benchmarking of a perturbative Metropolis Monte Carlo quantum mechanics/molecular mechanics program.

PubMed

Feldt, Jonas; Miranda, Sebastião; Pratas, Frederico; Roma, Nuno; Tomás, Pedro; Mata, Ricardo A

2017-12-28

In this work, we present an optimized perturbative quantum mechanics/molecular mechanics (QM/MM) method for use in Metropolis Monte Carlo simulations. The model adopted is particularly tailored for the simulation of molecular systems in solution but can be readily extended to other applications, such as catalysis in enzymatic environments. The electrostatic coupling between the QM and MM systems is simplified by applying perturbation theory to estimate the energy changes caused by a movement in the MM system. This approximation, together with the effective use of GPU acceleration, leads to a negligible added computational cost for the sampling of the environment. Benchmark calculations are carried out to evaluate the impact of the approximations applied and the overall computational performance.

Recent developments of the quantum chemical cluster approach for modeling enzyme reactions.

PubMed

Siegbahn, Per E M; Himo, Fahmi

2009-06-01

The quantum chemical cluster approach for modeling enzyme reactions is reviewed. Recent applications have used cluster models much larger than before which have given new modeling insights. One important and rather surprising feature is the fast convergence with cluster size of the energetics of the reactions. Even for reactions with significant charge separation it has in some cases been possible to obtain full convergence in the sense that dielectric cavity effects from outside the cluster do not contribute to any significant extent. Direct comparisons between quantum mechanics (QM)-only and QM/molecular mechanics (MM) calculations for quite large clusters in a case where the results differ significantly have shown that care has to be taken when using the QM/MM approach where there is strong charge polarization. Insights from the methods used, generally hybrid density functional methods, have also led to possibilities to give reasonable error limits for the results. Examples are finally given from the most extensive study using the cluster model, the one of oxygen formation at the oxygen-evolving complex in photosystem II.

Benchmarking Quantum Mechanics/Molecular Mechanics (QM/MM) Methods on the Thymidylate Synthase-Catalyzed Hydride Transfer.

PubMed

Świderek, Katarzyna; Arafet, Kemel; Kohen, Amnon; Moliner, Vicent

2017-03-14

Given the ubiquity of hydride-transfer reactions in enzyme-catalyzed processes, identifying the appropriate computational method for evaluating such biological reactions is crucial to perform theoretical studies of these processes. In this paper, the hydride-transfer step catalyzed by thymidylate synthase (TSase) is studied by examining hybrid quantum mechanics/molecular mechanics (QM/MM) potentials via multiple semiempirical methods and the M06-2X hybrid density functional. Calculations of protium and tritium transfer in these reactions across a range of temperatures allowed calculation of the temperature dependence of kinetic isotope effects (KIE). Dynamics and quantum-tunneling effects are revealed to have little effect on the reaction rate, but are significant in determining the KIEs and their temperature dependence. A good agreement with experiments is found, especially when computed for RM1/MM simulations. The small temperature dependence of quantum tunneling corrections and the quasiclassical contribution term cancel each other, while the recrossing transmission coefficient seems to be temperature-independent over the interval of 5-40 °C.

A Practical Quantum Mechanics Molecular Mechanics Method for the Dynamical Study of Reactions in Biomolecules.

PubMed

Mendieta-Moreno, Jesús I; Marcos-Alcalde, Iñigo; Trabada, Daniel G; Gómez-Puertas, Paulino; Ortega, José; Mendieta, Jesús

2015-01-01

Quantum mechanics/molecular mechanics (QM/MM) methods are excellent tools for the modeling of biomolecular reactions. Recently, we have implemented a new QM/MM method (Fireball/Amber), which combines an efficient density functional theory method (Fireball) and a well-recognized molecular dynamics package (Amber), offering an excellent balance between accuracy and sampling capabilities. Here, we present a detailed explanation of the Fireball method and Fireball/Amber implementation. We also discuss how this tool can be used to analyze reactions in biomolecules using steered molecular dynamics simulations. The potential of this approach is shown by the analysis of a reaction catalyzed by the enzyme triose-phosphate isomerase (TIM). The conformational space and energetic landscape for this reaction are analyzed without a priori assumptions about the protonation states of the different residues during the reaction. The results offer a detailed description of the reaction and reveal some new features of the catalytic mechanism. In particular, we find a new reaction mechanism that is characterized by the intramolecular proton transfer from O1 to O2 and the simultaneous proton transfer from Glu 165 to C2. Copyright © 2015 Elsevier Inc. All rights reserved.

Role of substrate dynamics in protein prenylation reactions.

PubMed

Chakravorty, Dhruva K; Merz, Kenneth M

2015-02-17

CONSPECTUS: The role dynamics plays in proteins is of intense contemporary interest. Fundamental insights into how dynamics affects reactivity and product distributions will facilitate the design of novel catalysts that can produce high quality compounds that can be employed, for example, as fuels and life saving drugs. We have used molecular dynamics (MD) methods and combined quantum mechanical/molecular mechanical (QM/MM) methods to study a series of proteins either whose substrates are too far away from the catalytic center or whose experimentally resolved substrate binding modes cannot explain the observed product distribution. In particular, we describe studies of farnesyl transferase (FTase) where the farnesyl pyrophosphate (FPP) substrate is ∼8 Å from the zinc-bound peptide in the active site of FTase. Using MD and QM/MM studies, we explain how the FPP substrate spans the gulf between it and the active site, and we have elucidated the nature of the transition state (TS) and offered an alternate explanation of experimentally observed kinetic isotope effects (KIEs). Our second story focuses on the nature of substrate dynamics in the aromatic prenyltransferase (APTase) protein NphB and how substrate dynamics affects the observed product distribution. Through the examples chosen we show the power of MD and QM/MM methods to provide unique insights into how protein substrate dynamics affects catalytic efficiency. We also illustrate how complex these reactions are and highlight the challenges faced when attempting to design de novo catalysts. While the methods used in our previous studies provided useful insights, several clear challenges still remain. In particular, we have utilized a semiempirical QM model (self-consistent charge density functional tight binding, SCC-DFTB) in our QM/MM studies since the problems we were addressing required extensive sampling. For the problems illustrated, this approach performed admirably (we estimate for these systems an uncertainty of ∼2 kcal/mol), but it is still a semiempirical model, and studies of this type would benefit greatly from more accurate ab initio or DFT models. However, the challenge with these methods is to reach the level of sampling needed to study systems where large conformational changes happen in the many nanoseconds to microsecond time regimes. Hence, how to couple expensive and accurate QM methods with sophisticated sampling algorithms is an important future challenge especially when large-scale studies of catalyst design become of interest. The use of MD and QM/MM models to elucidate enzyme catalytic pathways and to design novel catalytic agents is in its infancy but shows tremendous promise. While this Account summarizes where we have been, we also discuss briefly future directions that improve our fundamental ability to understand enzyme catalysis.

Approximation solution of Schrodinger equation for Q-deformed Rosen-Morse using supersymmetry quantum mechanics (SUSY QM)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alemgadmi, Khaled I. K., E-mail: azozkied@yahoo.com; Suparmi; Cari

2015-09-30

The approximate analytical solution of Schrodinger equation for Q-Deformed Rosen-Morse potential was investigated using Supersymmetry Quantum Mechanics (SUSY QM) method. The approximate bound state energy is given in the closed form and the corresponding approximate wave function for arbitrary l-state given for ground state wave function. The first excited state obtained using upper operator and ground state wave function. The special case is given for the ground state in various number of q. The existence of Rosen-Morse potential reduce energy spectra of system. The larger value of q, the smaller energy spectra of system.

Theoretical approaches for dynamical ordering of biomolecular systems.

PubMed

Okumura, Hisashi; Higashi, Masahiro; Yoshida, Yuichiro; Sato, Hirofumi; Akiyama, Ryo

2018-02-01

Living systems are characterized by the dynamic assembly and disassembly of biomolecules. The dynamical ordering mechanism of these biomolecules has been investigated both experimentally and theoretically. The main theoretical approaches include quantum mechanical (QM) calculation, all-atom (AA) modeling, and coarse-grained (CG) modeling. The selected approach depends on the size of the target system (which differs among electrons, atoms, molecules, and molecular assemblies). These hierarchal approaches can be combined with molecular dynamics (MD) simulation and/or integral equation theories for liquids, which cover all size hierarchies. We review the framework of quantum mechanical/molecular mechanical (QM/MM) calculations, AA MD simulations, CG modeling, and integral equation theories. Applications of these methods to the dynamical ordering of biomolecular systems are also exemplified. The QM/MM calculation enables the study of chemical reactions. The AA MD simulation, which omits the QM calculation, can follow longer time-scale phenomena. By reducing the number of degrees of freedom and the computational cost, CG modeling can follow much longer time-scale phenomena than AA modeling. Integral equation theories for liquids elucidate the liquid structure, for example, whether the liquid follows a radial distribution function. These theoretical approaches can analyze the dynamic behaviors of biomolecular systems. They also provide useful tools for exploring the dynamic ordering systems of biomolecules, such as self-assembly. This article is part of a Special Issue entitled "Biophysical Exploration of Dynamical Ordering of Biomolecular Systems" edited by Dr. Koichi Kato. Copyright © 2017 Elsevier B.V. All rights reserved.

Charge-dependent many-body exchange and dispersion interactions in combined QM/MM simulations

NASA Astrophysics Data System (ADS)

Kuechler, Erich R.; Giese, Timothy J.; York, Darrin M.

2015-12-01

Accurate modeling of the molecular environment is critical in condensed phase simulations of chemical reactions. Conventional quantum mechanical/molecular mechanical (QM/MM) simulations traditionally model non-electrostatic non-bonded interactions through an empirical Lennard-Jones (LJ) potential which, in violation of intuitive chemical principles, is bereft of any explicit coupling to an atom's local electronic structure. This oversight results in a model whereby short-ranged exchange-repulsion and long-ranged dispersion interactions are invariant to changes in the local atomic charge, leading to accuracy limitations for chemical reactions where significant atomic charge transfer can occur along the reaction coordinate. The present work presents a variational, charge-dependent exchange-repulsion and dispersion model, referred to as the charge-dependent exchange and dispersion (QXD) model, for hybrid QM/MM simulations. Analytic expressions for the energy and gradients are provided, as well as a description of the integration of the model into existing QM/MM frameworks, allowing QXD to replace traditional LJ interactions in simulations of reactive condensed phase systems. After initial validation against QM data, the method is demonstrated by capturing the solvation free energies of a series of small, chlorine-containing compounds that have varying charge on the chlorine atom. The model is further tested on the SN2 attack of a chloride anion on methylchloride. Results suggest that the QXD model, unlike the traditional LJ model, is able to simultaneously obtain accurate solvation free energies for a range of compounds while at the same time closely reproducing the experimental reaction free energy barrier. The QXD interaction model allows explicit coupling of atomic charge with many-body exchange and dispersion interactions that are related to atomic size and provides a more accurate and robust representation of non-electrostatic non-bonded QM/MM interactions.

Multicale modeling of the detonation of aluminized explosives using SPH-MD-QM method

NASA Astrophysics Data System (ADS)

Peng, Qing; Wang, Guangyu; Liu, Gui-Rong; de, Suvranu

Aluminized explosives have been applied in military industry since decades ago. Compared with ideal explosives, aluminized explosives feature both fast detonation and slow metal combustion chemistry, generating a complex multi-phase reactive flow. Here, we introduce a sequential multiscale model of SPH-MD-QM to simulate the detonation behavior of aluminized explosives. At the bottom level, first-principles quantum mechanics (QM) calculations are employed to obtain the training sets for fitting the ReaxFF potentials, which are used in turn in the reactive molecular dynamics (MD) simulations in the middle level to obtain the chemical reaction rates and equations of states. At the up lever, a smooth particle hydrodynamics (SPH) method incorporated ignition and growth model and afterburning model has been used for the simulation of the detonation and combustion of the aluminized explosive. Simulation is compared with experiment and good agreement is observed. The proposed multiscale method of SPH-MD-QM could be used to optimize the performance of aluminized explosives. The authors would like to acknowledge the generous financial support from the Defense Threat Reduction Agency (DTRA) Grant No. HDTRA1-13-1-0025 and the Office of Naval Research Grants ONR Award No. N00014-08-1-0462 and No. N00014-12-1-0527.

Proliferation of Observables and Measurement in Quantum-Classical Hybrids

NASA Astrophysics Data System (ADS)

Elze, Hans-Thomas

2012-01-01

Following a review of quantum-classical hybrid dynamics, we discuss the ensuing proliferation of observables and relate it to measurements of (would-be) quantum mechanical degrees of freedom performed by (would-be) classical ones (if they were separable). Hybrids consist in coupled classical (CL) and quantum mechanical (QM) objects. Numerous consistency requirements for their description have been discussed and are fulfilled here. We summarize a representation of quantum mechanics in terms of classical analytical mechanics which is naturally extended to QM-CL hybrids. This framework allows for superposition, separable, and entangled states originating in the QM sector, admits experimenter's "Free Will", and is local and nonsignaling. Presently, we study the set of hybrid observables, which is larger than the Cartesian product of QM and CL observables of its components; yet it is smaller than a corresponding product of all-classical observables. Thus, quantumness and classicality infect each other.

Simulation Studies of Mechanical Properties of Novel Silica Nano-structures

NASA Astrophysics Data System (ADS)

Muralidharan, Krishna; Torras Costa, Joan; Trickey, Samuel B.

2006-03-01

Advances in nanotechnology and the importance of silica as a technological material continue to stimulate computational study of the properties of possible novel silica nanostructures. Thus we have done classical molecular dynamics (MD) and multi-scale quantum mechanical (QM/MD) simulation studies of the mechanical properties of single-wall and multi-wall silica nano-rods of varying dimensions. Such nano-rods have been predicted by Mallik et al. to be unusually strong in tensile failure. Here we compare failure mechanisms of such nano-rods under tension, compression, and bending. The concurrent multi-scale QM/MD studies use the general PUPIL system (Torras et al.). In this case, PUPIL provides automated interoperation of the MNDO Transfer Hamiltonian QM code (Taylor et al.) and a locally written MD code. Embedding of the QM-forces domain is via the scheme of Mallik et al. Work supported by NSF ITR award DMR-0325553.

Ethanol dehydration in HZSM-5 studied by density functional theory: evidence for a concerted process.

PubMed

Kim, Seonah; Robichaud, David J; Beckham, Gregg T; Paton, Robert S; Nimlos, Mark R

2015-04-16

Dehydration over acidic zeolites is an important reaction class for the upgrading of biomass pyrolysis vapors to hydrocarbon fuels or to precursors for myriad chemical products. Here, we examine the dehydration of ethanol at a Brønsted acid site, T12, found in HZSM-5 using density functional theory (DFT). The geometries of both cluster and mixed quantum mechanics/molecular mechanics (QM:MM) models are prepared from the ZSM-5 crystal structure. Comparisons between these models and different DFT methods are conducted to show similar results among the models and methods used. Inclusion of the full catalyst cavity through a QM:MM approach is found to be important, since activation barriers are computed on average as 7 kcal mol(-1) lower than those obtained with a smaller cluster model. Two different pathways, concerted and stepwise, have been considered when examining dehydration and deprotonation steps. The current study shows that a concerted dehydration process is possible with a lower (4-5 kcal mol(-1)) activation barrier while previous literature studies have focused on a stepwise mechanism. Overall, this work demonstrates that fairly high activation energies (∼50 kcal mol(-1)) are required for ethanol dehydration. A concerted mechanism is favored over a stepwise mechanism because charge separation in the transition state is minimized. QM:MM approaches appear to provide superior results to cluster calculations due to a more accurate representation of charges on framework oxygen atoms.

Complexity Reduction in Large Quantum Systems: Fragment Identification and Population Analysis via a Local Optimized Minimal Basis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mohr, Stephan; Masella, Michel; Ratcliff, Laura E.

We present, within Kohn-Sham Density Functional Theory calculations, a quantitative method to identify and assess the partitioning of a large quantum mechanical system into fragments. We then introduce a simple and efficient formalism (which can be written as generalization of other well-known population analyses) to extract, from first principles, electrostatic multipoles for these fragments. The corresponding fragment multipoles can in this way be seen as reliable (pseudo-) observables. By applying our formalism within the code BigDFT, we show that the usage of a minimal set of in-situ optimized basis functions is of utmost importance for having at the same timemore » a proper fragment definition and an accurate description of the electronic structure. With this approach it becomes possible to simplify the modeling of environmental fragments by a set of multipoles, without notable loss of precision in the description of the active quantum mechanical region. Furthermore, this leads to a considerable reduction of the degrees of freedom by an effective coarsegraining approach, eventually also paving the way towards efficient QM/QM and QM/MM methods coupling together different levels of accuracy.« less

Complexity Reduction in Large Quantum Systems: Fragment Identification and Population Analysis via a Local Optimized Minimal Basis

DOE PAGES

Mohr, Stephan; Masella, Michel; Ratcliff, Laura E.; ...

2017-07-21

We present, within Kohn-Sham Density Functional Theory calculations, a quantitative method to identify and assess the partitioning of a large quantum mechanical system into fragments. We then introduce a simple and efficient formalism (which can be written as generalization of other well-known population analyses) to extract, from first principles, electrostatic multipoles for these fragments. The corresponding fragment multipoles can in this way be seen as reliable (pseudo-) observables. By applying our formalism within the code BigDFT, we show that the usage of a minimal set of in-situ optimized basis functions is of utmost importance for having at the same timemore » a proper fragment definition and an accurate description of the electronic structure. With this approach it becomes possible to simplify the modeling of environmental fragments by a set of multipoles, without notable loss of precision in the description of the active quantum mechanical region. Furthermore, this leads to a considerable reduction of the degrees of freedom by an effective coarsegraining approach, eventually also paving the way towards efficient QM/QM and QM/MM methods coupling together different levels of accuracy.« less

Protein Structure Validation and Refinement Using Amide Proton Chemical Shifts Derived from Quantum Mechanics

PubMed Central

Christensen, Anders S.; Linnet, Troels E.; Borg, Mikael; Boomsma, Wouter; Lindorff-Larsen, Kresten; Hamelryck, Thomas; Jensen, Jan H.

2013-01-01

We present the ProCS method for the rapid and accurate prediction of protein backbone amide proton chemical shifts - sensitive probes of the geometry of key hydrogen bonds that determine protein structure. ProCS is parameterized against quantum mechanical (QM) calculations and reproduces high level QM results obtained for a small protein with an RMSD of 0.25 ppm (r = 0.94). ProCS is interfaced with the PHAISTOS protein simulation program and is used to infer statistical protein ensembles that reflect experimentally measured amide proton chemical shift values. Such chemical shift-based structural refinements, starting from high-resolution X-ray structures of Protein G, ubiquitin, and SMN Tudor Domain, result in average chemical shifts, hydrogen bond geometries, and trans-hydrogen bond (h3 JNC') spin-spin coupling constants that are in excellent agreement with experiment. We show that the structural sensitivity of the QM-based amide proton chemical shift predictions is needed to obtain this agreement. The ProCS method thus offers a powerful new tool for refining the structures of hydrogen bonding networks to high accuracy with many potential applications such as protein flexibility in ligand binding. PMID:24391900

`Quantum Mechanics' and `Scientific Explanation' An Explanatory Strategy Aiming at Providing `Understanding'

NASA Astrophysics Data System (ADS)

Hadzidaki, Pandora

2008-01-01

Empirical studies persistently indicate that the usual explanatory strategies used in quantum mechanics (QM) instruction fail, in general, to yield understanding. In this study, we propose an instructional intervention, which: (a) incorporates into its subject matter a critical comparison of QM scientific content with the fundamental epistemological and ontological commitments of the prominent philosophical theories of explanation, a weak form of which we meet in QM teaching; (b) illuminates the reasons of their failure in the quantum domain; and (c) implements an explanatory strategy highly inspired by the epistemological pathways through which, during the birth-process of QM, science has gradually reached understanding. This strategy, an inherent element of which is the meta-cognitive and meta-scientific thinking, aims at leading learners not only to an essential understanding of QM worldview, but to a deep insight into the ‘Nature of Science’ as well.

Efficient parallel implementations of QM/MM-REMD (quantum mechanical/molecular mechanics-replica-exchange MD) and umbrella sampling: isomerization of H2O2 in aqueous solution.

PubMed

Fedorov, Dmitri G; Sugita, Yuji; Choi, Cheol Ho

2013-07-03

An efficient parallel implementation of QM/MM-based replica-exchange molecular dynamics (REMD) as well as umbrella samplings techniques was proposed by adopting the generalized distributed data interface (GDDI). Parallelization speed-up of 40.5 on 48 cores was achieved, making our QM/MM-MD engine a robust tool for studying complex chemical dynamics in solution. They were comparatively used to study the torsional isomerization of hydrogen peroxide in aqueous solution. All results by QM/MM-REMD and QM/MM umbrella sampling techniques yielded nearly identical potentials of mean force (PMFs) regardless of the particular QM theories for solute, showing that the overall dynamics are mainly determined by solvation. Although the entropic penalty of solvent rearrangements exists in cisoid conformers, it was found that both strong intermolecular hydrogen bonding and dipole-dipole interactions preferentially stabilize them in solution, reducing the torsional free-energy barrier at 0° by about 3 kcal/mol as compared to that in gas phase.

Periodic boundary conditions for QM/MM calculations: Ewald summation for extended Gaussian basis sets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Holden, Zachary C.; Richard, Ryan M.; Herbert, John M., E-mail: herbert@chemistry.ohio-state.edu

2013-12-28

An implementation of Ewald summation for use in mixed quantum mechanics/molecular mechanics (QM/MM) calculations is presented, which builds upon previous work by others that was limited to semi-empirical electronic structure for the QM region. Unlike previous work, our implementation describes the wave function's periodic images using “ChElPG” atomic charges, which are determined by fitting to the QM electrostatic potential evaluated on a real-space grid. This implementation is stable even for large Gaussian basis sets with diffuse exponents, and is thus appropriate when the QM region is described by a correlated wave function. Derivatives of the ChElPG charges with respect tomore » the QM density matrix are a potentially serious bottleneck in this approach, so we introduce a ChElPG algorithm based on atom-centered Lebedev grids. The ChElPG charges thus obtained exhibit good rotational invariance even for sparse grids, enabling significant cost savings. Detailed analysis of the optimal choice of user-selected Ewald parameters, as well as timing breakdowns, is presented.« less

A "Stepping Stone" Approach for Obtaining Quantum Free Energies of Hydration.

PubMed

Sampson, Chris; Fox, Thomas; Tautermann, Christofer S; Woods, Christopher; Skylaris, Chris-Kriton

2015-06-11

We present a method which uses DFT (quantum, QM) calculations to improve free energies of binding computed with classical force fields (classical, MM). To overcome the incomplete overlap of configurational spaces between MM and QM, we use a hybrid Monte Carlo approach to generate quickly correct ensembles of structures of intermediate states between a MM and a QM/MM description, hence taking into account a great fraction of the electronic polarization of the quantum system, while being able to use thermodynamic integration to compute the free energy of transition between the MM and QM/MM. Then, we perform a final transition from QM/MM to full QM using a one-step free energy perturbation approach. By using QM/MM as a stepping stone toward the full QM description, we find very small convergence errors (<1 kJ/mol) in the transition to full QM. We apply this method to compute hydration free energies, and we obtain consistent improvements over the MM values for all molecules we used in this study. This approach requires large-scale DFT calculations as the full QM systems involved the ligands and all waters in their simulation cells, so the linear-scaling DFT code ONETEP was used for these calculations.

Water solvent effects using continuum and discrete models: The nitromethane molecule, CH3NO2.

PubMed

Modesto-Costa, Lucas; Uhl, Elmar; Borges, Itamar

2015-11-15

The first three valence transitions of the two nitromethane conformers (CH3NO2) are two dark n → π* transitions and a very intense π → π* transition. In this work, these transitions in gas-phase and solvated in water of both conformers were investigated theoretically. The polarizable continuum model (PCM), two conductor-like screening (COSMO) models, and the discrete sequential quantum mechanics/molecular mechanics (S-QM/MM) method were used to describe the solvation effect on the electronic spectra. Time dependent density functional theory (TDDFT), configuration interaction including all single substitutions and perturbed double excitations (CIS(D)), the symmetry-adapted-cluster CI (SAC-CI), the multistate complete active space second order perturbation theory (CASPT2), and the algebraic-diagrammatic construction (ADC(2)) electronic structure methods were used. Gas-phase CASPT2, SAC-CI, and ADC(2) results are in very good agreement with published experimental and theoretical spectra. Among the continuum models, PCM combined either with CASPT2, SAC-CI, or B3LYP provided good agreement with available experimental data. COSMO combined with ADC(2) described the overall trends of the transition energy shifts. The effect of increasing the number of explicit water molecules in the S-QM/MM approach was discussed and the formation of hydrogen bonds was clearly established. By including explicitly 24 water molecules corresponding to the complete first solvation shell in the S-QM/MM approach, the ADC(2) method gives more accurate results as compared to the TDDFT approach and with similar computational demands. The ADC(2) with S-QM/MM model is, therefore, the best compromise for accurate solvent calculations in a polar environment. © 2015 Wiley Periodicals, Inc.

QM/MM investigations of organic chemistry oriented questions.

PubMed

Schmidt, Thomas C; Paasche, Alexander; Grebner, Christoph; Ansorg, Kay; Becker, Johannes; Lee, Wook; Engels, Bernd

2014-01-01

About 35 years after its first suggestion, QM/MM became the standard theoretical approach to investigate enzymatic structures and processes. The success is due to the ability of QM/MM to provide an accurate atomistic picture of enzymes and related processes. This picture can even be turned into a movie if nuclei-dynamics is taken into account to describe enzymatic processes. In the field of organic chemistry, QM/MM methods are used to a much lesser extent although almost all relevant processes happen in condensed matter or are influenced by complicated interactions between substrate and catalyst. There is less importance for theoretical organic chemistry since the influence of nonpolar solvents is rather weak and the effect of polar solvents can often be accurately described by continuum approaches. Catalytic processes (homogeneous and heterogeneous) can often be reduced to truncated model systems, which are so small that pure quantum-mechanical approaches can be employed. However, since QM/MM becomes more and more efficient due to the success in software and hardware developments, it is more and more used in theoretical organic chemistry to study effects which result from the molecular nature of the environment. It is shown by many examples discussed in this review that the influence can be tremendous, even for nonpolar reactions. The importance of environmental effects in theoretical spectroscopy was already known. Due to its benefits, QM/MM can be expected to experience ongoing growth for the next decade.In the present chapter we give an overview of QM/MM developments and their importance in theoretical organic chemistry, and review applications which give impressions of the possibilities and the importance of the relevant effects. Since there is already a bunch of excellent reviews dealing with QM/MM, we will discuss fundamental ingredients and developments of QM/MM very briefly with a focus on very recent progress. For the applications we follow a similar strategy.

Derivation of Reliable Geometries in QM Calculations of DNA Structures: Explicit Solvent QM/MM and Restrained Implicit Solvent QM Optimizations of G-Quadruplexes.

PubMed

Gkionis, Konstantinos; Kruse, Holger; Šponer, Jiří

2016-04-12

Modern dispersion-corrected DFT methods have made it possible to perform reliable QM studies on complete nucleic acid (NA) building blocks having hundreds of atoms. Such calculations, although still limited to investigations of potential energy surfaces, enhance the portfolio of computational methods applicable to NAs and offer considerably more accurate intrinsic descriptions of NAs than standard MM. However, in practice such calculations are hampered by the use of implicit solvent environments and truncation of the systems. Conventional QM optimizations are spoiled by spurious intramolecular interactions and severe structural deformations. Here we compare two approaches designed to suppress such artifacts: partially restrained continuum solvent QM and explicit solvent QM/MM optimizations. We report geometry relaxations of a set of diverse double-quartet guanine quadruplex (GQ) DNA stems. Both methods provide neat structures without major artifacts. However, each one also has distinct weaknesses. In restrained optimizations, all errors in the target geometries (i.e., low-resolution X-ray and NMR structures) are transferred to the optimized geometries. In QM/MM, the initial solvent configuration causes some heterogeneity in the geometries. Nevertheless, both approaches represent a decisive step forward compared to conventional optimizations. We refine earlier computations that revealed sizable differences in the relative energies of GQ stems computed with AMBER MM and QM. We also explore the dependence of the QM/MM results on the applied computational protocol.

Hybrid molecular dynamics simulation for plasma induced damage analysis

NASA Astrophysics Data System (ADS)

Matsukuma, Masaaki

2016-09-01

In order to enable further device size reduction (also known as Moore's law) and improved power performance, the semiconductor industry is introducing new materials and device structures into the semiconductor fabrication process. Materials now include III-V compounds, germanium, cobalt, ruthenium, hafnium, and others. The device structure in both memory and logic has been evolving from planar to three dimensional (3D). One such device is the FinFET, where the transistor gate is a vertical fin made either of silicon, silicon-germanium or germanium. These changes have brought renewed interests in the structural damages caused by energetic ion bombardment of the fin sidewalls which are exposed to the ion flux from the plasma during the fin-strip off step. Better control of the physical damage of the 3D devices requires a better understanding of the damage formation mechanisms on such new materials and structures. In this study, the damage formation processes by ion bombardment have been simulated for Si and Ge substrate by Quantum Mechanics/Molecular Mechanics (QM/MM) hybrid simulations and compared to the results from the classical molecular dynamics (MD) simulations. In our QM/MM simulations, the highly reactive region in which the structural damage is created is simulated with the Density Functional based Tight Binding (DFTB) method and the region remote from the primary region is simulated using classical MD with the Stillinger-Weber and Moliere potentials. The learn on the fly method is also used to reduce the computational load. Hence our QM/MM simulation is much faster than the full QC-MD simulations and the original QM/MM simulations. The amorphous layers profile simulated with QM/MM have obvious differences in their thickness for silicon and germanium substrate. The profile of damaged structure in the germanium substrate is characterized by a deeper tail then in silicon. These traits are also observed in the results from the mass selected ion beam experiments. This observed damage profile dependence on species and substrate cannot be reproduced using classical MD simulations. While the Moliere potential is convenient to describe the interactions between halogens and other atoms, more accurate interatomic modeling such as DFTB method which takes the molecular orbitals into account should be utilized to make the simulations more realistic. Based on the simulations results, the damage formation scenario will be discussed.

Born-Oppenheimer ab initio QM/MM Molecular Dynamics Simulations of Enzyme Reactions

PubMed Central

Zhou, Yanzi; Wang, Shenglong; Li, Yongle; Zhang, Yingkai

2016-01-01

There are two key requirements for reliably simulating enzyme reactions: one is a reasonably accurate potential energy surface to describe the bond forming/breaking process as well as to adequately model the heterogeneous enzyme environment; the other is to perform extensive sampling since an enzyme system consists of at least thousands of atoms and its energy landscape is very complex. One attractive approach to meet both daunting tasks is Born-Oppenheimer ab initio QM/MM molecular dynamics simulation (aiQM/MM-MD) with umbrella sampling. In this chapter, we describe our recently developed pseudobond Q-Chem–Amber interface, which employs a combined electrostatic-mechanical embedding scheme with periodic boundary condition and the particle mesh Ewald method for long-range electrostatics interactions. In our implementation, Q-Chem and the sander module of Amber are combined at the source code level without using system calls, and all necessary data communications between QM and MM calculations are achieved via computer memory. We demonstrate the applicability of this pseudobond Q-Chem–Amber interface by presenting two examples, one reaction in aqueous solution and one enzyme reaction. Finally, we describe our established aiQM/MM-MD enzyme simulation protocol, which has been successfully applied to study more than a dozen enzymes. PMID:27498636

QM/MM Molecular Dynamics Studies of Metal Binding Proteins

PubMed Central

Vidossich, Pietro; Magistrato, Alessandra

2014-01-01

Mixed quantum-classical (quantum mechanical/molecular mechanical (QM/MM)) simulations have strongly contributed to providing insights into the understanding of several structural and mechanistic aspects of biological molecules. They played a particularly important role in metal binding proteins, where the electronic effects of transition metals have to be explicitly taken into account for the correct representation of the underlying biochemical process. In this review, after a brief description of the basic concepts of the QM/MM method, we provide an overview of its capabilities using selected examples taken from our work. Specifically, we will focus on heme peroxidases, metallo-β-lactamases, α-synuclein and ligase ribozymes to show how this approach is capable of describing the catalytic and/or structural role played by transition (Fe, Zn or Cu) and main group (Mg) metals. Applications will reveal how metal ions influence the formation and reduction of high redox intermediates in catalytic cycles and enhance drug metabolism, amyloidogenic aggregate formation and nucleic acid synthesis. In turn, it will become manifest that the protein frame directs and modulates the properties and reactivity of the metal ions. PMID:25006697

Charge-dependent many-body exchange and dispersion interactions in combined QM/MM simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuechler, Erich R.; Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455-0431; Giese, Timothy J.

2015-12-21

Accurate modeling of the molecular environment is critical in condensed phase simulations of chemical reactions. Conventional quantum mechanical/molecular mechanical (QM/MM) simulations traditionally model non-electrostatic non-bonded interactions through an empirical Lennard-Jones (LJ) potential which, in violation of intuitive chemical principles, is bereft of any explicit coupling to an atom’s local electronic structure. This oversight results in a model whereby short-ranged exchange-repulsion and long-ranged dispersion interactions are invariant to changes in the local atomic charge, leading to accuracy limitations for chemical reactions where significant atomic charge transfer can occur along the reaction coordinate. The present work presents a variational, charge-dependent exchange-repulsion andmore » dispersion model, referred to as the charge-dependent exchange and dispersion (QXD) model, for hybrid QM/MM simulations. Analytic expressions for the energy and gradients are provided, as well as a description of the integration of the model into existing QM/MM frameworks, allowing QXD to replace traditional LJ interactions in simulations of reactive condensed phase systems. After initial validation against QM data, the method is demonstrated by capturing the solvation free energies of a series of small, chlorine-containing compounds that have varying charge on the chlorine atom. The model is further tested on the S{sub N}2 attack of a chloride anion on methylchloride. Results suggest that the QXD model, unlike the traditional LJ model, is able to simultaneously obtain accurate solvation free energies for a range of compounds while at the same time closely reproducing the experimental reaction free energy barrier. The QXD interaction model allows explicit coupling of atomic charge with many-body exchange and dispersion interactions that are related to atomic size and provides a more accurate and robust representation of non-electrostatic non-bonded QM/MM interactions.« less

A QM/MM-MD study on protein electronic properties: Circular dichroism spectra of oxytocin and insulin

NASA Astrophysics Data System (ADS)

Kitagawa, Yuya; Akinaga, Yoshinobu; Kawashima, Yukio; Jung, Jaewoon; Ten-no, Seiichiro

2012-06-01

A QM/MM (quantum-mechanical/molecular-mechanical) molecular-dynamics approach based on the generalized hybrid-orbital (GHO) method, in conjunction with the second-order perturbation (MP2) theory and the second-order approximate coupled-cluster (CC2) model, is employed to calculate electronic property accounting for a protein environment. Circular dichroism (CD) spectra originating from chiral disulfide bridges of oxytocin and insulin at room temperature are computed. It is shown that the sampling of thermal fluctuation of molecular geometries facilitated by the GHO-MD method plays an important role in the obtained spectra. It is demonstrated that, while the protein environments in an oxytocin molecule have significant electrostatic influence on its chiral center, it is compensated by solvent induced charges. This gives a reasonable explanation to experimental observations. GHO-MD simulations starting from different experimental structures of insulin indicate that existence of the disulfide bridges with negative dihedral angles is crucial.

Exploring chemical reaction mechanisms through harmonic Fourier beads path optimization.

PubMed

Khavrutskii, Ilja V; Smith, Jason B; Wallqvist, Anders

2013-10-28

Here, we apply the harmonic Fourier beads (HFB) path optimization method to study chemical reactions involving covalent bond breaking and forming on quantum mechanical (QM) and hybrid QM∕molecular mechanical (QM∕MM) potential energy surfaces. To improve efficiency of the path optimization on such computationally demanding potentials, we combined HFB with conjugate gradient (CG) optimization. The combined CG-HFB method was used to study two biologically relevant reactions, namely, L- to D-alanine amino acid inversion and alcohol acylation by amides. The optimized paths revealed several unexpected reaction steps in the gas phase. For example, on the B3LYP∕6-31G(d,p) potential, we found that alanine inversion proceeded via previously unknown intermediates, 2-iminopropane-1,1-diol and 3-amino-3-methyloxiran-2-ol. The CG-HFB method accurately located transition states, aiding in the interpretation of complex reaction mechanisms. Thus, on the B3LYP∕6-31G(d,p) potential, the gas phase activation barriers for the inversion and acylation reactions were 50.5 and 39.9 kcal∕mol, respectively. These barriers determine the spontaneous loss of amino acid chirality and cleavage of peptide bonds in proteins. We conclude that the combined CG-HFB method further advances QM and QM∕MM studies of reaction mechanisms.

Optimized and parallelized implementation of the electronegativity equalization method and the atom-bond electronegativity equalization method.

PubMed

Vareková, R Svobodová; Koca, J

2006-02-01

The most common way to calculate charge distribution in a molecule is ab initio quantum mechanics (QM). Some faster alternatives to QM have also been developed, the so-called "equalization methods" EEM and ABEEM, which are based on DFT. We have implemented and optimized the EEM and ABEEM methods and created the EEM SOLVER and ABEEM SOLVER programs. It has been found that the most time-consuming part of equalization methods is the reduction of the matrix belonging to the equation system generated by the method. Therefore, for both methods this part was replaced by the parallel algorithm WIRS and implemented within the PVM environment. The parallelized versions of the programs EEM SOLVER and ABEEM SOLVER showed promising results, especially on a single computer with several processors (compact PVM). The implemented programs are available through the Web page http://ncbr.chemi.muni.cz/~n19n/eem_abeem.

Performance of the AMOEBA Water Model in the Vicinity of QM Solutes: A Diagnosis Using Energy Decomposition Analysis.

PubMed

Mao, Yuezhi; Shao, Yihan; Dziedzic, Jacek; Skylaris, Chris-Kriton; Head-Gordon, Teresa; Head-Gordon, Martin

2017-05-09

The importance of incorporating solvent polarization effects into the modeling of solvation processes has been well-recognized, and therefore a new generation of hybrid quantum mechanics/molecular mechanics (QM/MM) approaches that accounts for this effect is desirable. We present a fully self-consistent, mutually polarizable QM/MM scheme using the AMOEBA force field, in which the total energy of the system is variationally minimized with respect to both the QM electronic density and the MM induced dipoles. This QM/AMOEBA model is implemented through the Q-Chem/LibEFP code interface and then applied to the evaluation of solute-solvent interaction energies for various systems ranging from the water dimer to neutral and ionic solutes (NH 3 , NH 4 + , CN - ) surrounded by increasing numbers of water molecules (up to 100). In order to analyze the resulting interaction energies, we also utilize an energy decomposition analysis (EDA) scheme which identifies contributions from permanent electrostatics, polarization, and van der Waals (vdW) interaction for the interaction between the QM solute and the solvent molecules described by AMOEBA. This facilitates a component-wise comparison against full QM calculations where the corresponding energy components are obtained via a modified version of the absolutely localized molecular orbitals (ALMO)-EDA. The results show that the present QM/AMOEBA model can yield reasonable solute-solvent interaction energies for neutral and cationic species, while further scrutiny reveals that this accuracy highly relies on the delicate balance between insufficiently favorable permanent electrostatics and softened vdW interaction. For anionic solutes where the charge penetration effect becomes more pronounced, the QM/MM interface turns out to be unbalanced. These results are consistent with and further elucidate our findings in a previous study using a slightly different QM/AMOEBA model ( Dziedzic et al. J. Chem. Phys. 2016 , 145 , 124106 ). The implications of these results for further refinement of this model are also discussed.

Quantum-mechanical engines working with an ideal gas with a finite number of particles confined in a power-law trap

NASA Astrophysics Data System (ADS)

Wang, Jianhui; Ma, Yongli; He, Jizhou

2015-07-01

Based on quantum thermodynamic processes, we make a quantum-mechanical (QM) extension of the typical heat engine cycles, such as the Carnot, Brayton, Otto, Diesel cycles, etc., with no introduction of the concept of temperature. When these QM engine cycles are implemented by an ideal gas confined in an arbitrary power-law trap, a relation between the quantum adiabatic exponent and trap exponent is found. The differences and similarities between the efficiency of a given QM engine cycle and its classical counterpart are revealed and discussed.

An overview of the transactional interpretation of quantum mechanics

NASA Astrophysics Data System (ADS)

Cramer, J. G.

We summarize the transactional interpretation (TI) of quantum mechanics (QM) and consider various points concerning the TI and its relation to the Copenhagen interpretation (CI). Questions concerning mapping the TI onto the CI, of advanced waves as solutions to proper wave equations, of collapse and the QM formalism, and of the relation of quantum mechanical interpretations to experimental tests and results are discussed.

Probing students’ conceptions at the classical-quantum interface

NASA Astrophysics Data System (ADS)

Chhabra, Mahima; Das, Ritwick

2018-03-01

Quantum mechanics (QM) is one of the core subject areas in the undergraduate physics curriculum and many of the advanced level physics courses involve direct or indirect application of the concepts and ideas taught in QM. On the other hand, proper understanding of QM interpretations requires an optimum level of understanding of fundamental concepts in classical physics such as energy, momentum, force and their role in determining motion of the particle. This study is an attempt to explore a group of undergraduate students’ mental models regarding fundamental concepts in classical physics which are actually the stepping stone for understanding and visualisation of QM. The data and analysis presented here elucidate the challenges students face to understand the classical ideas and how that affects their understanding of QM.

Quantum chemical study of the mechanism of action of vitamin K epoxide reductase (VKOR)

NASA Astrophysics Data System (ADS)

Deerfield, David, II; Davis, Charles H.; Wymore, Troy; Stafford, Darrel W.; Pedersen, Lee G.

Possible model, but simplistic, mechanisms for the action of vitamin K epoxide reductase (VKOR) are investigated with quantum mechanical methods (B3LYP/6-311G**). The geometries of proposed model intermediates in the mechanisms are energy optimized. Finally, the energetics of the proposed (pseudo-enzymatic) pathways are compared. We find that the several pathways are all energetically feasible. These results will be useful for designing quantum mechanical/molecular mechanical method (QM/MM) studies of the enzymatic pathway once three-dimensional structural data are determined and available for VKOR.

Performance of PZT8 Versus PZT4 Piezoceramic Materials in Ultrasonic Transducers

NASA Astrophysics Data System (ADS)

DeAngelis, Dominick A.; Schulze, Gary W.

PZT8 and PZT4 are the common "hard" piezoceramic materials used in power ultrasonic transducers (e.g., welding, cutting, sonar, etc.). PZT8 is perceived as the better choice for resonant devices, primarily due to its higher mechanical quality factor Qm. PZT8 is also considered a "harder" material compared to PZT4, since it has better stability at higher preloads and drive levels. Many transducer designers never consider PZT4 for their applications, even though it has clear advantages such as higher output (i.e., higher d33). Even the perceived advantage of PZT8 regarding Qm may not be significant for most Langevin, bolted stack type transducers if the mechanical joint losses dominate. This research is a case study on the performance of identical ultrasonic transducers used for semiconductor wire bonding, assembled with either PZT8 or PZT4 materials. The main purpose of the study is to establish rule-of-thumb transducer design guidelines for the selection of PZT8 versus PZT4 materials. Several metrics are investigated such as impedance, frequency, capacitance, dielectric loss, Qm, heating, displacement gain, and electro-mechanical coupling factor. The experimental and theoretical research methods include Bode plots, thermal IR camera imaging, scanning laser vibrometry and coupled-field finite element analysis.

Solvent Boundary Potentials for Hybrid QM/MM Computations Using Classical Drude Oscillators: A Fully Polarizable Model.

PubMed

Boulanger, Eliot; Thiel, Walter

2012-11-13

Accurate quantum mechanical/molecular mechanical (QM/MM) treatments should account for MM polarization and properly include long-range electrostatic interactions. We report on a development that covers both these aspects. Our approach combines the classical Drude oscillator (DO) model for the electronic polarizability of the MM atoms with the generalized solvent boundary Potential (GSBP) and the solvated macromolecule boundary potential (SMBP). These boundary potentials (BP) are designed to capture the long-range effects of the outer region of a large system on its interior. They employ a finite difference approximation to the Poisson-Boltzmann equation for computing electrostatic interactions and take into account outer-region bulk solvent through a polarizable dielectric continuum (PDC). This approach thus leads to fully polarizable three-layer QM/MM-DO/BP methods. As the mutual responses of each of the subsystems have to be taken into account, we propose efficient schemes to converge the polarization of each layer simultaneously. For molecular dynamics (MD) simulations using GSBP, this is achieved by considering the MM polarizable model as a dynamical degree of freedom, and hence contributions from the boundary potential can be evaluated for a frozen state of polarization at every time step. For geometry optimizations using SMBP, we propose a dual self-consistent field approach for relaxing the Drude oscillators to their ideal positions and converging the QM wave function with the proper boundary potential. The chosen coupling schemes are evaluated with a test system consisting of a glycine molecule in a water ball. Both boundary potentials are capable of properly reproducing the gradients at the inner-region atoms and the Drude oscillators. We show that the effect of the Drude oscillators must be included in all terms of the boundary potentials to obtain accurate results and that the use of a high dielectric constant for the PDC does not lead to a polarization catastrophe of the DO models. Optimum values for some key parameters are discussed. We also address the efficiency of these approaches compared to standard QM/MM-DO calculations without BP. In the SMBP case, computation times can be reduced by around 40% for each step of a geometry optimization, with some variation depending on the chosen QM method. In the GSBP case, the computational advantages of using the boundary potential increase with system size and with the number of MD steps.

Development of massive multilevel molecular dynamics simulation program, Platypus (PLATform for dYnamic Protein Unified Simulation), for the elucidation of protein functions.

PubMed

Takano, Yu; Nakata, Kazuto; Yonezawa, Yasushige; Nakamura, Haruki

2016-05-05

A massively parallel program for quantum mechanical-molecular mechanical (QM/MM) molecular dynamics simulation, called Platypus (PLATform for dYnamic Protein Unified Simulation), was developed to elucidate protein functions. The speedup and the parallelization ratio of Platypus in the QM and QM/MM calculations were assessed for a bacteriochlorophyll dimer in the photosynthetic reaction center (DIMER) on the K computer, a massively parallel computer achieving 10 PetaFLOPs with 705,024 cores. Platypus exhibited the increase in speedup up to 20,000 core processors at the HF/cc-pVDZ and B3LYP/cc-pVDZ, and up to 10,000 core processors by the CASCI(16,16)/6-31G** calculations. We also performed excited QM/MM-MD simulations on the chromophore of Sirius (SIRIUS) in water. Sirius is a pH-insensitive and photo-stable ultramarine fluorescent protein. Platypus accelerated on-the-fly excited-state QM/MM-MD simulations for SIRIUS in water, using over 4000 core processors. In addition, it also succeeded in 50-ps (200,000-step) on-the-fly excited-state QM/MM-MD simulations for the SIRIUS in water. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.

Insights into the mechanism and inhibition of fatty acid amide hydrolase from quantum mechanics/molecular mechanics (QM/MM) modelling.

PubMed

Lodola, Alessio; Mor, Marco; Sirirak, Jitnapa; Mulholland, Adrian J

2009-04-01

FAAH (fatty acid amide hydrolase) is a promising target for the treatment of several central nervous system and peripheral disorders. Combined QM/MM (quantum mechanics/molecular mechanics) calculations have elucidated the role of its unusual catalytic triad in the hydrolysis of oleamide and oleoylmethyl ester substrates, and have identified the productive inhibitor-binding orientation for the carbamoylating compound URB524. These are potentially crucial insights for designing new covalent inhibitors of this drug target.

Møller-Plesset perturbation theory gradient in the generalized hybrid orbital quantum mechanical and molecular mechanical method

NASA Astrophysics Data System (ADS)

Jung, Jaewoon; Sugita, Yuji; Ten-no, S.

2010-02-01

An analytic gradient expression is formulated and implemented for the second-order Møller-Plesset perturbation theory (MP2) based on the generalized hybrid orbital QM/MM method. The method enables us to obtain an accurate geometry at a reasonable computational cost. The performance of the method is assessed for various isomers of alanine dipepetide. We also compare the optimized structures of fumaramide-derived [2]rotaxane and cAMP-dependent protein kinase with experiment.

QMMMW: A wrapper for QM/MM simulations with QUANTUM ESPRESSO and LAMMPS

NASA Astrophysics Data System (ADS)

Ma, Changru; Martin-Samos, Layla; Fabris, Stefano; Laio, Alessandro; Piccinin, Simone

2015-10-01

We present QMMMW, a new program aimed at performing Quantum Mechanics/Molecular Mechanics (QM/MM) molecular dynamics. The package operates as a wrapper that patches PWscf code included in the QUANTUM ESPRESSO distribution and LAMMPS Molecular Dynamics Simulator. It is designed with a paradigm based on three guidelines: (i) minimal amount of modifications on the parent codes, (ii) flexibility and computational efficiency of the communication layer and (iii) accuracy of the Hamiltonian describing the interaction between the QM and MM subsystems. These three features are seldom present simultaneously in other implementations of QMMM. The QMMMW project is hosted by qe-forge at

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thompson, M.A.; Schenter, G.K.

We present a hybrid quantum mechanical/molecular mechanical (QM/MM) model for microscopic solvation effects that includes polarizability in the MM region (QM/MMpol). QM/MMpol treatment of both ground and excited states is presented in the formalism. We present QM/MMpol analysis of the ground and electronic excited states of the bacteriochlorophyll b dimer (P) of the photosynthetic reaction center (RC) of Rhodopseudomonas viridis using the INDO/S method. The static-charge potential from the MM model of the RC alone causes Q{sub y1} to have significantly better agreement with the Stark effect results than isolated P. However, consideration of the protein polarization potential is furthermore » required to obtain more complete agreement with Stark effect experiments. Thus, we calculate a Q{sub y1} transition energy at 10826 cm{sup -1} with a ground to excited state change in dipole moment of 4.8 D; an absorption Stark effect angle of 43{degree}; a net shift of 0.15 electrons from the L subunit to the M subunit of P; and a linear dichroism angle (between the transition moment of Q{sub y1} and the pseudo-C{sub 2} axis of the RC) of 81{degree}. These results are in good agreement with experiment. Interestingly, we find that net CT increase is greater for Q{sub y1} than for the second excited state of P (Q{sub y2}), a result that we anticipated in an early model dimer study. 77 refs., 3 figs., 2 tabs.« less

Ultrafast Adiabatic Photodehydration of 2-Hydroxymethylphenol and the Formation of Quinone Methide.

PubMed

Škalamera, Đani; Antol, Ivana; Mlinarić-Majerski, Kata; Vančik, Hrvoj; Phillips, David Lee; Ma, Jiani; Basarić, Nikola

2018-04-20

The photochemical reactivity of 2-hydroxymethylphenol (1) was investigated experimentally by photochemistry under cryogenic conditions, by detecting reactive intermediates by IR spectroscopy, and by using nanosecond and femtosecond transient absorption spectroscopic methods in solution at room temperature. In addition, theoretical studies were performed to facilitate the interpretation of the experimental results and also to simulate the reaction pathway to obtain a better understanding of the reaction mechanism. The main finding of this work is that photodehydration of 1 takes place in an ultrafast adiabatic photochemical reaction without any clear intermediate, delivering quinone methide (QM) in the excited state. Upon photoexcitation to a higher vibrational level of the singlet excited state, 1 undergoes vibrational relaxation leading to two photochemical pathways, one by which synchronous elimination of H 2 O gives QM 2 in its S 1 state and the other by which homolytic cleavage of the phenolic O-H bond produces a phenoxyl radical (S 0 ). Both are ultrafast processes that occur within a picosecond. The excited state of QM 2 (S 1 ) probably deactivates to S 0 through a conical intersection to give QM 2 (S 0 ), which subsequently delivers benzoxete 4. Elucidation of the reaction mechanisms for the photodehydration of phenols by which QMs are formed is important to tune the reactivity of QMs with DNA and proteins for the potential application of QMs in medicine as therapeutic agents. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

How Large Should the QM Region Be in QM/MM Calculations? The Case of Catechol O -Methyltransferase

DOE PAGES

Kulik, Heather J.; Zhang, Jianyu; Klinman, Judith P.; ...

2016-10-05

Hybrid quantum mechanical–molecular mechanical (QM/MM) simulations are widely used in studies of enzymatic catalysis. Until recently, it has been cost prohibitive to determine the asymptotic limit of key energetic and structural properties with respect to increasingly large QM regions. Here, leveraging recent advances in electronic structure efficiency and accuracy, we investigate catalytic properties in catechol O-methyltransferase, a prototypical methyltransferase critical to human health. Using QM regions ranging in size from reactants-only (64 atoms) to nearly one-third of the entire protein (940 atoms), we show that properties such as the activation energy approach within chemical accuracy of the large-QM asymptotic limitsmore » rather slowly, requiring approximately 500–600 atoms if the QM residues are chosen simply by distance from the substrate. This slow approach to asymptotic limit is due to charge transfer from protein residues to the reacting substrates. Our large QM/MM calculations enable identification of charge separation for fragments in the transition state as a key component of enzymatic methyl transfer rate enhancement. We introduce charge shift analysis that reveals the minimum number of protein residues (approximately 11–16 residues or 200–300 atoms for COMT) needed for quantitative agreement with large-QM simulations. The identified residues are not those that would be typically selected using criteria such as chemical intuition or proximity. These results provide a recipe for a more careful determination of QM region sizes in future QM/MM studies of enzymes.« less

Effect of Solvation on Electron Detachment and Excitation Energies of a Green Fluorescent Protein Chromophore Variant.

PubMed

Bose, Samik; Chakrabarty, Suman; Ghosh, Debashree

2016-05-19

Hybrid quantum mechanics/molecular mechanics (QM/MM) is applied to the fluorinated green fluorescent protein (GFP) chromophore (DFHBDI) in its deprotonated form to understand the solvatochromic shifts in its vertical detachment energy (VDE) and vertical excitation energy (VEE). This variant of the GFP chromophore becomes fluorescent in an RNA environment and has a wide range of applications in biomedical and biochemical fields. From microsolvation studies, we benchmark (with respect to full QM) the accuracy of our QM/MM calculations with effective fragment potential (EFP) as the MM method of choice. We show that while the solvatochromic shift in the VEE is minimal (0.1 eV blue shift) and its polarization component is only 0.03 eV, the effect of the solvent on the VDE is quite large (3.85 eV). We also show by accurate calculations on the solvatochromic shift of the VDE that polarization accounts for ∼0.23 eV and therefore cannot be neglected. The effect of the counterions on the VDE of the deprotonated chromophore in solvation is studied in detail, and a charge-smearing scheme is suggested for charged chromophores.

Quantum mechanics/molecular mechanics modeling of photoelectron spectra: the carbon 1s core-electron binding energies of ethanol-water solutions.

PubMed

Löytynoja, T; Niskanen, J; Jänkälä, K; Vahtras, O; Rinkevicius, Z; Ågren, H

2014-11-20

Using ethanol-water solutions as illustration, we demonstrate the capability of the hybrid quantum mechanics/molecular mechanics (QM/MM) paradigm to simulate core photoelectron spectroscopy: the binding energies and the chemical shifts. An integrated approach with QM/MM binding energy calculations coupled to preceding molecular dynamics sampling is adopted to generate binding energies averaged over the solute-solvent configurations available at a particular temperature and pressure and thus allowing for a statistical assessment with confidence levels for the final binding energies. The results are analyzed in terms of the contributions in the molecular mechanics model-electrostatic, polarization, and van der Waals-with atom or bond granulation of the corresponding MM charge and polarizability force-fields. The role of extramolecular charge transfer screening of the core-hole and explicit hydrogen bonding is studied by extending the QM core to cover the first solvation shell. The results are compared to those obtained from pure electrostatic and polarizable continuum models. Particularly, the dependence of the carbon 1s binding energies with respect to the ethanol concentration is studied. Our results indicate that QM/MM can be used as an all-encompassing model to study photoelectron binding energies and chemical shifts in solvent environments.

Computational Study of Environmental Effects on Torsional Free Energy Surface of N-Acetyl-N'-methyl-L-alanylamide Dipeptide

ERIC Educational Resources Information Center

Carlotto, Silvia; Zerbetto, Mirco

2014-01-01

We propose an articulated computational experiment in which both quantum mechanics (QM) and molecular mechanics (MM) methods are employed to investigate environment effects on the free energy surface for the backbone dihedral angles rotation of the small dipeptide N-Acetyl-N'-methyl-L-alanylamide. This computation exercise is appropriate for an…

Probing Nucleobase Interactions and Predicting Mechanisms of Synthetic Interest Using Computational Chemistry, and Furthering the Development of BVI Education in Chemistry

ERIC Educational Resources Information Center

Harrison, Jason Gordon

2013-01-01

Quantum mechanical (QM) and molecular docking methods are used to probe systems of biological and synthetic interest. Probing interactions of nucleobases within proteins, and properly modeling said interactions toward novel nucleobase development, is extremely difficult, and of great utility in RNA interference (RNAi) therapeutics. The issues in…

On the problem of time in quantum mechanics

NASA Astrophysics Data System (ADS)

Bauer, M.

2017-05-01

The problem of time in quantum mechanics (QM) concerns the fact that in the Schrödinger equation time is a parameter, not an operator. Pauli's objection to a time-energy uncertainty relation analogue to the position-momentum one, conjectured by Heisenberg early on, seemed to exclude the existence of such an operator. However Dirac's formulation of an electron's relativistic QM does allow the introduction of a dynamical time operator that is self-adjoint. Consequently, it can be considered as the generator of a unitary transformation of the system, as well as an additional system observable subject to uncertainty. In the present paper these aspects are examined within the standard framework of relativistic QM.

Ab Initio Modeling of the Electronic Absorption Spectrum of Previtamin D in Solution

NASA Astrophysics Data System (ADS)

Zhu, Tianyang

To study the solvent effects of water on the previtamin D absorption spectrum, we use the quantum mechanics (QM)/molecular mechanics (MM) method combined with replica-exchange molecular dynamics (REMD). The QM method is applied for the previtamin D molecule and the MM method is used for the water molecules. To enhance conformational sampling of the flexible previtamin D molecule we apply REMD. Based on the REMD structures, we calculate the macroscopic ensemble of the absorption spectrum in solution by time-dependent density functional theory (TDDFT). Comparison between the calculated spectrum in the gas phase and in the solution reveals minor influences of the solvent on the absorption spectrum. In the conventional molecule dynamics simulation, the previtamin D molecule can be trapped by local minimum and cannot overcome energetics barriers when it is calculated at the room temperature. In addition, the higher temperature calculation for the molecule in REMD allows to overcome energetics barriers and to change the structure to other rotational isomers, then switch to the lower temperature and gives a more complete result in the configuration space for the lower temperature.

QM and QM/MM Studies on Excited-State Relaxation Mechanisms of Unnatural Bases in Vacuo and Base Pairs in DNA.

PubMed

Wang, Qian; Xie, Xiao-Ying; Han, Juan; Cui, Ganglong

2017-11-22

Semisynthetic alphabet can potentially increase the genetic information stored in DNA through the formation of unusual base pairs such as d5SICS:dNaM. However, recent experiments show that near-visible-light irradiation on the d5SICS and dNaM chromophores could lead to genetic mutations and damages. Until now, their photophysical mechanisms remain elusive. Herein, we have employed MS-CASPT2//CASSCF and QM(MS-CASPT2//CASSCF)/MM methods to explore the spectroscopic properties and excited-state relaxation mechanisms of d5SICS, dNaM, and d5SICS:dNaM in DNA. We have found that (1) the S 2 state of d5SICS, the S 1 state of dNaM, and the S 2 state of d5SICS:dNaM are initially populated upon near-visible-light irradiation and (2) for d5SICS and d5SICS:dNaM, there are several parallel relaxation pathways to populate the lowest triplet state, but for dNaM, a main relaxation pathway is uncovered. Moreover, we have found that the excited-state relaxation mechanism of d5SICS:dNaM in DNA is similar to that of the isolated d5SICS chromophore. These mechanistic insights contribute to the understanding of photophysics and photochemistry of unusual base pairs and to the design of better semisynthetic genetic alphabet.

Theoretical Characterization of the Spectral Density of the Water-Soluble Chlorophyll-Binding Protein from Combined Quantum Mechanics/Molecular Mechanics Molecular Dynamics Simulations.

PubMed

Rosnik, Andreana M; Curutchet, Carles

2015-12-08

Over the past decade, both experimentalists and theorists have worked to develop methods to describe pigment-protein coupling in photosynthetic light-harvesting complexes in order to understand the molecular basis of quantum coherence effects observed in photosynthesis. Here we present an improved strategy based on the combination of quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations and excited-state calculations to predict the spectral density of electronic-vibrational coupling. We study the water-soluble chlorophyll-binding protein (WSCP) reconstituted with Chl a or Chl b pigments as the system of interest and compare our work with data obtained by Pieper and co-workers from differential fluorescence line-narrowing spectra (Pieper et al. J. Phys. Chem. B 2011, 115 (14), 4042-4052). Our results demonstrate that the use of QM/MM MD simulations where the nuclear positions are still propagated at the classical level leads to a striking improvement of the predicted spectral densities in the middle- and high-frequency regions, where they nearly reach quantitative accuracy. This demonstrates that the so-called "geometry mismatch" problem related to the use of low-quality structures in QM calculations, not the quantum features of pigments high-frequency motions, causes the failure of previous studies relying on similar protocols. Thus, this work paves the way toward quantitative predictions of pigment-protein coupling and the comprehension of quantum coherence effects in photosynthesis.

General N=2 supersymmetric quantum mechanical model: Supervariable approach to its off-shell nilpotent symmetries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krishna, S., E-mail: skrishna.bhu@gmail.com; Shukla, A., E-mail: ashukla038@gmail.com; Malik, R.P., E-mail: rpmalik1995@gmail.com

2014-12-15

Using the supersymmetric (SUSY) invariant restrictions on the (anti-)chiral supervariables, we derive the off-shell nilpotent symmetries of the general one (0+1)-dimensional N=2 SUSY quantum mechanical (QM) model which is considered on a (1, 2)-dimensional supermanifold (parametrized by a bosonic variable t and a pair of Grassmannian variables θ and θ-bar with θ{sup 2}=(θ-bar){sup 2}=0,θ(θ-bar)+(θ-bar)θ=0). We provide the geometrical meanings to the two SUSY transformations of our present theory which are valid for any arbitrary type of superpotential. We express the conserved charges and Lagrangian of the theory in terms of the supervariables (that are obtained after the application of SUSYmore » invariant restrictions) and provide the geometrical interpretation for the nilpotency property and SUSY invariance of the Lagrangian for the general N=2 SUSY quantum theory. We also comment on the mathematical interpretation of the above symmetry transformations. - Highlights: • A novel method has been proposed for the derivation of N=2 SUSY transformations. • General N=2 SUSY quantum mechanical (QM) model with a general superpotential, is considered. • The above SUSY QM model is generalized onto a (1, 2)-dimensional supermanifold. • SUSY invariant restrictions are imposed on the (anti-)chiral supervariables. • Geometrical meaning of the nilpotency property is provided.« less

HYDROGEN BONDING IN THE METHANOL DIMER

USDA-ARS?s Scientific Manuscript database

In this work, two methanol molecules are placed in different arrangements to study hydrogen bonding in carbohydrate materials such as cellulose. Energy was calculated as a function of both hydrogen bond length and angle over wide ranges, using quantum mechanics (QM). The QM wavefunctions are analyze...

Structure and dynamics of the CrIII ion in aqueous solution: Ab initio QM/MM molecular dynamics simulation.

PubMed

Kritayakornupong, Chinapong; Plankensteiner, Kristof; Rode, Bernd M

2004-10-01

Structural and dynamical properties of the Cr(III) ion in aqueous solution have been investigated using a combined ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulation. The hydration structure of Cr(III) was determined in terms of radial distribution functions, coordination numbers, and angular distributions. The QM/MM simulation gives coordination numbers of 6 and 15.4 for the first and second hydration shell, respectively. The first hydration shell is kinetically very inert but by no means rigid and variations of the first hydration shell geometry lead to distinct splitting in the vibrational spectra of Cr(H(2)O)(6) (3+). A mean residence time of 22 ps was obtained for water ligands residing in the second hydration shell, which is remarkably shorter than the experimentally estimated value. The hydration energy of -1108 +/- 7 kcal/mol, obtained from the QM/MM simulation, corresponds well to the experimental hydration enthalpy value. Copyright 2004 Wiley Periodicals, Inc.

Elucidation of hydrolysis mechanisms for fatty acid amide hydrolase and its Lys142Ala variant via QM/MM simulations.

PubMed

Tubert-Brohman, Ivan; Acevedo, Orlando; Jorgensen, William L

2006-12-27

Fatty acid amide hydrolase (FAAH) is a serine hydrolase that degrades anandamide, an endocannabinoid, and oleamide, a sleep-inducing lipid, and has potential applications as a therapeutic target for neurological disorders. Remarkably, FAAH hydrolyzes amides and esters with similar rates; however, the normal preference for esters reemerges when Lys142 is mutated to alanine. To elucidate the hydrolysis mechanisms and the causes behind this variation of selectivity, mixed quantum and molecular mechanics (QM/MM) calculations were carried out to obtain free-energy profiles for alternative mechanisms for the enzymatic hydrolyses. The methodology features free-energy perturbation calculations in Monte Carlo simulations with PDDG/PM3 as the QM method. For wild-type FAAH, the results support a mechanism, which features proton transfer from Ser217 to Lys142, simultaneous proton transfer from Ser241 to Ser217, and attack of Ser241 on the substrate's carbonyl carbon to yield a tetrahedral intermediate, which subsequently undergoes elimination with simultaneous protonation of the leaving group by a Lys142-Ser217 proton shuttle. For the Lys142Ala mutant, a striking multistep sequence is proposed with simultaneous proton transfer from Ser241 to Ser217, attack of Ser241 on the carbonyl carbon of the substrate, and elimination of the leaving group and its protonation by Ser217. Support comes from the free-energy results, which well reproduce the observation that the Lys142Ala mutation in FAAH decreases the rate of hydrolysis for oleamide significantly more than for methyl oleate.

Protein structure refinement using a quantum mechanics-based chemical shielding predictor.

PubMed

Bratholm, Lars A; Jensen, Jan H

2017-03-01

The accurate prediction of protein chemical shifts using a quantum mechanics (QM)-based method has been the subject of intense research for more than 20 years but so far empirical methods for chemical shift prediction have proven more accurate. In this paper we show that a QM-based predictor of a protein backbone and CB chemical shifts (ProCS15, PeerJ , 2016, 3, e1344) is of comparable accuracy to empirical chemical shift predictors after chemical shift-based structural refinement that removes small structural errors. We present a method by which quantum chemistry based predictions of isotropic chemical shielding values (ProCS15) can be used to refine protein structures using Markov Chain Monte Carlo (MCMC) simulations, relating the chemical shielding values to the experimental chemical shifts probabilistically. Two kinds of MCMC structural refinement simulations were performed using force field geometry optimized X-ray structures as starting points: simulated annealing of the starting structure and constant temperature MCMC simulation followed by simulated annealing of a representative ensemble structure. Annealing of the CHARMM structure changes the CA-RMSD by an average of 0.4 Å but lowers the chemical shift RMSD by 1.0 and 0.7 ppm for CA and N. Conformational averaging has a relatively small effect (0.1-0.2 ppm) on the overall agreement with carbon chemical shifts but lowers the error for nitrogen chemical shifts by 0.4 ppm. If an amino acid specific offset is included the ProCS15 predicted chemical shifts have RMSD values relative to experiments that are comparable to popular empirical chemical shift predictors. The annealed representative ensemble structures differ in CA-RMSD relative to the initial structures by an average of 2.0 Å, with >2.0 Å difference for six proteins. In four of the cases, the largest structural differences arise in structurally flexible regions of the protein as determined by NMR, and in the remaining two cases, the large structural change may be due to force field deficiencies. The overall accuracy of the empirical methods are slightly improved by annealing the CHARMM structure with ProCS15, which may suggest that the minor structural changes introduced by ProCS15-based annealing improves the accuracy of the protein structures. Having established that QM-based chemical shift prediction can deliver the same accuracy as empirical shift predictors we hope this can help increase the accuracy of related approaches such as QM/MM or linear scaling approaches or interpreting protein structural dynamics from QM-derived chemical shift.

A compact quantum correction model for symmetric double gate metal-oxide-semiconductor field-effect transistor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cho, Edward Namkyu; Shin, Yong Hyeon; Yun, Ilgu, E-mail: iyun@yonsei.ac.kr

2014-11-07

A compact quantum correction model for a symmetric double gate (DG) metal-oxide-semiconductor field-effect transistor (MOSFET) is investigated. The compact quantum correction model is proposed from the concepts of the threshold voltage shift (ΔV{sub TH}{sup QM}) and the gate capacitance (C{sub g}) degradation. First of all, ΔV{sub TH}{sup QM} induced by quantum mechanical (QM) effects is modeled. The C{sub g} degradation is then modeled by introducing the inversion layer centroid. With ΔV{sub TH}{sup QM} and the C{sub g} degradation, the QM effects are implemented in previously reported classical model and a comparison between the proposed quantum correction model and numerical simulationmore » results is presented. Based on the results, the proposed quantum correction model can be applicable to the compact model of DG MOSFET.« less

Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

PubMed Central

Oláh, Julianna; Mulholland, Adrian J.; Harvey, Jeremy N.

2011-01-01

Cytochrome P450 enzymes play key roles in the metabolism of the majority of drugs. Improved models for prediction of likely metabolites will contribute to drug development. In this work, two possible metabolic routes (aromatic carbon oxidation and O-demethylation) of dextromethorphan are compared using molecular dynamics (MD) simulations and density functional theory (DFT). The DFT results on a small active site model suggest that both reactions might occur competitively. Docking and MD studies of dextromethorphan in the active site of P450 2D6 show that the dextromethorphan is located close to heme oxygen in a geometry apparently consistent with competitive metabolism. In contrast, calculations of the reaction path in a large protein model [using a hybrid quantum mechanical–molecular mechanics (QM/MM) method] show a very strong preference for O-demethylation, in accordance with experimental results. The aromatic carbon oxidation reaction is predicted to have a high activation energy, due to the active site preventing formation of a favorable transition-state structure. Hence, the QM/MM calculations demonstrate a crucial role of many active site residues in determining reactivity of dextromethorphan in P450 2D6. Beyond substrate binding orientation and reactivity of Compound I, successful metabolite predictions must take into account the detailed mechanism of oxidation in the protein. These results demonstrate the potential of QM/MM methods to investigate specificity in drug metabolism. PMID:21444768

Predicting p Ka values from EEM atomic charges

PubMed Central

2013-01-01

The acid dissociation constant p Ka is a very important molecular property, and there is a strong interest in the development of reliable and fast methods for p Ka prediction. We have evaluated the p Ka prediction capabilities of QSPR models based on empirical atomic charges calculated by the Electronegativity Equalization Method (EEM). Specifically, we collected 18 EEM parameter sets created for 8 different quantum mechanical (QM) charge calculation schemes. Afterwards, we prepared a training set of 74 substituted phenols. Additionally, for each molecule we generated its dissociated form by removing the phenolic hydrogen. For all the molecules in the training set, we then calculated EEM charges using the 18 parameter sets, and the QM charges using the 8 above mentioned charge calculation schemes. For each type of QM and EEM charges, we created one QSPR model employing charges from the non-dissociated molecules (three descriptor QSPR models), and one QSPR model based on charges from both dissociated and non-dissociated molecules (QSPR models with five descriptors). Afterwards, we calculated the quality criteria and evaluated all the QSPR models obtained. We found that QSPR models employing the EEM charges proved as a good approach for the prediction of p Ka (63% of these models had R2 > 0.9, while the best had R2 = 0.924). As expected, QM QSPR models provided more accurate p Ka predictions than the EEM QSPR models but the differences were not significant. Furthermore, a big advantage of the EEM QSPR models is that their descriptors (i.e., EEM atomic charges) can be calculated markedly faster than the QM charge descriptors. Moreover, we found that the EEM QSPR models are not so strongly influenced by the selection of the charge calculation approach as the QM QSPR models. The robustness of the EEM QSPR models was subsequently confirmed by cross-validation. The applicability of EEM QSPR models for other chemical classes was illustrated by a case study focused on carboxylic acids. In summary, EEM QSPR models constitute a fast and accurate p Ka prediction approach that can be used in virtual screening. PMID:23574978

A Molecular Dynamics (MD) and Quantum Mechanics/Molecular Mechanics (QM/MM) study on Ornithine Cyclodeaminase (OCD): a tale of two iminiums.

PubMed

Ion, Bogdan F; Bushnell, Eric A C; Luna, Phil De; Gauld, James W

2012-10-11

Ornithine cyclodeaminase (OCD) is an NAD+-dependent deaminase that is found in bacterial species such as Pseudomonas putida. Importantly, it catalyzes the direct conversion of the amino acid L-ornithine to L-proline. Using molecular dynamics (MD) and a hybrid quantum mechanics/molecular mechanics (QM/MM) method in the ONIOM formalism, the catalytic mechanism of OCD has been examined. The rate limiting step is calculated to be the initial step in the overall mechanism: hydride transfer from the L-ornithine's C(α)-H group to the NAD+ cofactor with concomitant formation of a C(α)=NH(2)+ Schiff base with a barrier of 90.6 kJ mol-1. Importantly, no water is observed within the active site during the MD simulations suitably positioned to hydrolyze the C(α)=NH(2)+ intermediate to form the corresponding carbonyl. Instead, the reaction proceeds via a non-hydrolytic mechanism involving direct nucleophilic attack of the δ-amine at the C(α)-position. This is then followed by cleavage and loss of the α-NH(2) group to give the Δ1-pyrroline-2-carboxylate that is subsequently reduced to L-proline.

A Molecular Dynamics (MD) and Quantum Mechanics/Molecular Mechanics (QM/MM) Study on Ornithine Cyclodeaminase (OCD): A Tale of Two Iminiums

PubMed Central

Ion, Bogdan F.; Bushnell, Eric A. C.; De Luna, Phil; Gauld, James W.

2012-01-01

Ornithine cyclodeaminase (OCD) is an NAD+-dependent deaminase that is found in bacterial species such as Pseudomonas putida. Importantly, it catalyzes the direct conversion of the amino acid L-ornithine to L-proline. Using molecular dynamics (MD) and a hybrid quantum mechanics/molecular mechanics (QM/MM) method in the ONIOM formalism, the catalytic mechanism of OCD has been examined. The rate limiting step is calculated to be the initial step in the overall mechanism: hydride transfer from the L-ornithine’s Cα–H group to the NAD+ cofactor with concomitant formation of a Cα=NH2 + Schiff base with a barrier of 90.6 kJ mol−1. Importantly, no water is observed within the active site during the MD simulations suitably positioned to hydrolyze the Cα=NH2 + intermediate to form the corresponding carbonyl. Instead, the reaction proceeds via a non-hydrolytic mechanism involving direct nucleophilic attack of the δ-amine at the Cα-position. This is then followed by cleavage and loss of the α-NH2 group to give the Δ1-pyrroline-2-carboxylate that is subsequently reduced to L-proline. PMID:23202934

Using DFT methodology for more reliable predictive models: Design of inhibitors of Golgi α-Mannosidase II.

PubMed

Bobovská, Adela; Tvaroška, Igor; Kóňa, Juraj

2016-05-01

Human Golgi α-mannosidase II (GMII), a zinc ion co-factor dependent glycoside hydrolase (E.C.3.2.1.114), is a pharmaceutical target for the design of inhibitors with anti-cancer activity. The discovery of an effective inhibitor is complicated by the fact that all known potent inhibitors of GMII are involved in unwanted co-inhibition with lysosomal α-mannosidase (LMan, E.C.3.2.1.24), a relative to GMII. Routine empirical QSAR models for both GMII and LMan did not work with a required accuracy. Therefore, we have developed a fast computational protocol to build predictive models combining interaction energy descriptors from an empirical docking scoring function (Glide-Schrödinger), Linear Interaction Energy (LIE) method, and quantum mechanical density functional theory (QM-DFT) calculations. The QSAR models were built and validated with a library of structurally diverse GMII and LMan inhibitors and non-active compounds. A critical role of QM-DFT descriptors for the more accurate prediction abilities of the models is demonstrated. The predictive ability of the models was significantly improved when going from the empirical docking scoring function to mixed empirical-QM-DFT QSAR models (Q(2)=0.78-0.86 when cross-validation procedures were carried out; and R(2)=0.81-0.83 for a testing set). The average error for the predicted ΔGbind decreased to 0.8-1.1kcalmol(-1). Also, 76-80% of non-active compounds were successfully filtered out from GMII and LMan inhibitors. The QSAR models with the fragmented QM-DFT descriptors may find a useful application in structure-based drug design where pure empirical and force field methods reached their limits and where quantum mechanics effects are critical for ligand-receptor interactions. The optimized models will apply in lead optimization processes for GMII drug developments. Copyright © 2016 Elsevier Inc. All rights reserved.

Resonances in piecewise potentials and Supersymmetric Quantum Mechanics (SUSY-QM) for the construction of optical potentials

NASA Astrophysics Data System (ADS)

Orozco Cortés, Luis Fernando; Fernández García, Nicolás

2014-05-01

A method to obtain the general solution of any constant piecewise potential is presented, this is achieved by means of the analysis of the transfer matrices in each cutoff. The resonance phenomenon together with the supersymmetric quantum mechanics technique allow us to construct a wide family of complex potentials which can be used as theoretical models for optical systems. The method is applied to the particular case for which the potential function has six cutoff points.

Modelling chemical reactions by QM/MM calculations: the case of the tautomerization in fireflies bioluminescent systems

NASA Astrophysics Data System (ADS)

Berraud-Pache, Romain; Garcia-Iriepa, Cristina; Navizet, Isabelle

2018-04-01

In less than half a century, the hybrid QM/MM method has become one of the most used technique to model molecules embedded in a complex environment. A well-known application of the QM/MM method is for biological systems. Nowadays, one can understand how enzymatic reactions work or compute spectroscopic properties, like the wavelength of emission. Here, we have tackled the issue of modelling chemical reactions inside proteins. We have studied a bioluminescent system, fireflies, and deciphered if a keto-enol tautomerization is possible inside the protein. The two tautomers are candidates to be the emissive molecule of the bioluminescence but no outcome has been reached. One hypothesis is to consider a possible keto-enol tautomerization to treat this issue, as it has been already observed in water. A joint approach combining extensive MD simulations as well as computation of key intermediates like TS using QM/MM calculations is presented in this publication. We also emphasize the procedure and difficulties met during this approach in order to give a guide for this kind of chemical reactions using QM/MM methods.

Modeling Chemical Reactions by QM/MM Calculations: The Case of the Tautomerization in Fireflies Bioluminescent Systems

PubMed Central

Berraud-Pache, Romain; Garcia-Iriepa, Cristina; Navizet, Isabelle

2018-01-01

In less than half a century, the hybrid QM/MM method has become one of the most used technique to model molecules embedded in a complex environment. A well-known application of the QM/MM method is for biological systems. Nowadays, one can understand how enzymatic reactions work or compute spectroscopic properties, like the wavelength of emission. Here, we have tackled the issue of modeling chemical reactions inside proteins. We have studied a bioluminescent system, fireflies, and deciphered if a keto-enol tautomerization is possible inside the protein. The two tautomers are candidates to be the emissive molecule of the bioluminescence but no outcome has been reached. One hypothesis is to consider a possible keto-enol tautomerization to treat this issue, as it has been already observed in water. A joint approach combining extensive MD simulations as well as computation of key intermediates like TS using QM/MM calculations is presented in this publication. We also emphasize the procedure and difficulties met during this approach in order to give a guide for this kind of chemical reactions using QM/MM methods. PMID:29719820

Modeling Chemical Reactions by QM/MM Calculations: The Case of the Tautomerization in Fireflies Bioluminescent Systems.

PubMed

Berraud-Pache, Romain; Garcia-Iriepa, Cristina; Navizet, Isabelle

2018-01-01

In less than half a century, the hybrid QM/MM method has become one of the most used technique to model molecules embedded in a complex environment. A well-known application of the QM/MM method is for biological systems. Nowadays, one can understand how enzymatic reactions work or compute spectroscopic properties, like the wavelength of emission. Here, we have tackled the issue of modeling chemical reactions inside proteins. We have studied a bioluminescent system, fireflies, and deciphered if a keto-enol tautomerization is possible inside the protein. The two tautomers are candidates to be the emissive molecule of the bioluminescence but no outcome has been reached. One hypothesis is to consider a possible keto-enol tautomerization to treat this issue, as it has been already observed in water. A joint approach combining extensive MD simulations as well as computation of key intermediates like TS using QM/MM calculations is presented in this publication. We also emphasize the procedure and difficulties met during this approach in order to give a guide for this kind of chemical reactions using QM/MM methods.

Determinants of reactivity and selectivity in soluble epoxide hydrolase from quantum mechanics/molecular mechanics modeling.

PubMed

Lonsdale, Richard; Hoyle, Simon; Grey, Daniel T; Ridder, Lars; Mulholland, Adrian J

2012-02-28

Soluble epoxide hydrolase (sEH) is an enzyme involved in drug metabolism that catalyzes the hydrolysis of epoxides to form their corresponding diols. sEH has a broad substrate range and shows high regio- and enantioselectivity for nucleophilic ring opening by Asp333. Epoxide hydrolases therefore have potential synthetic applications. We have used combined quantum mechanics/molecular mechanics (QM/MM) umbrella sampling molecular dynamics (MD) simulations (at the AM1/CHARMM22 level) and high-level ab initio (SCS-MP2) QM/MM calculations to analyze the reactions, and determinants of selectivity, for two substrates: trans-stilbene oxide (t-SO) and trans-diphenylpropene oxide (t-DPPO). The calculated free energy barriers from the QM/MM (AM1/CHARMM22) umbrella sampling MD simulations show a lower barrier for phenyl attack in t-DPPO, compared with that for benzylic attack, in agreement with experiment. Activation barriers in agreement with experimental rate constants are obtained only with the highest level of QM theory (SCS-MP2) used. Our results show that the selectivity of the ring-opening reaction is influenced by several factors, including proximity to the nucleophile, electronic stabilization of the transition state, and hydrogen bonding to two active site tyrosine residues. The protonation state of His523 during nucleophilic attack has also been investigated, and our results show that the protonated form is most consistent with experimental findings. The work presented here illustrates how determinants of selectivity can be identified from QM/MM simulations. These insights may also provide useful information for the design of novel catalysts for use in the synthesis of enantiopure compounds.

Acceleration of Semiempirical QM/MM Methods through Message Passage Interface (MPI), Hybrid MPI/Open Multiprocessing, and Self-Consistent Field Accelerator Implementations.

PubMed

Ojeda-May, Pedro; Nam, Kwangho

2017-08-08

The strategy and implementation of scalable and efficient semiempirical (SE) QM/MM methods in CHARMM are described. The serial version of the code was first profiled to identify routines that required parallelization. Afterward, the code was parallelized and accelerated with three approaches. The first approach was the parallelization of the entire QM/MM routines, including the Fock matrix diagonalization routines, using the CHARMM message passage interface (MPI) machinery. In the second approach, two different self-consistent field (SCF) energy convergence accelerators were implemented using density and Fock matrices as targets for their extrapolations in the SCF procedure. In the third approach, the entire QM/MM and MM energy routines were accelerated by implementing the hybrid MPI/open multiprocessing (OpenMP) model in which both the task- and loop-level parallelization strategies were adopted to balance loads between different OpenMP threads. The present implementation was tested on two solvated enzyme systems (including <100 QM atoms) and an S N 2 symmetric reaction in water. The MPI version exceeded existing SE QM methods in CHARMM, which include the SCC-DFTB and SQUANTUM methods, by at least 4-fold. The use of SCF convergence accelerators further accelerated the code by ∼12-35% depending on the size of the QM region and the number of CPU cores used. Although the MPI version displayed good scalability, the performance was diminished for large numbers of MPI processes due to the overhead associated with MPI communications between nodes. This issue was partially overcome by the hybrid MPI/OpenMP approach which displayed a better scalability for a larger number of CPU cores (up to 64 CPUs in the tested systems).

The ReaxFF reactive force-field: Development, applications, and future directions

DOE PAGES

Senftle, Thomas; Hong, Sungwook; Islam, Md Mahbubul; ...

2016-03-04

The reactive force-field (ReaxFF) interatomic potential is a powerful computational tool for exploring, developing and optimizing material properties. Methods based on the principles of quantum mechanics (QM), while offering valuable theoretical guidance at the electronic level, are often too computationally intense for simulations that consider the full dynamic evolution of a system. Alternatively, empirical interatomic potentials that are based on classical principles require significantly fewer computational resources, which enables simulations to better describe dynamic processes over longer timeframes and on larger scales. Such methods, however, typically require a predefined connectivity between atoms, precluding simulations that involve reactive events. The ReaxFFmore » method was developed to help bridge this gap. Approaching the gap from the classical side, ReaxFF casts the empirical interatomic potential within a bond-order formalism, thus implicitly describing chemical bonding without expensive QM calculations. As a result, this article provides an overview of the development, application, and future directions of the ReaxFF method.« less

QM Automata: A New Class of Restricted Quantum Membrane Automata.

PubMed

Giannakis, Konstantinos; Singh, Alexandros; Kastampolidou, Kalliopi; Papalitsas, Christos; Andronikos, Theodore

2017-01-01

The term "Unconventional Computing" describes the use of non-standard methods and models in computing. It is a recently established field, with many interesting and promising results. In this work we combine notions from quantum computing with aspects of membrane computing to define what we call QM automata. Specifically, we introduce a variant of quantum membrane automata that operate in accordance with the principles of quantum computing. We explore the functionality and capabilities of the QM automata through indicative examples. Finally we suggest future directions for research on QM automata.

Bound state solution of Dirac equation for 3D harmonics oscillator plus trigonometric scarf noncentral potential using SUSY QM approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cari, C., E-mail: carinln@yahoo.com; Suparmi, A., E-mail: carinln@yahoo.com

2014-09-30

Dirac equation of 3D harmonics oscillator plus trigonometric Scarf non-central potential for spin symmetric case is solved using supersymmetric quantum mechanics approach. The Dirac equation for exact spin symmetry reduces to Schrodinger like equation. The relativistic energy and wave function for spin symmetric case are simply obtained using SUSY quantum mechanics method and idea of shape invariance.

A ring polymer molecular dynamics study of the isotopologues of the H + H2 reaction.

PubMed

Suleimanov, Yury V; de Tudela, Ricardo Pérez; Jambrina, Pablo G; Castillo, Jesús F; Sáez-Rábanos, Vicente; Manolopoulos, David E; Aoiz, F Javier

2013-03-14

The inclusion of Quantum Mechanical (QM) effects such as zero point energy (ZPE) and tunneling in simulations of chemical reactions, especially in the case of light atom transfer, is an important problem in computational chemistry. In this respect, the hydrogen exchange reaction and its isotopic variants constitute an excellent benchmark for the assessment of approximate QM methods. In particular, the recently developed ring polymer molecular dynamics (RPMD) technique has been demonstrated to give very good results for bimolecular chemical reactions in the gas phase. In this work, we have performed a detailed RPMD study of the H + H(2) reaction and its isotopologues Mu + H(2), D + H(2) and Heμ + H(2), at temperatures ranging from 200 to 1000 K. Thermal rate coefficients and kinetic isotope effects have been computed and compared with exact QM calculations as well as with quasiclassical trajectories and experiment. The agreement with the QM results is good for the heaviest isotopologues, with errors ranging from 15% to 45%, and excellent for Mu + H(2), with errors below 15%. We have seen that RPMD is able to capture the ZPE effect very accurately, a desirable feature of any method based on molecular dynamics. We have also verified Richardson and Althorpe's prediction [J. O. Richardson and S. C. Althorpe, J. Chem. Phys., 2009, 131, 214106] that RPMD will overestimate thermal rates for asymmetric reactions and underestimate them for symmetric reactions in the deep tunneling regime. The ZPE effect along the reaction coordinate must be taken into account when assigning the reaction symmetry in the multidimensional case.

A Didactic Proposed for Teaching the Concepts of Electrons and Light in Secondary School Using Feynman's Path Sum Method

ERIC Educational Resources Information Center

Fanaro, Maria de los Angeles; Arlego, Marcelo; Otero, Maria Rita

2012-01-01

This work comprises an investigation about basic Quantum Mechanics (QM) teaching in the high school. The organization of the concepts does not follow a historical line. The Path Integrals method of Feynman has been adopted as a Reference Conceptual Structure that is an alternative to the canonical formalism. We have designed a didactic sequence…

Correction of erroneously packed protein's side chains in the NMR structure based on ab initio chemical shift calculations.

PubMed

Zhu, Tong; Zhang, John Z H; He, Xiao

2014-09-14

In this work, protein side chain (1)H chemical shifts are used as probes to detect and correct side-chain packing errors in protein's NMR structures through structural refinement. By applying the automated fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) method for ab initio calculation of chemical shifts, incorrect side chain packing was detected in the NMR structures of the Pin1 WW domain. The NMR structure is then refined by using molecular dynamics simulation and the polarized protein-specific charge (PPC) model. The computationally refined structure of the Pin1 WW domain is in excellent agreement with the corresponding X-ray structure. In particular, the use of the PPC model yields a more accurate structure than that using the standard (nonpolarizable) force field. For comparison, some of the widely used empirical models for chemical shift calculations are unable to correctly describe the relationship between the particular proton chemical shift and protein structures. The AF-QM/MM method can be used as a powerful tool for protein NMR structure validation and structural flaw detection.

Quantum mechanics over sets

NASA Astrophysics Data System (ADS)

Ellerman, David

2014-03-01

In models of QM over finite fields (e.g., Schumacher's ``modal quantum theory'' MQT), one finite field stands out, Z2, since Z2 vectors represent sets. QM (finite-dimensional) mathematics can be transported to sets resulting in quantum mechanics over sets or QM/sets. This gives a full probability calculus (unlike MQT with only zero-one modalities) that leads to a fulsome theory of QM/sets including ``logical'' models of the double-slit experiment, Bell's Theorem, QIT, and QC. In QC over Z2 (where gates are non-singular matrices as in MQT), a simple quantum algorithm (one gate plus one function evaluation) solves the Parity SAT problem (finding the parity of the sum of all values of an n-ary Boolean function). Classically, the Parity SAT problem requires 2n function evaluations in contrast to the one function evaluation required in the quantum algorithm. This is quantum speedup but with all the calculations over Z2 just like classical computing. This shows definitively that the source of quantum speedup is not in the greater power of computing over the complex numbers, and confirms the idea that the source is in superposition.

On the self-interference in electron scattering: Copenhagen, Bohmian and geometrical interpretations of quantum mechanics

NASA Astrophysics Data System (ADS)

Tavernelli, Ivano

2018-06-01

Self-interference embodies the essence of the particle-wave formulation of quantum mechanics (QM). According to the Copenhagen interpretation of QM, self-interference by a double-slit requires a large transverse coherence of the incident wavepacket such that it covers the separation between the slits. Bohmian dynamics provides a first step in the separation of the particle-wave character of matter by introducing deterministic trajectories guided by a pilot wave that follows the time-dependent Schrödinger equation. In this work, I present a new description of the phenomenon of self-interference using the geometrical formulation of QM introduced in Tavernelli (2016). In particular, this formalism removes the need for the concept of wavefunction collapse in the interpretation of the act of measurement i.e., the emergence of the classical world. The three QM formulations (Schrödinger, Bohmian, and geometrical) are applied to the description of the scattering of a free electron by a hydrogen atom and a double-slit. The corresponding interpretations of self-interference are compared and discussed.

Physics and the role of mind

NASA Astrophysics Data System (ADS)

Klein, Stanley A.; Cochran, Christopher

2017-05-01

This paper explores the role of the mind in the physical world. We begin with a brief introduction to distinct types of retrocausal phenomena connected with parapsychology and physics. We provide an introduction to laws of quantum mechanics (QM) that lead some to surmise connections between QM and psychic phenomena (psi). Next, we present our argument that verification of psi will require changes to QM. As a possible placeholder for these changes we introduce "Mind", from Cartesian dualism. This area of research points the way to connections between two fundamental issues in science: the mind-matter hard problem and the measurement problem of QM. Positive outcomes of carefully executed experiments could demonstrate a close relationship between these two problems, including the possibility that sentience plays an important role in the fundamental laws of physics. We focus on a version of Daryl Bem's seeing the future experiments, which should allow for discrimination between various interpretations of QM. Finally, although the authors are psi skeptics, we suggest methodologies that may enable psi phenomena to be acceptable to mainstream science.

Physics-based scoring of protein-ligand interactions: explicit polarizability, quantum mechanics and free energies.

PubMed

Bryce, Richard A

2011-04-01

The ability to accurately predict the interaction of a ligand with its receptor is a key limitation in computer-aided drug design approaches such as virtual screening and de novo design. In this article, we examine current strategies for a physics-based approach to scoring of protein-ligand affinity, as well as outlining recent developments in force fields and quantum chemical techniques. We also consider advances in the development and application of simulation-based free energy methods to study protein-ligand interactions. Fuelled by recent advances in computational algorithms and hardware, there is the opportunity for increased integration of physics-based scoring approaches at earlier stages in computationally guided drug discovery. Specifically, we envisage increased use of implicit solvent models and simulation-based scoring methods as tools for computing the affinities of large virtual ligand libraries. Approaches based on end point simulations and reference potentials allow the application of more advanced potential energy functions to prediction of protein-ligand binding affinities. Comprehensive evaluation of polarizable force fields and quantum mechanical (QM)/molecular mechanical and QM methods in scoring of protein-ligand interactions is required, particularly in their ability to address challenging targets such as metalloproteins and other proteins that make highly polar interactions. Finally, we anticipate increasingly quantitative free energy perturbation and thermodynamic integration methods that are practical for optimization of hits obtained from screened ligand libraries.

Direct hydride shift mechanism and stereoselectivity of P450nor confirmed by QM/MM calculations.

PubMed

Krámos, Balázs; Menyhárd, Dóra K; Oláh, Julianna

2012-01-19

Nitric oxide reductase (P450(nor)) found in Fusarium oxysporum catalyzes the reduction of nitric oxide to N(2)O in a multistep process. The reducing agent, NADH, is bound in the distal pocket of the enzyme, and direct hydride transfer occurs from NADH to the nitric oxide bound heme enzyme, forming intermediate I. Here we studied the possibility of hydride transfer from NADH to both the nitrogen and oxygen of the heme-bound nitric oxide, using quantum chemical and combined quantum mechanics/molecular mechanics (QM/MM) calculations, on two different protein models, representing both possible stereochemistries, a syn- and an anti-NADH arrangement. All calculations clearly favor hydride transfer to the nitrogen of nitric oxide, and the QM-only barrier and kinetic isotope effects are good agreement with the experimental values of intermediate I formation. We obtained higher barriers in the QM/MM calculations for both pathways, but hydride transfer to the nitrogen of nitric oxide is still clearly favored. The barriers obtained for the syn, Pro-R conformation of NADH are lower and show significantly less variation than the barriers obtained in the case of anti conformation. The effect of basis set and wide range of functionals on the obtained results are also discussed.

Development of a quantum mechanics-based free-energy perturbation method: use in the calculation of relative solvation free energies.

PubMed

Reddy, M Rami; Singh, U C; Erion, Mark D

2004-05-26

Free-energy perturbation (FEP) is considered the most accurate computational method for calculating relative solvation and binding free-energy differences. Despite some success in applying FEP methods to both drug design and lead optimization, FEP calculations are rarely used in the pharmaceutical industry. One factor limiting the use of FEP is its low throughput, which is attributed in part to the dependence of conventional methods on the user's ability to develop accurate molecular mechanics (MM) force field parameters for individual drug candidates and the time required to complete the process. In an attempt to find an FEP method that could eventually be automated, we developed a method that uses quantum mechanics (QM) for treating the solute, MM for treating the solute surroundings, and the FEP method for computing free-energy differences. The thread technique was used in all transformations and proved to be essential for the successful completion of the calculations. Relative solvation free energies for 10 structurally diverse molecular pairs were calculated, and the results were in close agreement with both the calculated results generated by conventional FEP methods and the experimentally derived values. While considerably more CPU demanding than conventional FEP methods, this method (QM/MM-based FEP) alleviates the need for development of molecule-specific MM force field parameters and therefore may enable future automation of FEP-based calculations. Moreover, calculation accuracy should be improved over conventional methods, especially for calculations reliant on MM parameters derived in the absence of experimental data.

Progress in ab initio QM/MM free-energy simulations of electrostatic energies in proteins: accelerated QM/MM studies of pKa, redox reactions and solvation free energies.

PubMed

Kamerlin, Shina C L; Haranczyk, Maciej; Warshel, Arieh

2009-02-05

Hybrid quantum mechanical/molecular mechanical (QM/MM) approaches have been used to provide a general scheme for chemical reactions in proteins. However, such approaches still present a major challenge to computational chemists, not only because of the need for very large computer time in order to evaluate the QM energy but also because of the need for proper computational sampling. This review focuses on the sampling issue in QM/MM evaluations of electrostatic energies in proteins. We chose this example since electrostatic energies play a major role in controlling the function of proteins and are key to the structure-function correlation of biological molecules. Thus, the correct treatment of electrostatics is essential for the accurate simulation of biological systems. Although we will be presenting different types of QM/MM calculations of electrostatic energies (and related properties) here, our focus will be on pKa calculations. This reflects the fact that pKa's of ionizable groups in proteins provide one of the most direct benchmarks for the accuracy of electrostatic models of macromolecules. While pKa calculations by semimacroscopic models have given reasonable results in many cases, existing attempts to perform pKa calculations using QM/MM-FEP have led to discrepancies between calculated and experimental values. In this work, we accelerate our QM/MM calculations using an updated mean charge distribution and a classical reference potential. We examine both a surface residue (Asp3) of the bovine pancreatic trypsin inhibitor and a residue buried in a hydrophobic pocket (Lys102) of the T4-lysozyme mutant. We demonstrate that, by using this approach, we are able to reproduce the relevant side chain pKa's with an accuracy of 3 kcal/mol. This is well within the 7 kcal/mol energy difference observed in studies of enzymatic catalysis, and is thus sufficient accuracy to determine the main contributions to the catalytic energies of enzymes. We also provide an overall perspective of the potential of QM/MM calculations in general evaluations of electrostatic free energies, pointing out that our approach should provide a very powerful and accurate tool to predict the electrostatics of not only solution but also enzymatic reactions, as well as the solvation free energies of even larger systems, such as nucleic acid bases incorporated into DNA.

Genome sequencing and transcriptome analysis of Trichoderma reesei QM9978 strain reveals a distal chromosome translocation to be responsible for loss of vib1 expression and loss of cellulase induction.

PubMed

Ivanova, Christa; Ramoni, Jonas; Aouam, Thiziri; Frischmann, Alexa; Seiboth, Bernhard; Baker, Scott E; Le Crom, Stéphane; Lemoine, Sophie; Margeot, Antoine; Bidard, Frédérique

2017-01-01

The hydrolysis of biomass to simple sugars used for the production of biofuels in biorefineries requires the action of cellulolytic enzyme mixtures. During the last 50 years, the ascomycete Trichoderma reesei , the main source of industrial cellulase and hemicellulase cocktails, has been subjected to several rounds of classical mutagenesis with the aim to obtain higher production levels. During these random genetic events, strains unable to produce cellulases were generated. Here, whole genome sequencing and transcriptomic analyses of the cellulase-negative strain QM9978 were used for the identification of mutations underlying this cellulase-negative phenotype. Sequence comparison of the cellulase-negative strain QM9978 to the reference strain QM6a identified a total of 43 mutations, of which 33 were located either close to or in coding regions. From those, we identified 23 single-nucleotide variants, nine InDels, and one translocation. The translocation occurred between chromosomes V and VII, is located upstream of the putative transcription factor vib1 , and abolishes its expression in QM9978 as detected during the transcriptomic analyses. Ectopic expression of vib1 under the control of its native promoter as well as overexpression of vib1 under the control of a strong constitutive promoter restored cellulase expression in QM9978, thus confirming that the translocation event is the reason for the cellulase-negative phenotype. Gene deletion of vib1 in the moderate producer strain QM9414 and in the high producer strain Rut-C30 reduced cellulase expression in both cases. Overexpression of vib1 in QM9414 and Rut-C30 had no effect on cellulase production, most likely because vib1 is already expressed at an optimal level under normal conditions. We were able to establish a link between a chromosomal translocation in QM9978 and the cellulase-negative phenotype of the strain. We identified the transcription factor vib1 as a key regulator of cellulases in T. reesei whose expression is absent in QM9978. We propose that in T. reesei , as in Neurospora crassa , vib1 is involved in cellulase induction, although the exact mechanism remains to be elucidated. The data presented here show an example of a combined genome sequencing and transcriptomic approach to explain a specific trait, in this case the QM9978 cellulase-negative phenotype, and how it helps to better understand the mechanisms during cellulase gene regulation. When focusing on mutations on the single base-pair level, changes on the chromosome level can be easily overlooked and through this work we provide an example that stresses the importance of the big picture of the genomic landscape during analysis of sequencing data.

Most Courses Are Not Born Digital: An Overview of the Quality Matters Peer Review Process for Online Course Design

ERIC Educational Resources Information Center

Varonis, Evageline Marlos

2014-01-01

Purpose: The purpose of this paper is to discuss benefits of and barriers to online learning and describe utilization of the Quality Matters (QM) peer review process as a method to assure the quality of online courses. It outlines the QM higher education rubric, explains how the collaborative QM peer review process facilitates online course design…

QM/MM MD and free energy simulation study of methyl transfer processes catalyzed by PKMTs and PRMTs.

PubMed

Chu, Yuzhuo; Guo, Hong

2015-01-16

Methyl transfer processes catalyzed by protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs) control important biological events including transcriptional regulation and cell signaling. One important property of these enzymes is that different PKMTs and PRMTs catalyze the formation of different methylated product (product specificity). These different methylation states lead to different biological outcomes. Here we review the results of quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) and free energy simulations that have been performed to study the reaction mechanism of PKMTs and PRMTs and the mechanism underlying the product specificity of the methyl transfer processes.

The new physician as unwitting quantum mechanic: is adapting Dirac's inference system best practice for personalized medicine, genomics, and proteomics?

PubMed

Robson, Barry

2007-08-01

What is the Best Practice for automated inference in Medical Decision Support for personalized medicine? A known system already exists as Dirac's inference system from quantum mechanics (QM) using bra-kets and bras where A and B are states, events, or measurements representing, say, clinical and biomedical rules. Dirac's system should theoretically be the universal best practice for all inference, though QM is notorious as sometimes leading to bizarre conclusions that appear not to be applicable to the macroscopic world of everyday world human experience and medical practice. It is here argued that this apparent difficulty vanishes if QM is assigned one new multiplication function @, which conserves conditionality appropriately, making QM applicable to classical inference including a quantitative form of the predicate calculus. An alternative interpretation with the same consequences is if every i = radical-1 in Dirac's QM is replaced by h, an entity distinct from 1 and i and arguably a hidden root of 1 such that h2 = 1. With that exception, this paper is thus primarily a review of the application of Dirac's system, by application of linear algebra in the complex domain to help manipulate information about associations and ontology in complicated data. Any combined bra-ket can be shown to be composed only of the sum of QM-like bra and ket weights c(), times an exponential function of Fano's mutual information measure I(A; B) about the association between A and B, that is, an association rule from data mining. With the weights and Fano measure re-expressed as expectations on finite data using Riemann's Incomplete (i.e., Generalized) Zeta Functions, actual counts of observations for real world sparse data can be readily utilized. Finally, the paper compares identical character, distinguishability of states events or measurements, correlation, mutual information, and orthogonal character, important issues in data mining and biomedical analytics, as in QM.

Protein structure refinement using a quantum mechanics-based chemical shielding predictor† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c6sc04344e Click here for additional data file.

PubMed Central

2017-01-01

The accurate prediction of protein chemical shifts using a quantum mechanics (QM)-based method has been the subject of intense research for more than 20 years but so far empirical methods for chemical shift prediction have proven more accurate. In this paper we show that a QM-based predictor of a protein backbone and CB chemical shifts (ProCS15, PeerJ, 2016, 3, e1344) is of comparable accuracy to empirical chemical shift predictors after chemical shift-based structural refinement that removes small structural errors. We present a method by which quantum chemistry based predictions of isotropic chemical shielding values (ProCS15) can be used to refine protein structures using Markov Chain Monte Carlo (MCMC) simulations, relating the chemical shielding values to the experimental chemical shifts probabilistically. Two kinds of MCMC structural refinement simulations were performed using force field geometry optimized X-ray structures as starting points: simulated annealing of the starting structure and constant temperature MCMC simulation followed by simulated annealing of a representative ensemble structure. Annealing of the CHARMM structure changes the CA-RMSD by an average of 0.4 Å but lowers the chemical shift RMSD by 1.0 and 0.7 ppm for CA and N. Conformational averaging has a relatively small effect (0.1–0.2 ppm) on the overall agreement with carbon chemical shifts but lowers the error for nitrogen chemical shifts by 0.4 ppm. If an amino acid specific offset is included the ProCS15 predicted chemical shifts have RMSD values relative to experiments that are comparable to popular empirical chemical shift predictors. The annealed representative ensemble structures differ in CA-RMSD relative to the initial structures by an average of 2.0 Å, with >2.0 Å difference for six proteins. In four of the cases, the largest structural differences arise in structurally flexible regions of the protein as determined by NMR, and in the remaining two cases, the large structural change may be due to force field deficiencies. The overall accuracy of the empirical methods are slightly improved by annealing the CHARMM structure with ProCS15, which may suggest that the minor structural changes introduced by ProCS15-based annealing improves the accuracy of the protein structures. Having established that QM-based chemical shift prediction can deliver the same accuracy as empirical shift predictors we hope this can help increase the accuracy of related approaches such as QM/MM or linear scaling approaches or interpreting protein structural dynamics from QM-derived chemical shift. PMID:28451325

The Complete, Temperature Resolved Experimental Spectrum of Methanol Between 560 and 654 GHZ

NASA Astrophysics Data System (ADS)

Fortman, Sarah M.; Neese, Christopher F.; De Lucia, Frank C.

2013-06-01

The complete spectrum of methanol (CH_3OH) in the 560.4-654.0 GHz spectral region has been characterized over a range of astrophysically significant temperatures, 248-397 K. Analysis of experimental spectra recorded with absolute intensity calibration over a slow temperature ramp provides a means for the simulation of the spectrum as a function of temperature without a complete quantum mechanical (QM) model. These results include contributions from v_t = 3 and other higher states that are difficult to model via QM techniques. They also contain contributions from the ^{13}C isotopologue in natural abundance. These results are used to both provide catalogs in the usual line frequency, linestrength, and lower state energy format and in a frequency point-by-point format that is particularly well suited for the characterization of blended lines. In contrast to our earlier work on the semi-rigid species ethyl cyanide and vinyl cyanide, significant intensity difference between these experimental values and those calculated by QM methods were found for some of the lines. Analysis of these differences points to the difficulty of the calculation of dipole matrix elements in the context of the internal rotation of the methanol molecule. We will compare our experimental intensities with the most recent QM model, as well as an earlier QM model that includes the variation of the dipole moment function with the torsional angle. S. M. Fortman, I. R. Medvedev, C. F. Neese, and F. C. De Lucia, Astrophys. J. 737, 20/1-6 (2011). L.-H. Xu, et al. J. Mol. Spectrosc. 251, 305-313 (2008). M. A. Mekhtiev, P. D. Godfrey, and J. T. Hougen, J. Mol. Spectrosc. 194, 171-178 (1999).

Quantum mechanical fragment methods based on partitioning atoms or partitioning coordinates.

PubMed

Wang, Bo; Yang, Ke R; Xu, Xuefei; Isegawa, Miho; Leverentz, Hannah R; Truhlar, Donald G

2014-09-16

Conspectus The development of more efficient and more accurate ways to represent reactive potential energy surfaces is a requirement for extending the simulation of large systems to more complex systems, longer-time dynamical processes, and more complete statistical mechanical sampling. One way to treat large systems is by direct dynamics fragment methods. Another way is by fitting system-specific analytic potential energy functions with methods adapted to large systems. Here we consider both approaches. First we consider three fragment methods that allow a given monomer to appear in more than one fragment. The first two approaches are the electrostatically embedded many-body (EE-MB) expansion and the electrostatically embedded many-body expansion of the correlation energy (EE-MB-CE), which we have shown to yield quite accurate results even when one restricts the calculations to include only electrostatically embedded dimers. The third fragment method is the electrostatically embedded molecular tailoring approach (EE-MTA), which is more flexible than EE-MB and EE-MB-CE. We show that electrostatic embedding greatly improves the accuracy of these approaches compared with the original unembedded approaches. Quantum mechanical fragment methods share with combined quantum mechanical/molecular mechanical (QM/MM) methods the need to treat a quantum mechanical fragment in the presence of the rest of the system, which is especially challenging for those parts of the rest of the system that are close to the boundary of the quantum mechanical fragment. This is a delicate matter even for fragments that are not covalently bonded to the rest of the system, but it becomes even more difficult when the boundary of the quantum mechanical fragment cuts a bond. We have developed a suite of methods for more realistically treating interactions across such boundaries. These methods include redistributing and balancing the external partial atomic charges and the use of tuned fluorine atoms for capping dangling bonds, and we have shown that they can greatly improve the accuracy. Finally we present a new approach that goes beyond QM/MM by combining the convenience of molecular mechanics with the accuracy of fitting a potential function to electronic structure calculations on a specific system. To make the latter practical for systems with a large number of degrees of freedom, we developed a method to interpolate between local internal-coordinate fits to the potential energy. A key issue for the application to large systems is that rather than assigning the atoms or monomers to fragments, we assign the internal coordinates to reaction, secondary, and tertiary sets. Thus, we make a partition in coordinate space rather than atom space. Fits to the local dependence of the potential energy on tertiary coordinates are arrayed along a preselected reaction coordinate at a sequence of geometries called anchor points; the potential energy function is called an anchor points reactive potential. Electrostatically embedded fragment methods and the anchor points reactive potential, because they are based on treating an entire system by quantum mechanical electronic structure methods but are affordable for large and complex systems, have the potential to open new areas for accurate simulations where combined QM/MM methods are inadequate.

PyCPR - a python-based implementation of the Conjugate Peak Refinement (CPR) algorithm for finding transition state structures.

PubMed

Gisdon, Florian J; Culka, Martin; Ullmann, G Matthias

2016-10-01

Conjugate peak refinement (CPR) is a powerful and robust method to search transition states on a molecular potential energy surface. Nevertheless, the method was to the best of our knowledge so far only implemented in CHARMM. In this paper, we present PyCPR, a new Python-based implementation of the CPR algorithm within the pDynamo framework. We provide a detailed description of the theory underlying our implementation and discuss the different parts of the implementation. The method is applied to two different problems. First, we illustrate the method by analyzing the gauche to anti-periplanar transition of butane using a semiempirical QM method. Second, we reanalyze the mechanism of a glycyl-radical enzyme, namely of 4-hydroxyphenylacetate decarboxylase (HPD) using QM/MM calculations. In the end, we suggest a strategy how to use our implementation of the CPR algorithm. The integration of PyCPR into the framework pDynamo allows the combination of CPR with the large variety of methods implemented in pDynamo. PyCPR can be used in combination with quantum mechanical and molecular mechanical methods (and hybrid methods) implemented directly in pDynamo, but also in combination with external programs such as ORCA using pDynamo as interface. PyCPR is distributed as free, open source software and can be downloaded from http://www.bisb.uni-bayreuth.de/index.php?page=downloads . Graphical Abstract PyCPR is a search tool for finding saddle points on the potential energy landscape of a molecular system.

Photodissociation dynamics of CH{sub 3}C(O)SH in argon matrix: A QM/MM nonadiabatic dynamics simulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xia, Shu-Hua; Liu, Xiang-Yang; Fang, Qiu

2015-11-21

In this work, we have first employed the combined quantum mechanics/molecular mechanics (QM/MM) method to study the photodissociation mechanism of thioacetic acid CH{sub 3}C(O)SH in the S{sub 1}, T{sub 1}, and S{sub 0} states in argon matrix. CH{sub 3}C(O)SH is treated quantum mechanically using the complete active space self-consistent field and complete active space second-order perturbation theory methods; argon matrix is described classically using Lennard-Jones potentials. We find that the C-S bond fission is predominant due to its small barriers of ca. 3.0 and 1.0 kcal/mol in the S{sub 1} and T{sub 1} states. It completely suppresses the nearby C—Cmore » bond fission. After the bond fission, the S{sub 1} radical pair of CH{sub 3}CO and SH can decay to the S{sub 0} and T{sub 1} states via internal conversion and intersystem crossing, respectively. In the S{sub 0} state, the radical pair can either recombine to form CH{sub 3}C(O)SH or proceed to form molecular products of CH{sub 2}CO and H{sub 2}S. We have further employed our recently developed QM/MM generalized trajectory-based surface-hopping method to simulate the photodissociation dynamics of CH{sub 3}C(O)SH. In 1 ps dynamics simulation, 56% trajectories stay at the Franck-Condon region; the S{sub 1} C—S bond fission takes place in the remaining 44% trajectories. Among all nonadiabatic transitions, the S{sub 1} → S{sub 0} internal conversion is major (55%) but the S{sub 1} → T{sub 1} intersystem crossing is still comparable and cannot be ignored, which accounts for 28%. Finally, we have found a radical channel generating the molecular products of CH{sub 2}CO and H{sub 2}S, which is complementary to the concerted molecular channel. The present work sets the stage for simulating photodissociation dynamics of similar thio-carbonyl systems in matrix.« less

Amino acid analogues bind to carbon nanotube via π-π interactions: Comparison of molecular mechanical and quantum mechanical calculations

NASA Astrophysics Data System (ADS)

Yang, Zaixing; Wang, Zhigang; Tian, Xingling; Xiu, Peng; Zhou, Ruhong

2012-01-01

Understanding the interaction between carbon nanotubes (CNTs) and biomolecules is essential to the CNT-based nanotechnology and biotechnology. Some recent experiments have suggested that the π-π stacking interactions between protein's aromatic residues and CNTs might play a key role in their binding, which raises interest in large scale modeling of protein-CNT complexes and associated π-π interactions at atomic detail. However, there is concern on the accuracy of classical fixed-charge molecular force fields due to their classical treatments and lack of polarizability. Here, we study the binding of three aromatic residue analogues (mimicking phenylalanine, tyrosine, and tryptophan) and benzene to a single-walled CNT, and compare the molecular mechanical (MM) calculations using three popular fixed-charge force fields (OPLSAA, AMBER, and CHARMM), with quantum mechanical (QM) calculations using the density-functional tight-binding method with the inclusion of dispersion correction (DFTB-D). Two typical configurations commonly found in π-π interactions are used, one with the aromatic rings parallel to the CNT surface (flat), and the other perpendicular (edge). Our calculations reveal that compared to the QM results the MM approaches can appropriately reproduce the strength of π-π interactions for both configurations, and more importantly, the energy difference between them, indicating that the various contributions to π-π interactions have been implicitly included in the van der Waals parameters of the standard MM force fields. Meanwhile, these MM models are less accurate in predicting the exact structural binding patterns (matching surface), meaning there are still rooms to be improved. In addition, we have provided a comprehensive and reliable QM picture for the π-π interactions of aromatic molecules with CNTs in gas phase, which might be used as a benchmark for future force field developments.

Amino acid analogues bind to carbon nanotube via π-π interactions: comparison of molecular mechanical and quantum mechanical calculations.

PubMed

Yang, Zaixing; Wang, Zhigang; Tian, Xingling; Xiu, Peng; Zhou, Ruhong

2012-01-14

Understanding the interaction between carbon nanotubes (CNTs) and biomolecules is essential to the CNT-based nanotechnology and biotechnology. Some recent experiments have suggested that the π-π stacking interactions between protein's aromatic residues and CNTs might play a key role in their binding, which raises interest in large scale modeling of protein-CNT complexes and associated π-π interactions at atomic detail. However, there is concern on the accuracy of classical fixed-charge molecular force fields due to their classical treatments and lack of polarizability. Here, we study the binding of three aromatic residue analogues (mimicking phenylalanine, tyrosine, and tryptophan) and benzene to a single-walled CNT, and compare the molecular mechanical (MM) calculations using three popular fixed-charge force fields (OPLSAA, AMBER, and CHARMM), with quantum mechanical (QM) calculations using the density-functional tight-binding method with the inclusion of dispersion correction (DFTB-D). Two typical configurations commonly found in π-π interactions are used, one with the aromatic rings parallel to the CNT surface (flat), and the other perpendicular (edge). Our calculations reveal that compared to the QM results the MM approaches can appropriately reproduce the strength of π-π interactions for both configurations, and more importantly, the energy difference between them, indicating that the various contributions to π-π interactions have been implicitly included in the van der Waals parameters of the standard MM force fields. Meanwhile, these MM models are less accurate in predicting the exact structural binding patterns (matching surface), meaning there are still rooms to be improved. In addition, we have provided a comprehensive and reliable QM picture for the π-π interactions of aromatic molecules with CNTs in gas phase, which might be used as a benchmark for future force field developments.

Quantum mechanical calculations related to ionization and charge transfer in DNA

NASA Astrophysics Data System (ADS)

Cauët, E.; Valiev, M.; Weare, J. H.; Liévin, J.

2012-07-01

Ionization and charge migration in DNA play crucial roles in mechanisms of DNA damage caused by ionizing radiation, oxidizing agents and photo-irradiation. Therefore, an evaluation of the ionization properties of the DNA bases is central to the full interpretation and understanding of the elementary reactive processes that occur at the molecular level during the initial exposure and afterwards. Ab initio quantum mechanical (QM) methods have been successful in providing highly accurate evaluations of key parameters, such as ionization energies (IE) of DNA bases. Hence, in this study, we performed high-level QM calculations to characterize the molecular energy levels and potential energy surfaces, which shed light on ionization and charge migration between DNA bases. In particular, we examined the IEs of guanine, the most easily oxidized base, isolated and embedded in base clusters, and investigated the mechanism of charge migration over two and three stacked guanines. The IE of guanine in the human telomere sequence has also been evaluated. We report a simple molecular orbital analysis to explain how modifications in the base sequence are expected to change the efficiency of the sequence as a hole trap. Finally, the application of a hybrid approach combining quantum mechanics with molecular mechanics brings an interesting discussion as to how the native aqueous DNA environment affects the IE threshold of nucleobases.

Density-Dependent Formulation of Dispersion-Repulsion Interactions in Hybrid Multiscale Quantum/Molecular Mechanics (QM/MM) Models.

PubMed

Curutchet, Carles; Cupellini, Lorenzo; Kongsted, Jacob; Corni, Stefano; Frediani, Luca; Steindal, Arnfinn Hykkerud; Guido, Ciro A; Scalmani, Giovanni; Mennucci, Benedetta

2018-03-13

Mixed multiscale quantum/molecular mechanics (QM/MM) models are widely used to explore the structure, reactivity, and electronic properties of complex chemical systems. Whereas such models typically include electrostatics and potentially polarization in so-called electrostatic and polarizable embedding approaches, respectively, nonelectrostatic dispersion and repulsion interactions are instead commonly described through classical potentials despite their quantum mechanical origin. Here we present an extension of the Tkatchenko-Scheffler semiempirical van der Waals (vdW TS ) scheme aimed at describing dispersion and repulsion interactions between quantum and classical regions within a QM/MM polarizable embedding framework. Starting from the vdW TS expression, we define a dispersion and a repulsion term, both of them density-dependent and consistently based on a Lennard-Jones-like potential. We explore transferable atom type-based parametrization strategies for the MM parameters, based on either vdW TS calculations performed on isolated fragments or on a direct estimation of the parameters from atomic polarizabilities taken from a polarizable force field. We investigate the performance of the implementation by computing self-consistent interaction energies for the S22 benchmark set, designed to represent typical noncovalent interactions in biological systems, in both equilibrium and out-of-equilibrium geometries. Overall, our results suggest that the present implementation is a promising strategy to include dispersion and repulsion in multiscale QM/MM models incorporating their explicit dependence on the electronic density.

Hardening of electromechanical properties in piezoceramics using a composite approach

NASA Astrophysics Data System (ADS)

K. V., Lalitha; Riemer, Lukas M.; Koruza, Jurij; Rödel, Jürgen

2017-07-01

Piezoelectric applications such as ultrasonic motors, transformers and therapeutic ultrasonics demand high power generation with low losses, which is facilitated by "hard" ferroelectrics. Hardening of piezoelectric properties, characterized by high mechanical quality factor (Qm), is usually achieved by doping with lower valence elements, thereby tailoring the domain wall dynamics. In the present study, we demonstrate a hardening mechanism by developing composites of 0.94(Na1/2Bi1/2)TiO3-0.06BaTiO3 (NBT-6BT) with ZnO inclusions, as an alternative to chemical modifications. A decrease in the saturation polarization and total strain, higher internal bias fields, lower hysteretic losses and a two-fold increase in Qm are observed in comparison to NBT-6BT. The composite with 0.1 mole ratio of ZnO exhibits the highest Qm of 320 with d33 = 125 pC/N and Kp = 0.29. A one-to-one correspondence between the increase in Qm and the decrease in the domain wall mobility is established from the ac field dependence of permittivity, in the framework of the Rayleigh law. A further increase in ZnO content beyond a mole ratio of 0.1 reduces Qm, but retains it at a higher level, as compared to NBT-6BT. The results are explained based on the poling-induced strain incompatibility between the matrix and the hard ZnO phase. This composite approach is therefore considered a generic hardening concept and can be extended to other ferroelectric systems.

Bipartite qutrit local realist inequalities and the robustness of their quantum mechanical violation

NASA Astrophysics Data System (ADS)

Das, Debarshi; Datta, Shounak; Goswami, Suchetana; Majumdar, A. S.; Home, Dipankar

2017-10-01

Distinct from the type of local realist inequality (known as the Collins-Gisin-Linden-Massar-Popescu or CGLMP inequality) usually used for bipartite qutrit systems, we formulate a new set of local realist inequalities for bipartite qutrits by generalizing Wigner's argument that was originally formulated for the bipartite qubit singlet state. This treatment assumes existence of the overall joint probability distributions in the underlying stochastic hidden variable space for the measurement outcomes pertaining to the relevant trichotomic observables, satisfying the locality condition and yielding the measurable marginal probabilities. Such generalized Wigner inequalities (GWI) do not reduce to Bell-CHSH type inequalities by clubbing any two outcomes, and are violated by quantum mechanics (QM) for both the bipartite qutrit isotropic and singlet states using trichotomic observables defined by six-port beam splitter as well as by the spin-1 component observables. The efficacy of GWI is then probed in these cases by comparing the QM violation of GWI with that obtained for the CGLMP inequality. This comparison is done by incorporating white noise in the singlet and isotropic qutrit states. It is found that for the six-port beam splitter observables, QM violation of GWI is more robust than that of the CGLMP inequality for singlet qutrit states, while for isotropic qutrit states, QM violation of the CGLMP inequality is more robust. On the other hand, for the spin-1 component observables, QM violation of GWI is more robust for both the types of states considered.

The Use of Multiscale Molecular Simulations in Understanding a Relationship between the Structure and Function of Biological Systems of the Brain: The Application to Monoamine Oxidase Enzymes

PubMed Central

Vianello, Robert; Domene, Carmen; Mavri, Janez

2016-01-01

HIGHLIGHTS Computational techniques provide accurate descriptions of the structure and dynamics of biological systems, contributing to their understanding at an atomic level.Classical MD simulations are a precious computational tool for the processes where no chemical reactions take place.QM calculations provide valuable information about the enzyme activity, being able to distinguish among several mechanistic pathways, provided a carefully selected cluster model of the enzyme is considered.Multiscale QM/MM simulation is the method of choice for the computational treatment of enzyme reactions offering quantitative agreement with experimentally determined reaction parameters.Molecular simulation provide insight into the mechanism of both the catalytic activity and inhibition of monoamine oxidases, thus aiding in the rational design of their inhibitors that are all employed and antidepressants and antiparkinsonian drugs. Aging society and therewith associated neurodegenerative and neuropsychiatric diseases, including depression, Alzheimer's disease, obsessive disorders, and Parkinson's disease, urgently require novel drug candidates. Targets include monoamine oxidases A and B (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and various receptors and transporters. For rational drug design it is particularly important to combine experimental synthetic, kinetic, toxicological, and pharmacological information with structural and computational work. This paper describes the application of various modern computational biochemistry methods in order to improve the understanding of a relationship between the structure and function of large biological systems including ion channels, transporters, receptors, and metabolic enzymes. The methods covered stem from classical molecular dynamics simulations to understand the physical basis and the time evolution of the structures, to combined QM, and QM/MM approaches to probe the chemical mechanisms of enzymatic activities and their inhibition. As an illustrative example, the later will focus on the monoamine oxidase family of enzymes, which catalyze the degradation of amine neurotransmitters in various parts of the brain, the imbalance of which is associated with the development and progression of a range of neurodegenerative disorders. Inhibitors that act mainly on MAO A are used in the treatment of depression, due to their ability to raise serotonin concentrations, while MAO B inhibitors decrease dopamine degradation and improve motor control in patients with Parkinson disease. Our results give strong support that both MAO isoforms, A and B, operate through the hydride transfer mechanism. Relevance of MAO catalyzed reactions and MAO inhibition in the context of neurodegeneration will be discussed. PMID:27471444

Predicted detonation properties at the Chapman-Jouguet state for proposed energetic materials (MTO and MTO3N) from combined ReaxFF and quantum mechanics reactive dynamics.

PubMed

Zhou, Tingting; Zybin, Sergey V; Goddard, William A; Cheng, Tao; Naserifar, Saber; Jaramillo-Botero, Andres; Huang, Fenglei

2018-02-07

The development of new energetic materials (EMs) with improved detonation performance but low sensitivity and environmental impact is of considerable importance for applications in civilian and military fields. Often new designs are difficult to synthesize so predictions of performance in advance is most valuable. Examples include MTO (2,4,6-triamino-1,3,5-triazine-1,3,5-trioxide) and MTO3N (2,4,6-trinitro-1,3,5-triazine-1,3,5-trioxide) suggested by Klapötke as candidate EMs but not yet successfully synthesized. We propose and apply to these materials a new approach, RxMD(cQM), in which ReaxFF Reactive Molecular Dynamics (RxMD) is first used to predict the reaction products and thermochemical properties at the Chapman Jouguet (CJ) state for which the system is fully reacted and at chemical equilibrium. Quantum mechanics dynamics (QMD) is then applied to refine the pressure of the ReaxFF predicted CJ state to predict a more accurate final CJ point, leading to a very practical calculation that includes accurate long range vdW interactions needed for accurate pressure. For MTO, this RxMD(cQM) method predicts a detonation pressure of P CJ = 40.5 GPa and a detonation velocity of D CJ = 8.8 km s -1 , while for MTO3N it predicts P CJ = 39.9 GPa and D CJ = 8.4 km s -1 , making them comparable to HMX (P CJ = 39.5 GPa, D CJ = 9.1 km s -1 ) and worth synthesizing. This first-principles-based RxMD(cQM) methodology provides an excellent compromise between computational cost and accuracy including the formation of clusters that burn too slowly, providing a practical mean of assessing detonation performances for novel candidate EMs. This RxMD(cQM) method that links first principles atomistic molecular dynamics simulations with macroscopic properties to promote in silico design of new EMs should also be of general applicability to materials synthesis and processing.

Progresses in Ab Initio QM/MM Free Energy Simulations of Electrostatic Energies in Proteins: Accelerated QM/MM Studies of pKa, Redox Reactions and Solvation Free Energies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kamerlin, Shina C. L.; Haranczyk, Maciej; Warshel, Arieh

2009-03-01

Hybrid quantum mechanical / molecular mechanical (QM/MM) approaches have been used to provide a general scheme for chemical reactions in proteins. However, such approaches still present a major challenge to computational chemists, not only because of the need for very large computer time in order to evaluate the QM energy but also because of the need for propercomputational sampling. This review focuses on the sampling issue in QM/MM evaluations of electrostatic energies in proteins. We chose this example since electrostatic energies play a major role in controlling the function of proteins and are key to the structure-function correlation of biologicalmore » molecules. Thus, the correct treatment of electrostatics is essential for the accurate simulation of biological systems. Although we will be presenting here different types of QM/MM calculations of electrostatic energies (and related properties), our focus will be on pKa calculations. This reflects the fact that pKa of ionizable groups in proteins provide one of the most direct benchmarks for the accuracy of electrostatic models of macromolecules. While pKa calculations by semimacroscopic models have given reasonable results in many cases, existing attempts to perform pKa calculations using QM/MM-FEP have led to large discrepancies between calculated and experimental values. In this work, we accelerate our QM/MM calculations using an updated mean charge distribution and a classical reference potential. We examine both a surface residue (Asp3) of the bovine pancreatic trypsin inhibitor, as well as a residue buried in a hydrophobic pocket (Lys102) of the T4-lysozyme mutant. We demonstrate that by using this approach, we are able to reproduce the relevant sidechain pKas with an accuracy of 3 kcal/mol. This is well within the 7 kcal/mol energy difference observed in studies of enzymatic catalysis, and is thus sufficient accuracy to determine the main contributions to the catalytic energies of enzymes. We also provide an overall perspective of the potential of QM/MM calculations in general evaluations of electrostatic free energies, pointing out that our approach should provide a very powerful and accurate tool to predict the electrostatics of not only solution but also enzymatic reactions, as well as the solvation free energies of even larger systems, such as nucleic acid bases incorporated into DNA.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Löytynoja, T., E-mail: tuomas.loytynoja@oulu.fi; Division of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology, SE-106 91 Stockholm; Li, X.

We study a newly devised quantum mechanics capacitance molecular mechanics (QMCMM) method for the calculation of core-electron binding energies in the case of molecules adsorbed on metal surfaces. This yet untested methodology is applied to systems with monolayer of methanol/methyl nitrite on an Ag(111) surface at 100 K temperature. It was found out that the studied C, N, and O 1s core-hole energies converge very slowly as a function of the radius of the metallic cluster, which was ascribed to build up of positive charge on the edge of the Ag slab. Further analysis revealed that an extrapolation process canmore » be used to obtain binding energies that deviated less than 0.5 eV against experiments, except in the case of methanol O 1s where the difference was as large as 1.8 eV. Additional QM-cluster calculations suggest that the latter error can be connected to the lack of charge transfer over the QM–CMM boundary. Thus, the results indicate that the QMCMM and QM-cluster methods can complement each other in a holistic picture of molecule-adsorbate core-ionization studies, where all types of intermolecular interactions are considered.« less

Effects of nonadditive interactions on ion solvation at the water/vapor interface: a molecular dynamics study.

PubMed

Yagasaki, Takuma; Saito, Shinji; Ohmine, Iwao

2010-12-09

The solvation of halide ions at the water/vapor interface is investigated by using molecular dynamics simulations with nonpolarizable molecular mechanical (MM), polarizable MM, and quantum mechanical (QM)/MM methods. The free energy profile of the ion solvation is decomposed into the energy and the entropic contributions along the ion displacement from inside to the surface of water. It is found that the surface affinity of the ion, relative to the bulk value, is determined by a subtle balance between the energetic destabilization and the entropic stabilization with the ion displacement. The amount of energetic destabilization is found to be reduced when nonadditive interactions are included, as in the polarizable MM and QM/MM models. The structure of water around the ion at the interface is also largely modified when the higher order effects are considered. For example, the induced dipole effect enhances the solvation structure around the ion at the interface significantly and thus reduces the amount of entropic stabilization at the interface, relative to in the bulk. It is found that this induced dipole effect causes the slowing in the ion-water hydrogen bond dynamics at the interface. On the other hand, the higher order induced multipole effects in the QM/MM method suppress both the excessive enhancement of the solvation structure and the slowing of the ion-water hydrogen bond dynamics at the interface. The present study demonstrates that not only the induced dipole moment but also the higher order induced multipole moments, which are neglected in standard empirical models, are essential for the correct description of the ion solvation at the water/vapor interface.

QM/MM studies of the mechanism of unusual bifunctional fructose-1,6-bisphosphate aldolase/phosphatase.

PubMed

Hou, Qianqian; Sheng, Xiang; Liu, Yongjun

2014-06-21

Archaeal fructose-1,6-bisphosphate aldolase/phosphatase (FBPA/P) is a newly identified unusual bifunctional enzyme (Nature, 2010, 464, 1077), which contains one single catalytic domain but catalyzes two chemically distinct reactions of gluconeogenesis. It is different from the ordinary enzymes whose active sites are responsible for a specific reaction. To explore the catalytic characteristic of FBPA/P, the aldol condensation mechanism of bifunctional FBPA/P has been investigated using quantum mechanics/molecular mechanics (QM/MM) method. The whole reaction process can be divided into two half-reactions involving seven elementary steps. A Schiff base intermediate is theoretically confirmed, agreeing well with the recently resolved crystal structures (Nature, 2011, 478, 538). The free energy barrier of the rate-limiting step is calculated to be 22.2 kcal mol(-1), which is a concerted process of a nucleophilic attack by the enolic carbon to the ketonic carbon and a proton transfer from Tyr229 to the ketonic oxygen. Lys232 plays an important role in forming a Schiff base intermediate with the substrate (DHAP). Tyr229 functions as a proton shuttle during the catalysis. This is the first theoretical study on the aldol condensation mechanism of FBPA/P, which may provide useful information for understanding bifunctional enzymes.

Transition-state optimization by the free energy gradient method: Application to aqueous-phase Menshutkin reaction between ammonia and methyl chloride

NASA Astrophysics Data System (ADS)

Hirao, Hajime; Nagae, Yukihiko; Nagaoka, Masataka

2001-11-01

The transition state (TS) for the Menshutkin reaction H 3N+CH 3Cl→H 3NCH 3++Cl - in aqueous solution was located on the free energy surface (FES) by the free energy gradient (FEG) method. The solute-solvent system was described by a hybrid quantum mechanical and molecular mechanical (QM/MM) method. The reaction path in water was found to deviate largely from that in the gas phase. It was concluded that, in such a reaction including charge separation, TS structure optimization on an FES is inevitable for obtaining valid information about a TS in solution.

Continuum-atomistic simulation of picosecond laser heating of copper with electron heat capacity from ab initio calculation

NASA Astrophysics Data System (ADS)

Ji, Pengfei; Zhang, Yuwen

2016-03-01

On the basis of ab initio quantum mechanics (QM) calculation, the obtained electron heat capacity is implemented into energy equation of electron subsystem in two temperature model (TTM). Upon laser irradiation on the copper film, energy transfer from the electron subsystem to the lattice subsystem is modeled by including the electron-phonon coupling factor in molecular dynamics (MD) and TTM coupled simulation. The results show temperature and thermal melting difference between the QM-MD-TTM integrated simulation and pure MD-TTM coupled simulation. The successful construction of the QM-MD-TTM integrated simulation provides a general way that is accessible to other metals in laser heating.

Analytical gradients for MP2, double hybrid functionals, and TD‐DFT with polarizable embedding described by fluctuating charges

PubMed Central

Carnimeo, Ivan; Cappelli, Chiara

2015-01-01

A polarizable quantum mechanics (QM)/ molecular mechanics (MM) approach recently developed for Hartree–Fock (HF) and Kohn–Sham (KS) methods has been extended to energies and analytical gradients for MP2, double hybrid functionals, and TD‐DFT models, thus allowing the computation of equilibrium structures for excited electronic states together with more accurate results for ground electronic states. After a detailed presentation of the theoretical background and of some implementation details, a number of test cases are analyzed to show that the polarizable embedding model based on fluctuating charges (FQ) is remarkably more accurate than the corresponding electronic embedding based on a fixed charge (FX) description. In particular, a set of electronegativities and hardnesses has been optimized for interactions between QM and FQ regions together with new repulsion–dispersion parameters. After validation of both the numerical implementation and of the new parameters, absorption electronic spectra have been computed for representative model systems including vibronic effects. The results show remarkable agreement with full QM computations and significant improvement with respect to the corresponding FX results. The last part of the article provides some hints about computation of solvatochromic effects on absorption spectra in aqueous solution as a function of the number of FQ water molecules and on the use of FX external shells to improve the convergence of the results. © 2015 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. PMID:26399473

Time Domain Propagation of Quantum and Classical Systems using a Wavelet Basis Set Method

NASA Astrophysics Data System (ADS)

Lombardini, Richard; Nowara, Ewa; Johnson, Bruce

2015-03-01

The use of an orthogonal wavelet basis set (Optimized Maximum-N Generalized Coiflets) to effectively model physical systems in the time domain, in particular the electromagnetic (EM) pulse and quantum mechanical (QM) wavefunction, is examined in this work. Although past research has demonstrated the benefits of wavelet basis sets to handle computationally expensive problems due to their multiresolution properties, the overlapping supports of neighboring wavelet basis functions poses problems when dealing with boundary conditions, especially with material interfaces in the EM case. Specifically, this talk addresses this issue using the idea of derivative matching creating fictitious grid points (T.A. Driscoll and B. Fornberg), but replaces the latter element with fictitious wavelet projections in conjunction with wavelet reconstruction filters. Two-dimensional (2D) systems are analyzed, EM pulse incident on silver cylinders and the QM electron wave packet circling the proton in a hydrogen atom system (reduced to 2D), and the new wavelet method is compared to the popular finite-difference time-domain technique.

Have Nursing Home Compare quality measure scores changed over time in response to competition?

PubMed

Castle, Nicholas G; Engberg, John; Liu, Darren

2007-06-01

Currently, the Centers for Medicare and Medicaid Services report on 15 Quality Measures (QMs) on the Nursing Home Compare (NHC) website. It is assumed that nursing homes are able to make improvements on these QMs, and in doing so they will attract more residents. In this investigation, we examine changes in QM scores, and whether competition and/or excess demand have influenced these change scores over a period of 1 year. Data come from NHC and the On-line Survey Certification And Recording (OSCAR) system. QM change scores are calculated using values from January 2003 to January 2004. A series of regression analyses are used to examine the association of competition and excess demand on QM scores. Eight QMs show an average decrease in scores (ie, better quality) and six QMs show an average increase in scores (ie, worse quality). However, for 13 of the 14 QMs these average changes averaged less than 1%. The regression analyses show an association between higher competition and improving QM scores and an association between lower occupancy and improving QM scores. As would be predicted based on the market-driven mechanism underlying quality improvements using report cards, we show that it is in the most competitive markets and those with the lowest average occupancy rates that improvements in the QM scores are more likely.

A Novel Multiscale QM-MD-SPH Computational Method for Heterogeneous Multicomponent Reactive Systems

DTIC Science & Technology

2017-11-30

The first-principle study on the equation of state of hmx under high pressure. Science China Physics, Mechanics and Astronomy , 54(5):831–835, 2011...J J Monaghan, J C Lattanzio. A refined particle method for astrophysical problems. Astronomy and astrophysics 149 (1985): 135-143. 133 [148] J J...Monaghan. Smoothed particle hydrodynamics. Annual review of astronomy and astrophysics 30.1 (1992): 543-574. [149] J P Morris. A study of the

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hégely, Bence; Nagy, Péter R.; Kállay, Mihály, E-mail: kallay@mail.bme.hu

Exact schemes for the embedding of density functional theory (DFT) and wave function theory (WFT) methods into lower-level DFT or WFT approaches are introduced utilizing orbital localization. First, a simple modification of the projector-based embedding scheme of Manby and co-workers [J. Chem. Phys. 140, 18A507 (2014)] is proposed. We also use localized orbitals to partition the system, but instead of augmenting the Fock operator with a somewhat arbitrary level-shift projector we solve the Huzinaga-equation, which strictly enforces the Pauli exclusion principle. Second, the embedding of WFT methods in local correlation approaches is studied. Since the latter methods split up themore » system into local domains, very simple embedding theories can be defined if the domains of the active subsystem and the environment are treated at a different level. The considered embedding schemes are benchmarked for reaction energies and compared to quantum mechanics (QM)/molecular mechanics (MM) and vacuum embedding. We conclude that for DFT-in-DFT embedding, the Huzinaga-equation-based scheme is more efficient than the other approaches, but QM/MM or even simple vacuum embedding is still competitive in particular cases. Concerning the embedding of wave function methods, the clear winner is the embedding of WFT into low-level local correlation approaches, and WFT-in-DFT embedding can only be more advantageous if a non-hybrid density functional is employed.« less

Exact density functional and wave function embedding schemes based on orbital localization

NASA Astrophysics Data System (ADS)

Hégely, Bence; Nagy, Péter R.; Ferenczy, György G.; Kállay, Mihály

2016-08-01

Exact schemes for the embedding of density functional theory (DFT) and wave function theory (WFT) methods into lower-level DFT or WFT approaches are introduced utilizing orbital localization. First, a simple modification of the projector-based embedding scheme of Manby and co-workers [J. Chem. Phys. 140, 18A507 (2014)] is proposed. We also use localized orbitals to partition the system, but instead of augmenting the Fock operator with a somewhat arbitrary level-shift projector we solve the Huzinaga-equation, which strictly enforces the Pauli exclusion principle. Second, the embedding of WFT methods in local correlation approaches is studied. Since the latter methods split up the system into local domains, very simple embedding theories can be defined if the domains of the active subsystem and the environment are treated at a different level. The considered embedding schemes are benchmarked for reaction energies and compared to quantum mechanics (QM)/molecular mechanics (MM) and vacuum embedding. We conclude that for DFT-in-DFT embedding, the Huzinaga-equation-based scheme is more efficient than the other approaches, but QM/MM or even simple vacuum embedding is still competitive in particular cases. Concerning the embedding of wave function methods, the clear winner is the embedding of WFT into low-level local correlation approaches, and WFT-in-DFT embedding can only be more advantageous if a non-hybrid density functional is employed.

Recent advances in jointed quantum mechanics and molecular mechanics calculations of biological macromolecules: schemes and applications coupled to ab initio calculations.

PubMed

Hagiwara, Yohsuke; Tateno, Masaru

2010-10-20

We review the recent research on the functional mechanisms of biological macromolecules using theoretical methodologies coupled to ab initio quantum mechanical (QM) treatments of reaction centers in proteins and nucleic acids. Since in most cases such biological molecules are large, the computational costs of performing ab initio calculations for the entire structures are prohibitive. Instead, simulations that are jointed with molecular mechanics (MM) calculations are crucial to evaluate the long-range electrostatic interactions, which significantly affect the electronic structures of biological macromolecules. Thus, we focus our attention on the methodologies/schemes and applications of jointed QM/MM calculations, and discuss the critical issues to be elucidated in biological macromolecular systems. © 2010 IOP Publishing Ltd

Binding free energies for nicotine analogs inhibiting cytochrome P450 2A6 by a combined use of molecular dynamics simulations and QM/MM-PBSA calculations.

PubMed

Lu, Haiting; Huang, Xiaoqin; AbdulHameed, Mohamed Diwan M; Zhan, Chang-Guo

2014-04-01

Molecular dynamics (MD) simulations and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations have been performed to explore the dynamic behaviors of cytochrome P450 2A6 (CYP2A6) binding with nicotine analogs (that are typical inhibitors) and to calculate their binding free energies in combination with Poisson-Boltzmann surface area (PBSA) calculations. The combined MD simulations and QM/MM-PBSA calculations reveal that the most important structural parameters affecting the CYP2A6-inhibitor binding affinity are two crucial internuclear distances, that is, the distance between the heme iron atom of CYP2A6 and the coordinating atom of the inhibitor, and the hydrogen-bonding distance between the N297 side chain of CYP2A6 and the pyridine nitrogen of the inhibitor. The combined MD simulations and QM/MM-PBSA calculations have led to dynamic CYP2A6-inhibitor binding structures that are consistent with the observed dynamic behaviors and structural features of CYP2A6-inhibitor binding, and led to the binding free energies that are in good agreement with the experimentally-derived binding free energies. The agreement between the calculated binding free energies and the experimentally-derived binding free energies suggests that the combined MD and QM/MM-PBSA approach may be used as a valuable tool to accurately predict the CYP2A6-inhibitor binding affinities in future computational design of new, potent and selective CYP2A6 inhibitors. Copyright © 2014 Elsevier Ltd. All rights reserved.

HCl dissociating on a rigid Au(111) surface: A six-dimensional quantum mechanical study on a new potential energy surface based on the RPBE functional.

PubMed

Liu, Tianhui; Fu, Bina; Zhang, Dong H

2017-04-28

The dissociative chemisorption of HCl on the Au(111) surface has recently been an interesting and important subject, regarding the discrepancy between the theoretical dissociation probabilities and the experimental sticking probabilities. We here constructed an accurate full-dimensional (six-dimensional (6D)) potential energy surface (PES) based on the density functional theory (DFT) with the revised Perdew-Burke-Ernzerhof (RPBE) functional, and performed 6D quantum mechanical (QM) calculations for HCl dissociating on a rigid Au(111) surface. The effects of vibrational excitations, rotational orientations, and site-averaging approximation on the present RPBE PES are investigated. Due to the much higher barrier height obtained on the RPBE PES than on the PW91 PES, the agreement between the present theoretical and experimental results is greatly improved. In particular, at the very low kinetic energy, the QM-RPBE dissociation probability agrees well with the experimental data. However, the computed QM-RPBE reaction probabilities are still markedly different from the experimental values at most of the energy regions. In addition, the QM-RPBE results achieve good agreement with the recent ab initio molecular dynamics calculations based on the RPBE functional at high kinetic energies.

DUQuE quality management measures: associations between quality management at hospital and pathway levels.

PubMed

Wagner, Cordula; Groene, Oliver; Thompson, Caroline A; Dersarkissian, Maral; Klazinga, Niek S; Arah, Onyebuchi A; Suñol, Rosa

2014-04-01

The assessment of integral quality management (QM) in a hospital requires measurement and monitoring from different perspectives and at various levels of care delivery. Within the DUQuE project (Deepening our Understanding of Quality improvement in Europe), seven measures for QM were developed. This study investigates the relationships between the various quality measures. It is a multi-level, cross-sectional, mixed-method study. As part of the DUQuE project, we invited a random sample of 74 hospitals in 7 countries. The quality managers of these hospitals were the main respondents. Furthermore, data of site visits of external surveyors assessing the participating hospitals were used. Three measures of QM at hospitals level focusing on integral systems (QMSI), compliance with the Plan-Do-Study-Act quality improvement cycle (QMCI) and implementation of clinical quality (CQII). Four measures of QM activities at care pathway level focusing on Specialized expertise and responsibility (SER), Evidence-based organization of pathways (EBOP), Patient safety strategies (PSS) and Clinical review (CR). Positive significant associations were found between the three hospitals level QM measures. Results of the relationships between levels were mixed and showed most associations between QMCI and department-level QM measures for all four types of departments. QMSI was associated with PSS in all types of departments. By using the seven measures of QM, it is possible to get a more comprehensive picture of the maturity of QM in hospitals, with regard to the different levels and across various types of hospital departments.

MurD ligase from E. coli: Tetrahedral intermediate formation study by hybrid quantum mechanical/molecular mechanical replica path method.

PubMed

Perdih, Andrej; Hodoscek, Milan; Solmajer, Tom

2009-02-15

MurD (UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase), a three-domain bacterial protein, catalyses a highly specific incorporation of D-glutamate to the cytoplasmic intermediate UDP-N-acetyl-muramoyl-L-alanine (UMA) utilizing ATP hydrolysis to ADP and P(i). This reaction is part of a biosynthetic path yielding bacterial peptidoglycan. On the basis of structural studies of MurD complexes, a stepwise catalytic mechanism was proposed that commences with a formation of the acyl-phosphate intermediate, followed by a nucleophilic attack of D-glutamate that, through the formation of a tetrahedral reaction intermediate and subsequent phosphate dissociation, affords the final product, UDP-N-acetyl-muramoyl-L-alanine-D-glutamate (UMAG). A hybrid quantum mechanical/molecular mechanical (QM/MM) molecular modeling approach was utilized, combining the B3LYP QM level of theory with empirical force field simulations to evaluate three possible reaction pathways leading to tetrahedral intermediate formation. Geometries of the starting structures based on crystallographic experimental data and tetrahedral intermediates were carefully examined together with a role of crucial amino acids and water molecules. The replica path method was used to generate the reaction pathways between the starting structures and the corresponding tetrahedral reaction intermediates, offering direct comparisons with a sequential kinetic mechanism and the available structural data for this enzyme. The acquired knowledge represents new and valuable information to assist in the ongoing efforts leading toward novel inhibitors of MurD as potential antibacterial drugs. (c) 2008 Wiley-Liss, Inc.

Intermolecular interactions in the condensed phase: Evaluation of semi-empirical quantum mechanical methods

NASA Astrophysics Data System (ADS)

Christensen, Anders S.; Kromann, Jimmy C.; Jensen, Jan H.; Cui, Qiang

2017-10-01

To facilitate further development of approximate quantum mechanical methods for condensed phase applications, we present a new benchmark dataset of intermolecular interaction energies in the solution phase for a set of 15 dimers, each containing one charged monomer. The reference interaction energy in solution is computed via a thermodynamic cycle that integrates dimer binding energy in the gas phase at the coupled cluster level and solute-solvent interaction with density functional theory; the estimated uncertainty of such calculated interaction energy is ±1.5 kcal/mol. The dataset is used to benchmark the performance of a set of semi-empirical quantum mechanical (SQM) methods that include DFTB3-D3, DFTB3/CPE-D3, OM2-D3, PM6-D3, PM6-D3H+, and PM7 as well as the HF-3c method. We find that while all tested SQM methods tend to underestimate binding energies in the gas phase with a root-mean-squared error (RMSE) of 2-5 kcal/mol, they overestimate binding energies in the solution phase with an RMSE of 3-4 kcal/mol, with the exception of DFTB3/CPE-D3 and OM2-D3, for which the systematic deviation is less pronounced. In addition, we find that HF-3c systematically overestimates binding energies in both gas and solution phases. As most approximate QM methods are parametrized and evaluated using data measured or calculated in the gas phase, the dataset represents an important first step toward calibrating QM based methods for application in the condensed phase where polarization and exchange repulsion need to be treated in a balanced fashion.

QM/MM investigation of the concentration effects on the second-order nonlinear optical responses of solutions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hidalgo Cardenuto, Marcelo, E-mail: marcelo.hidalgo@unamur.be, E-mail: benoit.champagne@unamur.be; Instituto de Física, Universidade de São Paulo, CP 66318, 05314-970 São Paulo, SP; Champagne, Benoît, E-mail: marcelo.hidalgo@unamur.be, E-mail: benoit.champagne@unamur.be

2014-12-21

A multiscale approach combining quantum mechanics (QM) and molecular mechanics methods has been employed to investigate the effects of solute-solute interactions and therefore of concentration on the first hyperpolarizability of solutions of nitrobenzene in benzene. First, spatial distributions of solute and solvent molecules are generated using Monte Carlo simulations where the intermolecular interactions are described using the Lennard-Jones potentials and Coulomb terms. Then, a reduced number of statistically-uncorrelated configurations are sampled and submitted to time-dependent Hartree-Fock calculations of the first hyperpolarizability. When only one molecule is described quantum-mechanically and is embedded in the electrostatic polarization field of the solution describedmore » by point charges, β{sub HRS} and β{sub //} as well as the depolarization ratio increase in parallel with the concentration in nitrobenzene. This effect is attributed to the increase of the polarization field associated with the presence of polar nitrobenzene molecules in the surrounding. Then, the first solvation shell is considered explicitly in the QM calculation to address solute-solute interactions effects. When the number of nitrobenzenes in the first solvation shell increases, β{sub HRS} and β{sub //} normalized to the number of nitrobenzene molecules decrease and this decrease attains roughly 50% when there are 3 nitrobenzene molecules in the first solvation shell. These drastic reductions of the first hyperpolarizability result from (partial) centro-symmetric arrangements between the nitrobenzene molecules, as supported by the relationship between β and the angle between the nitrobenzene charge transfer axes. Moreover, these β decreases originate mostly from the reduction of the dipolar β component, whereas the octupolar one is rather constant as a function of the nitrobenzene concentration.« less

A QM/MM study of the initial excited state dynamics of green-absorbing proteorhodopsin.

PubMed

Borin, Veniamin A; Wiebeler, Christian; Schapiro, Igor

2018-04-17

The primary photochemical reaction of the green-absorbing proteorhodopsin is studied by means of a hybrid quantum mechanics/molecular mechanics (QM/MM) approach. The simulations are based on a homology model derived from the blue-absorbing proteorhodopsin crystal structure. The geometry of retinal and the surrounding sidechains in the protein binding pocket were optimized using the QM/MM method. Starting from this geometry the isomerization was studied with a relaxed scan along the C13[double bond, length as m-dash]C14 dihedral. It revealed an "aborted bicycle pedal" mechanism of isomerization that was originally proposed by Warshel for bovine rhodopsin and bacteriorhodopsin. However, the isomerization involved the concerted rotation about C13[double bond, length as m-dash]C14 and C15[double bond, length as m-dash]N, with the latter being highly twisted but not isomerized. Further, the simulation showed an increased steric interaction between the hydrogen at the C14 of the isomerizing bond and the hydroxyl group at the neighbouring tyrosine 200. In addition, we have simulated a nonadiabatic trajectory which showed the timing of the isomerization. In the first 20 fs upon excitation the order of the conjugated double and single bonds is inverted, consecutively the C13[double bond, length as m-dash]C14 rotation is activated for 200 fs until the S1-S0 transition is detected. However, the isomerization is reverted due to the specific interaction with the tyrosine as observed along the relaxed scan calculation. Our simulations indicate that the retinal - tyrosine 200 interaction plays an important role in the outcome of the photoisomerization.

Configurational assignments of conformationally restricted bis-monoterpene hydroquinones: Utility in exploration of endangered plants

Treesearch

Joonseok Oh; John J. Bowling; Amar G. Chittiboyina; Robert J. Doerksen; Daneel Ferreira; Theodor D. Leininger; Mark T. Hamann

2013-01-01

Endangered plant species are an important resource for new chemistry. Lindera melissifolia is native to the Southeastern U.S. and scarcely populates the edges of lakes and ponds. Quantum mechanics (QM) used in combination with NMR/ECD is a powerful tool for the assignment of absolute configuration in lieu of X-ray crystallography. Methods: The EtOAc extract of L....

Successful application of the DBLOC method to the hydroxylation of camphor by cytochrome p450

PubMed Central

Jerome, Steven V.; Hughes, Thomas F.

2015-01-01

Abstract The activation barrier for the hydroxylation of camphor by cytochrome P450 was computed using a mixed quantum mechanics/molecular mechanics (QM/MM) model of the full protein‐ligand system and a fully QM calculation using a cluster model of the active site at the B3LYP/LACVP*/LACV3P** level of theory, which consisted of B3LYP/LACV3P** single point energies computed at B3LYP/LACVP* optimized geometries. From the QM/MM calculation, a barrier height of 17.5 kcal/mol was obtained, while the experimental value was known to be less than or equal to 10 kcal/mol. This process was repeated using the D3 correction for hybrid DFT in order to investigate whether the inadequate treatment of dispersion interaction was responsible for the overestimation of the barrier. While the D3 correction does reduce the computed barrier to 13.3 kcal/mol, it was still in disagreement with experiment. After application of a series of transition metal optimized localized orbital corrections (DBLOC) and without any refitting of parameters, the barrier was further reduced to 10.0 kcal/mol, which was consistent with the experimental results. The DBLOC method to C—H bond activation in methane monooxygenase (MMO) was also applied, as a second, independent test. The barrier in MMO was known, by experiment, to be 15.4 kcal/mol.1 After application of the DBLOC corrections to the MMO barrier compute by B3LYP, in a previous study, and accounting for dispersion with Grimme's D3 method, the unsigned deviation from experiment was improved from 3.2 to 2.3 kcal/mol. These results suggested that the combination of dispersion plus localized orbital corrections could yield significant quantitative improvements in modeling the catalytic chemistry of transition‐metal containing enzymes, within the limitations of the statistical errors of the model, which appear to be on the order of approximately 2 kcal/mole. PMID:26441133

Hybrid quantum and molecular mechanics embedded cluster models for chemistry on silicon and silicon carbide surfaces

NASA Astrophysics Data System (ADS)

Shoemaker, James Richard

Fabrication of silicon carbide (SiC) semiconductor devices are of interest for aerospace applications because of their high-temperature tolerance. Growth of an insulating SiO2 layer on SiC by oxidation is a poorly understood process, and sometimes produces interface defects that degrade device performance. Accurate theoretical models of surface chemistry, using quantum mechanics (QM), do not exist because of the huge computational cost of solving Schrodinger's equation for a molecular cluster large enough to represent a surface. Molecular mechanics (MM), which describes a molecule as a collection of atoms interacting through classical potentials, is a fast computational method, good at predicting molecular structure, but cannot accurately model chemical reactions. A new hybrid QM/MM computational method for surface chemistry was developed and applied to silicon and SiC surfaces. The addition of MM steric constraints was shown to have a large effect on the energetics of O atom adsorption on SiC. Adsorption of O atoms on Si-terminated SiC(111) favors above surface sites, in contrast to Si(111), but favors subsurface adsorption sites on C- terminated SiC(111). This difference, and the energetics of C atom etching via CO2 desorption, can explain the observed poor performance of SiC devices in which insulating layers were grown on C-terminated surfaces.

QM/QM approach to model energy disorder in amorphous organic semiconductors.

PubMed

Friederich, Pascal; Meded, Velimir; Symalla, Franz; Elstner, Marcus; Wenzel, Wolfgang

2015-02-10

It is an outstanding challenge to model the electronic properties of organic amorphous materials utilized in organic electronics. Computation of the charge carrier mobility is a challenging problem as it requires integration of morphological and electronic degrees of freedom in a coherent methodology and depends strongly on the distribution of polaron energies in the system. Here we represent a QM/QM model to compute the polaron energies combining density functional methods for molecules in the vicinity of the polaron with computationally efficient density functional based tight binding methods in the rest of the environment. For seven widely used amorphous organic semiconductor materials, we show that the calculations are accelerated up to 1 order of magnitude without any loss in accuracy. Considering that the quantum chemical step is the efficiency bottleneck of a workflow to model the carrier mobility, these results are an important step toward accurate and efficient disordered organic semiconductors simulations, a prerequisite for accelerated materials screening and consequent component optimization in the organic electronics industry.

The Heisenberg Microscope: A Powerful Instructional Tool for Promoting Meta-Cognitive and Meta-Scientific Thinking on Quantum Mechanics and the ‚Nature of Science'

NASA Astrophysics Data System (ADS)

Hadzidaki, Pandora

2008-06-01

In this paper, we present a multi-dimensional study concerning Heisenberg’s ‚gamma ray microscope’, a thought experiment, which is intimately connected with the historical development of quantum mechanics (QM), and also with the most disputed interpretations of quantum theory. In this study: (a) we investigate how philosophers of science read and explicate the function of thought experimentation in physical science; (b) in the light of relevant philosophical theories, we examine the complicated epistemological questions raised by the ‚gamma-ray microscope’ during the birth-process of QM and the contribution of this thought experiment to the clarification of the physical meaning of Heisenberg’s indeterminacy relations; (c) on the basis of the preceding analysis, we propose an instructional intervention, which aims at leading learners not only to an essential understanding of QM worldview, but to a deep insight into the Nature of Science as well.

Automated Training of ReaxFF Reactive Force Fields for Energetics of Enzymatic Reactions.

PubMed

Trnka, Tomáš; Tvaroška, Igor; Koča, Jaroslav

2018-01-09

Computational studies of the reaction mechanisms of various enzymes are nowadays based almost exclusively on hybrid QM/MM models. Unfortunately, the success of this approach strongly depends on the selection of the QM region, and computational cost is a crucial limiting factor. An interesting alternative is offered by empirical reactive molecular force fields, especially the ReaxFF potential developed by van Duin and co-workers. However, even though an initial parametrization of ReaxFF for biomolecules already exists, it does not provide the desired level of accuracy. We have conducted a thorough refitting of the ReaxFF force field to improve the description of reaction energetics. To minimize the human effort required, we propose a fully automated approach to generate an extensive training set comprised of thousands of different geometries and molecular fragments starting from a few model molecules. Electrostatic parameters were optimized with QM electrostatic potentials as the main target quantity, avoiding excessive dependence on the choice of reference atomic charges and improving robustness and transferability. The remaining force field parameters were optimized using the VD-CMA-ES variant of the CMA-ES optimization algorithm. This method is able to optimize hundreds of parameters simultaneously with unprecedented speed and reliability. The resulting force field was validated on a real enzymatic system, ppGalNAcT2 glycosyltransferase. The new force field offers excellent qualitative agreement with the reference QM/MM reaction energy profile, matches the relative energies of intermediate and product minima almost exactly, and reduces the overestimation of transition state energies by 27-48% compared with the previous parametrization.

SU-E-T-489: Quantum versus Classical Trajectory Monte Carlo Simulations of Low Energy Electron Transport.

PubMed

Thomson, R; Kawrakow, I

2012-06-01

Widely-used classical trajectory Monte Carlo simulations of low energy electron transport neglect the quantum nature of electrons; however, at sub-1 keV energies quantum effects have the potential to become significant. This work compares quantum and classical simulations within a simplified model of electron transport in water. Electron transport is modeled in water droplets using quantum mechanical (QM) and classical trajectory Monte Carlo (MC) methods. Water droplets are modeled as collections of point scatterers representing water molecules from which electrons may be isotropically scattered. The role of inelastic scattering is investigated by introducing absorption. QM calculations involve numerically solving a system of coupled equations for the electron wavefield incident on each scatterer. A minimum distance between scatterers is introduced to approximate structured water. The average QM water droplet incoherent cross section is compared with the MC cross section; a relative error (RE) on the MC results is computed. RE varies with electron energy, average and minimum distances between scatterers, and scattering amplitude. The mean free path is generally the relevant length scale for estimating RE. The introduction of a minimum distance between scatterers increases RE substantially (factors of 5 to 10), suggesting that the structure of water must be modeled for accurate simulations. Inelastic scattering does not improve agreement between QM and MC simulations: for the same magnitude of elastic scattering, the introduction of inelastic scattering increases RE. Droplet cross sections are sensitive to droplet size and shape; considerable variations in RE are observed with changing droplet size and shape. At sub-1 keV energies, quantum effects may become non-negligible for electron transport in condensed media. Electron transport is strongly affected by the structure of the medium. Inelastic scatter does not improve agreement between QM and MC simulations of low energy electron transport in condensed media. © 2012 American Association of Physicists in Medicine.

Nuclear quantum effects and kinetic isotope effects in enzyme reactions.

PubMed

Vardi-Kilshtain, Alexandra; Nitoker, Neta; Major, Dan Thomas

2015-09-15

Enzymes are extraordinarily effective catalysts evolved to perform well-defined and highly specific chemical transformations. Studying the nature of rate enhancements and the mechanistic strategies in enzymes is very important, both from a basic scientific point of view, as well as in order to improve rational design of biomimetics. Kinetic isotope effect (KIE) is a very important tool in the study of chemical reactions and has been used extensively in the field of enzymology. Theoretically, the prediction of KIEs in condensed phase environments such as enzymes is challenging due to the need to include nuclear quantum effects (NQEs). Herein we describe recent progress in our group in the development of multi-scale simulation methods for the calculation of NQEs and accurate computation of KIEs. We also describe their application to several enzyme systems. In particular we describe the use of combined quantum mechanics/molecular mechanics (QM/MM) methods in classical and quantum simulations. The development of various novel path-integral methods is reviewed. These methods are tailor suited to enzyme systems, where only a few degrees of freedom involved in the chemistry need to be quantized. The application of the hybrid QM/MM quantum-classical simulation approach to three case studies is presented. The first case involves the proton transfer in alanine racemase. The second case presented involves orotidine 5'-monophosphate decarboxylase where multidimensional free energy simulations together with kinetic isotope effects are combined in the study of the reaction mechanism. Finally, we discuss the proton transfer in nitroalkane oxidase, where the enzyme employs tunneling as a catalytic fine-tuning tool. Copyright © 2015 Elsevier Inc. All rights reserved.

A Multidimensional B-Spline Correction for Accurate Modeling Sugar Puckering in QM/MM Simulations.

PubMed

Huang, Ming; Dissanayake, Thakshila; Kuechler, Erich; Radak, Brian K; Lee, Tai-Sung; Giese, Timothy J; York, Darrin M

2017-09-12

The computational efficiency of approximate quantum mechanical methods allows their use for the construction of multidimensional reaction free energy profiles. It has recently been demonstrated that quantum models based on the neglect of diatomic differential overlap (NNDO) approximation have difficulty modeling deoxyribose and ribose sugar ring puckers and thus limit their predictive value in the study of RNA and DNA systems. A method has been introduced in our previous work to improve the description of the sugar puckering conformational landscape that uses a multidimensional B-spline correction map (BMAP correction) for systems involving intrinsically coupled torsion angles. This method greatly improved the adiabatic potential energy surface profiles of DNA and RNA sugar rings relative to high-level ab initio methods even for highly problematic NDDO-based models. In the present work, a BMAP correction is developed, implemented, and tested in molecular dynamics simulations using the AM1/d-PhoT semiempirical Hamiltonian for biological phosphoryl transfer reactions. Results are presented for gas-phase adiabatic potential energy surfaces of RNA transesterification model reactions and condensed-phase QM/MM free energy surfaces for nonenzymatic and RNase A-catalyzed transesterification reactions. The results show that the BMAP correction is stable, efficient, and leads to improvement in both the potential energy and free energy profiles for the reactions studied, as compared with ab initio and experimental reference data. Exploration of the effect of the size of the quantum mechanical region indicates the best agreement with experimental reaction barriers occurs when the full CpA dinucleotide substrate is treated quantum mechanically with the sugar pucker correction.

Reductive half-reaction of aldehyde oxidoreductase toward acetaldehyde: Ab initio and free energy quantum mechanical/molecular mechanical calculations.

PubMed

Dieterich, Johannes M; Werner, Hans-Joachim; Mata, Ricardo A; Metz, Sebastian; Thiel, Walter

2010-01-21

Energy and free energy barriers for acetaldehyde conversion in aldehyde oxidoreductase are determined for three reaction pathways using quantum mechanical/molecular mechanical (QM/MM) calculations on the solvated enzyme. Ab initio single-point QM/MM energies are obtained at the stationary points optimized at the DFT(B3LYP)/MM level. These ab initio calculations employ local correlation treatments [LMP2 and LCCSD(T0)] in combination with augmented triple- and quadruple-zeta basis sets, and the final coupled cluster results include MP2-based corrections for basis set incompleteness and for the domain approximation. Free energy perturbation (FEP) theory is used to generate free energy profiles at the DFT(B3LYP)/MM level for the most important reaction steps by sampling along the corresponding reaction paths using molecular dynamics. The ab initio and FEP QM/MM results are combined to derive improved estimates of the free energy barriers, which differ from the corresponding DFT(B3LYP)/MM energy barriers by about 3 kcal mol(-1). The present results confirm the qualitative mechanistic conclusions from a previous DFT(B3LYP)/MM study. Most favorable is a three-step Lewis base catalyzed mechanism with an initial proton transfer from the cofactor to the Glu869 residue, a subsequent nucleophilic attack that yields a tetrahedral intermediate (IM2), and a final rate-limiting hydride transfer. The competing metal center activated pathway has the same final step but needs to overcome a higher barrier in the initial step on the route to IM2. The concerted mechanism has the highest free energy barrier and can be ruled out. While confirming the qualitative mechanistic scenario proposed previously on the basis of DFT(B3LYP)/MM energy profiles, the present ab initio and FEP QM/MM calculations provide corrections to the barriers that are important when aiming at high accuracy.

Simulating chemical reactions in ionic liquids using QM/MM methodology.

PubMed

Acevedo, Orlando

2014-12-18

The use of ionic liquids as a reaction medium for chemical reactions has dramatically increased in recent years due in large part to the numerous reported advances in catalysis and organic synthesis. In some extreme cases, ionic liquids have been shown to induce mechanistic changes relative to conventional solvents. Despite the large interest in the solvents, a clear understanding of the molecular factors behind their chemical impact is largely unknown. This feature article reviews our efforts developing and applying mixed quantum and molecular mechanical (QM/MM) methodology to elucidate the microscopic details of how these solvents operate to enhance rates and alter mechanisms for industrially and academically important reactions, e.g., Diels-Alder, Kemp eliminations, nucleophilic aromatic substitutions, and β-eliminations. Explicit solvent representation provided the medium dependence of the activation barriers and atomic-level characterization of the solute-solvent interactions responsible for the experimentally observed "ionic liquid effects". Technical advances are also discussed, including a linear-scaling pairwise electrostatic interaction alternative to Ewald sums, an efficient polynomial fitting method for modeling proton transfers, and the development of a custom ionic liquid OPLS-AA force field.

Artificial Bee Colony Optimization of Capping Potentials for Hybrid Quantum Mechanical/Molecular Mechanical Calculations.

PubMed

Schiffmann, Christoph; Sebastiani, Daniel

2011-05-10

We present an algorithmic extension of a numerical optimization scheme for analytic capping potentials for use in mixed quantum-classical (quantum mechanical/molecular mechanical, QM/MM) ab initio calculations. Our goal is to minimize bond-cleavage-induced perturbations in the electronic structure, measured by means of a suitable penalty functional. The optimization algorithm-a variant of the artificial bee colony (ABC) algorithm, which relies on swarm intelligence-couples deterministic (downhill gradient) and stochastic elements to avoid local minimum trapping. The ABC algorithm outperforms the conventional downhill gradient approach, if the penalty hypersurface exhibits wiggles that prevent a straight minimization pathway. We characterize the optimized capping potentials by computing NMR chemical shifts. This approach will increase the accuracy of QM/MM calculations of complex biomolecules.

Advances in quantum simulations of ATPase catalysis in the myosin motor.

PubMed

Kiani, Farooq Ahmad; Fischer, Stefan

2015-04-01

During its contraction cycle, the myosin motor catalyzes the hydrolysis of ATP. Several combined quantum/classical mechanics (QM/MM) studies of this step have been published, which substantially contributed to our thinking about the catalytic mechanism. The methodological difficulties encountered over the years in the simulation of this complex reaction are now understood: (a) Polarization of the protein peptide groups surrounding the highly charged ATP(4-) cannot be neglected. (b) Some unsuspected protein groups need to be treated QM. (c) Interactions with the γ-phosphate versus the β-phosphate favor a concurrent versus a sequential mechanism, respectively. Thus, these practical aspects strongly influence the computed mechanism, and should be considered when studying other catalyzed phosphor-ester hydrolysis reactions, such as in ATPases or GTPases. Copyright © 2015 Elsevier Ltd. All rights reserved.

Entanglement model of homeopathy as an example of generalized entanglement predicted by weak quantum theory.

PubMed

Walach, H

2003-08-01

Homeopathy is scientifically banned, both for lack of consistent empirical findings, but more so for lack of a sound theoretical model to explain its purported effects. This paper makes an attempt to introduce an explanatory idea based on a generalized version of quantum mechanics (QM), the weak quantum theory (WQT). WQT uses the algebraic formalism of QM proper, but drops some restrictions and definitions typical for QM. This results in a general axiomatic framework similar to QM, but more generalized and applicable to all possible systems. Most notably, WQT predicts entanglement, which in QM is known as Einstein-Podolsky-Rosen (EPR) correlatedness within quantum systems. According to WQT, this entanglement is not only tied to quantum systems, but is to be expected whenever a global and a local variable describing a system are complementary. This idea is used here to reconstruct homeopathy as an exemplification of generalized entanglement as predicted by WQT. It transpires that homeopathy uses two instances of generalized entanglement: one between the remedy and the original substance (potentiation principle) and one between the individual symptoms of a patient and the general symptoms of a remedy picture (similarity principle). By bringing these two elements together, double entanglement ensues, which is reminiscent of cryptographic and teleportation applications of entanglement in QM proper. Homeopathy could be a macroscopic analogue to quantum teleportation. This model is exemplified and some predictions are derived, which make it possible to test the model. Copyright 2003 S. Karger GmbH, Freiburg

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rodríguez-Cantano, Rocío; Pérez de Tudela, Ricardo; Bartolomei, Massimiliano

Coronene-doped helium clusters have been studied by means of classical and quantum mechanical (QM) methods using a recently developed He–C{sub 24}H{sub 12} global potential based on the use of optimized atom-bond improved Lennard-Jones functions. Equilibrium energies and geometries at global and local minima for systems with up to 69 He atoms were calculated by means of an evolutive algorithm and a basin-hopping approach and compared with results from path integral Monte Carlo (PIMC) calculations at 2 K. A detailed analysis performed for the smallest sizes shows that the precise localization of the He atoms forming the first solvation layer overmore » the molecular substrate is affected by differences between relative potential minima. The comparison of the PIMC results with the predictions from the classical approaches and with diffusion Monte Carlo results allows to examine the importance of both the QM and thermal effects.« less

Computing the Absorption and Emission Spectra of 5-Methylcytidine in Different Solvents: A Test-Case for Different Solvation Models.

PubMed

Martínez-Fernández, L; Pepino, A J; Segarra-Martí, J; Banyasz, A; Garavelli, M; Improta, R

2016-09-13

The optical spectra of 5-methylcytidine in three different solvents (tetrahydrofuran, acetonitrile, and water) is measured, showing that both the absorption and the emission maximum in water are significantly blue-shifted (0.08 eV). The absorption spectra are simulated based on CAM-B3LYP/TD-DFT calculations but including solvent effects with three different approaches: (i) a hybrid implicit/explicit full quantum mechanical approach, (ii) a mixed QM/MM static approach, and (iii) a QM/MM method exploiting the structures issuing from molecular dynamics classical simulations. Ab-initio Molecular dynamics simulations based on CAM-B3LYP functionals have also been performed. The adopted approaches all reproduce the main features of the experimental spectra, giving insights on the chemical-physical effects responsible for the solvent shifts in the spectra of 5-methylcytidine and providing the basis for discussing advantages and limitations of the adopted solvation models.

Theoretical studies of the ATP hydrolysis mechanism of myosin.

PubMed

Okimoto, N; Yamanaka, K; Ueno, J; Hata, M; Hoshino, T; Tsuda, M

2001-11-01

The ATP hydrolysis mechanism of myosin was studied using quantum chemical (QM) and molecular dynamics calculations. The initial model compound for QM calculations was constructed on the basis of the energy-minimized structure of the myosin(S1dc)-ATP complex, which was determined by molecular mechanics calculations. The result of QM calculations suggested that the ATP hydrolysis mechanism of myosin consists of a single elementary reaction in which a water molecule nucleophilically attacked gamma-phosphorus of ATP. In addition, we performed molecular dynamics simulations of the initial and final states of the ATP hydrolysis reaction, that is, the myosin-ATP and myosin-ADP.Pi complexes. These calculations revealed roles of several amino acid residues (Lys185, Thr186, Ser237, Arg238, and Glu459) in the ATPase pocket. Lys185 maintains the conformation of beta- and gamma-phosphate groups of ATP by forming the hydrogen bonds. Thr186 and Ser237 are coordinated to a Mg(2+) ion, which interacts with the phosphates of ATP and therefore contributes to the stabilization of the ATP structure. Arg238 and Glu459, which consisted of the gate of the ATPase pocket, retain the water molecule acting on the hydrolysis at the appropriate position for initiating the hydrolysis.

Structural Basis of the Interaction of Cyclin-Dependent Kinase 2 with Roscovitine and Its Analogues Having Bioisosteric Central Heterocycles.

PubMed

Nekardová, Michaela; Vymětalová, Ladislava; Khirsariya, Prashant; Kováčová, Silvia; Hylsová, Michaela; Jorda, Radek; Kryštof, Vladimír; Fanfrlík, Jindřich; Hobza, Pavel; Paruch, Kamil

2017-04-05

The structural basis for the interaction of roscovitine and analogues containing 13 different bioisosteric central heterocycles with the enzyme cyclin-dependent kinase 2 (CDK2) is elucidated. Although all the central scaffolds are very similar to the purine core of roscovitine, the experimentally determined IC 50 values of the inhibitors span three orders of magnitude. By using an extensive computational chemistry approach, the affinities of the inhibitors to CDK2 are determined as calculated binding scores of complexes of the inhibitors with the protein. The interactions of the inhibitors with CDK2 are computationally described by using a hybrid quantum mechanics/semi-empirical quantum mechanics method (QM/SQM), which combines the DFT-D method for the QM part and the PM6-D3H4X method for the SQM part. The solvent effect is described by the COSMO implicit solvation model at the SQM level for the whole system. The contributions of the scaffolds and the individual substituents, quantified and evaluated in relation to conformations of optimized protein-inhibitor complexes, are found not to be simply additive. The inhibitory activity of the selected candidates, including two newly prepared compounds, is tested against CDK2. The results of the calculations are in close agreement with the experimental data. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Can't Count or Won't Count? Embedding Quantitative Methods in Substantive Sociology Curricula: A Quasi-Experiment.

PubMed

Williams, Malcolm; Sloan, Luke; Cheung, Sin Yi; Sutton, Carole; Stevens, Sebastian; Runham, Libby

2016-06-01

This paper reports on a quasi-experiment in which quantitative methods (QM) are embedded within a substantive sociology module. Through measuring student attitudes before and after the intervention alongside control group comparisons, we illustrate the impact that embedding has on the student experience. Our findings are complex and even contradictory. Whilst the experimental group were less likely to be distrustful of statistics and appreciate how QM inform social research, they were also less confident about their statistical abilities, suggesting that through 'doing' quantitative sociology the experimental group are exposed to the intricacies of method and their optimism about their own abilities is challenged. We conclude that embedding QM in a single substantive module is not a 'magic bullet' and that a wider programme of content and assessment diversification across the curriculum is preferential.

Conformational Analysis of Free and Bound Retinoic Acid

PubMed Central

Fu, Zheng; Li, Xue; Merz, Kenneth M.

2012-01-01

The conformational profiles of unbound all-trans and 9-cis retinoic acid (RA) have been determined using classical and quantum mechanical calculations. Sixty-six all-trans-RA (ATRA) and forty-eight 9-cis-RA energy minimum conformers were identified via HF/6-31G* geometry optimizations in vacuo. Their relative conformational energies were estimated utilizing the M06, M06-2x and MP2 methods combined with the 6-311+G(d,p), aug-cc-pVDZ and aug-cc-pVTZ basis sets, as well as complete basis set MP2 extrapolations using the latter two basis sets. Single-point energy calculations performed with the M06-2x density functional were found to yield similar results to MP2/CBS for the low-energy retinoic acid conformations. Not unexpectedly, the conformational propensities of retinoic acid were governed by the orientation and arrangement of the torsion angles associated with the polyene tail. We also used previously reported QM/MM X-ray refinement results on four ATRA-protein crystal structures plus one newly refined 9-cis-RA complex (PDB ID 1XDK) in order to investigate the conformational preferences of bound retinoic acid. In the re-refined RA conformers the conjugated double bonds are nearly coplanar, which is consistent with the global minimum identified by the Omega/QM method rather than the corresponding crystallographically determined conformations given in the PDB. Consequently, a 91.3% average reduction of the local strain energy in the gas phase, as well as 92.1% in PCM solvent, was observed using the QM/MM refined structures versus the PDB deposited RA conformations. These results thus demonstrate that our QM/MM X-ray refinement approach can significantly enhance the quality of X-ray crystal structures refined by conventional refinement protocols, thereby providing reliable drug-target structural information for use in structure-based drug discovery applications. PMID:22844234

Ab initio calculation of proton-coupled electron transfer rates using the external-potential representation: A ubiquinol complex in solution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamamoto, Takeshi; Kato, Shigeki

2007-06-14

In quantum-mechanical/molecular-mechanical (QM/MM) treatment of chemical reactions in condensed phases, one solves the electronic Schroedinger equation for the solute (or an active site) under the electrostatic field from the environment. This Schroedinger equation depends parametrically on the solute nuclear coordinates R and the external electrostatic potential V. This fact suggests that one may use R and V as natural collective coordinates for describing the entire system, where V plays the role of collective solvent variables. In this paper such an (R,V) representation of the QM/MM canonical ensemble is described, with particular focus on how to treat charge transfer processes inmore » this representation. As an example, the above method is applied to the proton-coupled electron transfer of a ubiquinol analog with phenoxyl radical in acetonitrile solvent. Ab initio free-energy surfaces are calculated as functions of R and V using the reference interaction site model self-consistent field method, the equilibrium points and the minimum free-energy crossing point are located in the (R,V) space, and then the kinetic isotope effects (KIEs) are evaluated approximately. The results suggest that a stiffer proton potential at the transition state may be responsible for unusual KIEs observed experimentally for related systems.« less

Energetics of short hydrogen bonds in photoactive yellow protein.

PubMed

Saito, Keisuke; Ishikita, Hiroshi

2012-01-03

Recent neutron diffraction studies of photoactive yellow protein (PYP) proposed that the H bond between protonated Glu46 and the chromophore [ionized p-coumaric acid (pCA)] was a low-barrier H bond (LBHB). Using the atomic coordinates of the high-resolution crystal structure, we analyzed the energetics of the short H bond by two independent methods: electrostatic pK(a) calculations and a quantum mechanical/molecular mechanical (QM/MM) approach. (i) In the QM/MM optimized geometry, we reproduced the two short H-bond distances of the crystal structure: Tyr42-pCA (2.50 Å) and Glu46-pCA (2.57 Å). However, the H atoms obviously belonged to the Tyr or Glu moieties, and were not near the midpoint of the donor and acceptor atoms. (ii) The potential-energy curves of the two H bonds resembled those of standard asymmetric double-well potentials, which differ from those of LBHB. (iii) The calculated pK(a) values for Glu46 and pCA were 8.6 and 5.4, respectively. The pK(a) difference was unlikely to satisfy the prerequisite for LBHB. (iv) The LBHB in PYP was originally proposed to stabilize the ionized pCA because deprotonated Arg52 cannot stabilize it. However, the calculated pK(a) of Arg52 and QM/MM optimized geometry suggested that Arg52 was protonated on the protein surface. The short H bond between Glu46 and ionized pCA in the PYP ground state could be simply explained by electrostatic stabilization without invoking LBHB.

Mechanisms of single-walled carbon nanotube nucleation, growth, and healing determined using QM/MD methods.

PubMed

Page, Alister J; Ohta, Yasuhito; Irle, Stephan; Morokuma, Keiji

2010-10-19

Since their discovery in the early 1990s, single-walled carbon nanotubes (SWNTs) have spawned previously unimaginable commercial and industrial technologies. Their versatility stems from their unique electronic, physical/chemical, and mechanical properties, which set them apart from traditional materials. Many researchers have investigated SWNT growth mechanisms in the years since their discovery. The most prevalent of these is the vapor-liquid-solid (VLS) mechanism, which is based on experimental observations. Within the VLS mechanism, researchers assume that the formation of a SWNT starts with co-condensation of carbon and metal atoms from vapor to form liquid metal carbide. Once the liquid reaches supersaturation, the solid phase nanotubes begin to grow. The growth process is partitioned into three distinct stages: nucleation of a carbon "cap-precursor," "cap-to-tube" transformation, and continued SWNT growth. In recent years, molecular dynamics (MD) simulations have come to the fore with respect to SWNT growth. MD simulations lead to spatial and temporal resolutions of these processes that are superior to those possible using current experimental techniques, and so provide valuable information regarding the growth process that researchers cannot obtain experimentally. In this Account, we review our own recent efforts to simulate SWNT nucleation, growth, and healing phenomena on transition-metal catalysts using quantum mechanical molecular dynamics (QM/MD) methods. In particular, we have validated each stage of the SWNT condensation mechanism using a self-consistent-charge density-functional tight-binding (SCC-DFTB) methodology. With respect to the nucleation of a SWNT cap-precursor (stage 1), we have shown that the presence of a transition-metal carbide particle is not a necessary prerequisite for SWNT nucleation, contrary to conventional experimental presumptions. The formation and coalescence of polyyne chains on the metal surface occur first, followed by the formation of the SWNT cap-precursor, "ring condensation", and the creation of an sp(2)-hybridized carbon structure. In our simulations, the nucleation process takes approximately 400 ps. This first step occurs over a much longer time scale than the second stage of SWNT condensation (approximately 50 ps). We therefore observe SWNT nucleation to be akin to the rate-limiting step of the SWNT formation process. In addition to the QM/MD simulation of various stages of SWNT nucleation, growth, and healing processes, we have determined the effects of temperature, catalyst composition, and catalyst size on the kinetics and mechanism of SWNT growth. With respect to temperature dependence, we observe a "sweet-spot" with respect to the efficiency of SWNT growth. In addition, Ni-catalyzed SWNT growth is observed to be 70-100% faster compared to Fe-catalyzed SWNT growth, depending on the catalyst particle size. We also observe a noticeable increase in SWNT growth rates using smaller catalyst particles. Finally, we review our recent QM/MD investigation of SWNT healing. In particular, we recount mechanisms by which adatom defects, monovacancy defects, and a "5-7 defect" are removed from a nascent SWNT. The effectiveness of these healing mechanisms depends on the rate at which carbon moieties are incorporated into the growing SWNT. Explicitly, we observe that healing is promoted using a slower carbon supply rate. From this rudimentary control of SWNT healing, we propose a route towards chirality-controlled SWNT growth.

Benchmarking the American Society of Breast Surgeon Member Performance for More Than a Million Quality Measure-Patient Encounters.

PubMed

Landercasper, Jeffrey; Fayanju, Oluwadamilola M; Bailey, Lisa; Berry, Tiffany S; Borgert, Andrew J; Buras, Robert; Chen, Steven L; Degnim, Amy C; Froman, Joshua; Gass, Jennifer; Greenberg, Caprice; Mautner, Starr Koslow; Krontiras, Helen; Ramirez, Luis D; Sowden, Michelle; Wexelman, Barbara; Wilke, Lee; Rao, Roshni

2018-02-01

Nine breast cancer quality measures (QM) were selected by the American Society of Breast Surgeons (ASBrS) for the Centers for Medicare and Medicaid Services (CMS) Quality Payment Programs (QPP) and other performance improvement programs. We report member performance. Surgeons entered QM data into an electronic registry. For each QM, aggregate "performance met" (PM) was reported (median, range and percentiles) and benchmarks (target goals) were calculated by CMS methodology, specifically, the Achievable Benchmark of Care™ (ABC) method. A total of 1,286,011 QM encounters were captured from 2011-2015. For 7 QM, first and last PM rates were as follows: (1) needle biopsy (95.8, 98.5%), (2) specimen imaging (97.9, 98.8%), (3) specimen orientation (98.5, 98.3%), (4) sentinel node use (95.1, 93.4%), (5) antibiotic selection (98.0, 99.4%), (6) antibiotic duration (99.0, 99.8%), and (7) no surgical site infection (98.8, 98.9%); all p values < 0.001 for trends. Variability and reasons for noncompliance by surgeon for each QM were identified. The CMS-calculated target goals (ABC™ benchmarks) for PM for 6 QM were 100%, suggesting that not meeting performance is a "never should occur" event. Surgeons self-reported a large number of specialty-specific patient-measure encounters into a registry for self-assessment and participation in QPP. Despite high levels of performance demonstrated initially in 2011 with minimal subsequent change, the ASBrS concluded "perfect" performance was not a realistic goal for QPP. Thus, after review of our normative performance data, the ASBrS recommended different benchmarks than CMS for each QM.

Yoink: An interaction-based partitioning API.

PubMed

Zheng, Min; Waller, Mark P

2018-05-15

Herein, we describe the implementation details of our interaction-based partitioning API (application programming interface) called Yoink for QM/MM modeling and fragment-based quantum chemistry studies. Interactions are detected by computing density descriptors such as reduced density gradient, density overlap regions indicator, and single exponential decay detector. Only molecules having an interaction with a user-definable QM core are added to the QM region of a hybrid QM/MM calculation. Moreover, a set of molecule pairs having density-based interactions within a molecular system can be computed in Yoink, and an interaction graph can then be constructed. Standard graph clustering methods can then be applied to construct fragments for further quantum chemical calculations. The Yoink API is licensed under Apache 2.0 and can be accessed via yoink.wallerlab.org. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

Binding-affinity predictions of HSP90 in the D3R Grand Challenge 2015 with docking, MM/GBSA, QM/MM, and free-energy simulations

NASA Astrophysics Data System (ADS)

Misini Ignjatović, Majda; Caldararu, Octav; Dong, Geng; Muñoz-Gutierrez, Camila; Adasme-Carreño, Francisco; Ryde, Ulf

2016-09-01

We have estimated the binding affinity of three sets of ligands of the heat-shock protein 90 in the D3R grand challenge blind test competition. We have employed four different methods, based on five different crystal structures: first, we docked the ligands to the proteins with induced-fit docking with the Glide software and calculated binding affinities with three energy functions. Second, the docked structures were minimised in a continuum solvent and binding affinities were calculated with the MM/GBSA method (molecular mechanics combined with generalised Born and solvent-accessible surface area solvation). Third, the docked structures were re-optimised by combined quantum mechanics and molecular mechanics (QM/MM) calculations. Then, interaction energies were calculated with quantum mechanical calculations employing 970-1160 atoms in a continuum solvent, combined with energy corrections for dispersion, zero-point energy and entropy, ligand distortion, ligand solvation, and an increase of the basis set to quadruple-zeta quality. Fourth, relative binding affinities were estimated by free-energy simulations, using the multi-state Bennett acceptance-ratio approach. Unfortunately, the results were varying and rather poor, with only one calculation giving a correlation to the experimental affinities larger than 0.7, and with no consistent difference in the quality of the predictions from the various methods. For one set of ligands, the results could be strongly improved (after experimental data were revealed) if it was recognised that one of the ligands displaced one or two water molecules. For the other two sets, the problem is probably that the ligands bind in different modes than in the crystal structures employed or that the conformation of the ligand-binding site or the whole protein changes.

Binding-affinity predictions of HSP90 in the D3R Grand Challenge 2015 with docking, MM/GBSA, QM/MM, and free-energy simulations.

PubMed

Misini Ignjatović, Majda; Caldararu, Octav; Dong, Geng; Muñoz-Gutierrez, Camila; Adasme-Carreño, Francisco; Ryde, Ulf

2016-09-01

We have estimated the binding affinity of three sets of ligands of the heat-shock protein 90 in the D3R grand challenge blind test competition. We have employed four different methods, based on five different crystal structures: first, we docked the ligands to the proteins with induced-fit docking with the Glide software and calculated binding affinities with three energy functions. Second, the docked structures were minimised in a continuum solvent and binding affinities were calculated with the MM/GBSA method (molecular mechanics combined with generalised Born and solvent-accessible surface area solvation). Third, the docked structures were re-optimised by combined quantum mechanics and molecular mechanics (QM/MM) calculations. Then, interaction energies were calculated with quantum mechanical calculations employing 970-1160 atoms in a continuum solvent, combined with energy corrections for dispersion, zero-point energy and entropy, ligand distortion, ligand solvation, and an increase of the basis set to quadruple-zeta quality. Fourth, relative binding affinities were estimated by free-energy simulations, using the multi-state Bennett acceptance-ratio approach. Unfortunately, the results were varying and rather poor, with only one calculation giving a correlation to the experimental affinities larger than 0.7, and with no consistent difference in the quality of the predictions from the various methods. For one set of ligands, the results could be strongly improved (after experimental data were revealed) if it was recognised that one of the ligands displaced one or two water molecules. For the other two sets, the problem is probably that the ligands bind in different modes than in the crystal structures employed or that the conformation of the ligand-binding site or the whole protein changes.

Unique Kinase Catalytic Mechanism of AceK with a Single Magnesium Ion

PubMed Central

Li, Quanjie; Zheng, Jimin; Tan, Hongwei; Li, Xichen; Chen, Guangju; Jia, Zongchao

2013-01-01

Isocitrate dehydrogenase kinase/phosphatase (AceK) is the founding member of the protein phosphorylation system in prokaryotes. Based on the novel and unique structural characteristics of AceK recently uncovered, we sought to understand its kinase reaction mechanism, along with other features involved in the phosphotransfer process. Herein we report density functional theory QM calculations of the mechanism of the phosphotransfer reaction catalysed by AceK. The transition states located by the QM calculations indicate that the phosphorylation reaction, catalysed by AceK, follows a dissociative mechanism with Asp457 serving as the catalytic base to accept the proton delivered by the substrate. Our results also revealed that AceK prefers a single Mg2+-containing active site in the phosphotransfer reaction. The catalytic roles of conserved residues in the active site are discussed. PMID:23977203

Quantum Mechanics/Molecular Mechanics Free Energy Maps and Nonadiabatic Simulations for a Photochemical Reaction in DNA: Cyclobutane Thymine Dimer.

PubMed

Mendieta-Moreno, Jesús I; Trabada, Daniel G; Mendieta, Jesús; Lewis, James P; Gómez-Puertas, Paulino; Ortega, José

2016-11-03

The absorption of ultraviolet radiation by DNA may result in harmful genetic lesions that affect DNA replication and transcription, ultimately causing mutations, cancer, and/or cell death. We analyze the most abundant photochemical reaction in DNA, the cyclobutane thymine dimer, using hybrid quantum mechanics/molecular mechanics (QM/MM) techniques and QM/MM nonadiabatic molecular dynamics. We find that, due to its double helix structure, DNA presents a free energy barrier between nonreactive and reactive conformations leading to the photolesion. Moreover, our nonadiabatic simulations show that most of the photoexcited reactive conformations return to standard B-DNA conformations after an ultrafast nonradiative decay to the ground state. This work highlights the importance of dynamical effects (free energy, excited-state dynamics) for the study of photochemical reactions in biological systems.

An Alternative Mechanism for the Methylation of Phosphoethanolamine Catalyzed by Plasmodium falciparum Phosphoethanolamine Methyltransferase*♦

PubMed Central

Saen-oon, Suwipa; Lee, Soon Goo; Jez, Joseph M.; Guallar, Victor

2014-01-01

The phosphobase methylation pathway catalyzed by the phosphoethanolamine methyltransferase in Plasmodium falciparum (PfPMT), the malaria parasite, offers an attractive target for anti-parasitic drug development. PfPMT methylates phosphoethanolamine (pEA) to phosphocholine for use in membrane biogenesis. Quantum mechanics and molecular mechanics (QM/MM) calculations tested the proposed reaction mechanism for methylation of pEA involving the previously identified Tyr-19–His-132 dyad, which indicated an energetically unfavorable mechanism. Instead, the QM/MM calculations suggested an alternative mechanism involving Asp-128. The reaction coordinate involves the stepwise transfer of a proton to Asp-128 via a bridging water molecule followed by a typical Sn2-type methyl transfer from S-adenosylmethionine to pEA. Functional analysis of the D128A, D128E, D128Q, and D128N PfPMT mutants shows a loss of activity with pEA but not with the final substrate of the methylation pathway. X-ray crystal structures of the PfPMT-D128A mutant in complex with S-adenosylhomocysteine and either pEA or phosphocholine reveal how mutation of Asp-128 disrupts a hydrogen bond network in the active site. The combined QM/MM, biochemical, and structural studies identify a key role for Asp-128 in the initial step of the phosphobase methylation pathway in Plasmodium and provide molecular insight on the evolution of multiple activities in the active site of the PMT. PMID:25288796

An alternative mechanism for the methylation of phosphoethanolamine catalyzed by Plasmodium falciparum phosphoethanolamine methyltransferase

DOE PAGES

Saen-oon, Suwipa; Lee, Soon Goo; Jez, Joseph M.; ...

2014-10-06

Here, the phosphobase methylation pathway catalyzed by the phosphoethanolamine methyltransferase in Plasmodium falciparum (PfPMT), the malaria parasite, offers an attractive target for anti-parasitic drug development. PfPMT methylates phosphoethanolamine (pEA) to phosphocholine for use in membrane biogenesis. Quantum mechanics and molecular mechanics (QM/MM) calculations tested the proposed reaction mechanism for methylation of pEA involving the previously identified Tyr-19–His-132 dyad, which indicated an energetically unfavorable mechanism. Instead, the QM/MM calculations suggested an alternative mechanism involving Asp-128. The reaction coordinate involves the stepwise transfer of a proton to Asp-128 via a bridging water molecule followed by a typical S n2-type methyl transfer frommore » S-adenosylmethionine to pEA. Functional analysis of the D128A, D128E, D128Q, and D128N PfPMT mutants shows a loss of activity with pEA but not with the final substrate of the methylation pathway. X-ray crystal structures of the PfPMT-D128A mutant in complex with S-adenosylhomocysteine and either pEA or phosphocholine reveal how mutation of Asp-128 disrupts a hydrogen bond network in the active site. The combined QM/MM, biochemical, and structural studies identify a key role for Asp-128 in the initial step of the phosphobase methylation pathway in Plasmodium and provide molecular insight on the evolution of multiple activities in the active site of the PMT.« less

An alternative mechanism for the methylation of phosphoethanolamine catalyzed by Plasmodium falciparum phosphoethanolamine methyltransferase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saen-oon, Suwipa; Lee, Soon Goo; Jez, Joseph M.

Here, the phosphobase methylation pathway catalyzed by the phosphoethanolamine methyltransferase in Plasmodium falciparum (PfPMT), the malaria parasite, offers an attractive target for anti-parasitic drug development. PfPMT methylates phosphoethanolamine (pEA) to phosphocholine for use in membrane biogenesis. Quantum mechanics and molecular mechanics (QM/MM) calculations tested the proposed reaction mechanism for methylation of pEA involving the previously identified Tyr-19–His-132 dyad, which indicated an energetically unfavorable mechanism. Instead, the QM/MM calculations suggested an alternative mechanism involving Asp-128. The reaction coordinate involves the stepwise transfer of a proton to Asp-128 via a bridging water molecule followed by a typical S n2-type methyl transfer frommore » S-adenosylmethionine to pEA. Functional analysis of the D128A, D128E, D128Q, and D128N PfPMT mutants shows a loss of activity with pEA but not with the final substrate of the methylation pathway. X-ray crystal structures of the PfPMT-D128A mutant in complex with S-adenosylhomocysteine and either pEA or phosphocholine reveal how mutation of Asp-128 disrupts a hydrogen bond network in the active site. The combined QM/MM, biochemical, and structural studies identify a key role for Asp-128 in the initial step of the phosphobase methylation pathway in Plasmodium and provide molecular insight on the evolution of multiple activities in the active site of the PMT.« less

A Qualitative Metasynthesis of Consultation Process Research: What We Know and Where to Go

ERIC Educational Resources Information Center

Newman, Daniel S.; McKenney, Elizabeth L. W.; Silva, Arlene E.; Clare, Mary; Salmon, Diane; Jackson, Safiyah

2017-01-01

Qualitative metasynthesis (QM) is a research methodology that permits the meaningful integration and interpretation of qualitative research. This study applies a QM approach combined with constructivist grounded theory methods, bolstered by several features of research credibility, to examine the state of consultee-centered consultation (CCC) and…

Final report of the SIM.QM-S8 supplementary comparison, trace metals in drinking water

NASA Astrophysics Data System (ADS)

Yang, Lu; Nadeau, Kenny; Gedara Pihillagawa, Indu; Meija, Juris; Mester, Zoltan; Napoli, Romina; Pérez Zambra, Ramiro; Ferreira, Elizabeth; Alejandro Ahumada Forigua, Diego; Abella Gamba, Johanna Paola

2018-01-01

After completing a supplementary comparison SIM.QM-S7, the National Metrology Institute of Colombia (NMIC) requested to National Research Council of Canada (NRC) a subsequent bilateral comparison, because INMC considered that its results in SIM.QM-S7 unrepresentative of its standards. In this context, NRC agreed to coordinate this bilateral comparison with the aim of demonstrating the measurement capabilities of trace elements in fresh water. Participants included NMIC and LATU. No measurement method was prescribed by the coordinating laboratory. Therefore, NMIs used measurement methods of their choice. However, the majority of NMIs/DIs used ICP-MS. This SIM.QM-S8 Supplementary Comparison provides NMIs with the needed evidence for CMC claims for trace elements in fresh waters and similar matrices. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Machine Learning Force Field Parameters from Ab Initio Data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Ying; Li, Hui; Pickard, Frank C.

Machine learning (ML) techniques with the genetic algorithm (GA) have been applied to determine a polarizable force field parameters using only ab initio data from quantum mechanics (QM) calculations of molecular clusters at the MP2/6-31G(d,p), DFMP2(fc)/jul-cc-pVDZ, and DFMP2(fc)/jul-cc-pVTZ levels to predict experimental condensed phase properties (i.e., density and heat of vaporization). The performance of this ML/GA approach is demonstrated on 4943 dimer electrostatic potentials and 1250 cluster interaction energies for methanol. Excellent agreement between the training data set from QM calculations and the optimized force field model was achieved. The results were further improved by introducing an offset factor duringmore » the machine learning process to compensate for the discrepancy between the QM calculated energy and the energy reproduced by optimized force field, while maintaining the local “shape” of the QM energy surface. Throughout the machine learning process, experimental observables were not involved in the objective function, but were only used for model validation. The best model, optimized from the QM data at the DFMP2(fc)/jul-cc-pVTZ level, appears to perform even better than the original AMOEBA force field (amoeba09.prm), which was optimized empirically to match liquid properties. The present effort shows the possibility of using machine learning techniques to develop descriptive polarizable force field using only QM data. The ML/GA strategy to optimize force fields parameters described here could easily be extended to other molecular systems.« less

Can’t Count or Won’t Count? Embedding Quantitative Methods in Substantive Sociology Curricula: A Quasi-Experiment

PubMed Central

Williams, Malcolm; Sloan, Luke; Cheung, Sin Yi; Sutton, Carole; Stevens, Sebastian; Runham, Libby

2015-01-01

This paper reports on a quasi-experiment in which quantitative methods (QM) are embedded within a substantive sociology module. Through measuring student attitudes before and after the intervention alongside control group comparisons, we illustrate the impact that embedding has on the student experience. Our findings are complex and even contradictory. Whilst the experimental group were less likely to be distrustful of statistics and appreciate how QM inform social research, they were also less confident about their statistical abilities, suggesting that through ‘doing’ quantitative sociology the experimental group are exposed to the intricacies of method and their optimism about their own abilities is challenged. We conclude that embedding QM in a single substantive module is not a ‘magic bullet’ and that a wider programme of content and assessment diversification across the curriculum is preferential. PMID:27330225

Quantum non-objectivity from performativity of quantum phenomena

NASA Astrophysics Data System (ADS)

Khrennikov, Andrei; Schumann, Andrew

2014-12-01

We analyze the logical foundations of quantum mechanics (QM) by stressing non-objectivity of quantum observables, which is a consequence of the absence of logical atoms in QM. We argue that the matter of quantum non-objectivity is that, on the one hand, the formalism of QM constructed as a mathematical theory is self-consistent, but, on the other hand, quantum phenomena as results of experimenters’ performances are not self-consistent. This self-inconsistency is an effect of the language of QM differing greatly from the language of human performances. The former is the language of a mathematical theory that uses some Aristotelian and Russellian assumptions (e.g., the assumption that there are logical atoms). The latter language consists of performative propositions that are self-inconsistent only from the viewpoint of conventional mathematical theory, but they satisfy another logic that is non-Aristotelian. Hence, the representation of quantum reality in linguistic terms may be different: the difference between a mathematical theory and a logic of performative propositions. To solve quantum self-inconsistency, we apply the formalism of non-classical self-referent logics.

Quantum Locality, Rings a Bell?: Bell's Inequality Meets Local Reality and True Determinism

NASA Astrophysics Data System (ADS)

Sánchez-Kuntz, Natalia; Nahmad-Achar, Eduardo

2018-01-01

By assuming a deterministic evolution of quantum systems and taking realism into account, we carefully build a hidden variable theory for Quantum Mechanics (QM) based on the notion of ontological states proposed by 't Hooft (The cellular automaton interpretation of quantum mechanics, arXiv:1405.1548v3, 2015; Springer Open 185, https://doi.org/10.1007/978-3-319-41285-6, 2016). We view these ontological states as the ones embedded with realism and compare them to the (usual) quantum states that represent superpositions, viewing the latter as mere information of the system they describe. Such a deterministic model puts forward conditions for the applicability of Bell's inequality: the usual inequality cannot be applied to the usual experiments. We build a Bell-like inequality that can be applied to the EPR scenario and show that this inequality is always satisfied by QM. In this way we show that QM can indeed have a local interpretation, and thus meet with the causal structure imposed by the Theory of Special Relativity in a satisfying way.

Principles of Empiricism and the Interpretation of Quantum Mechanics

NASA Astrophysics Data System (ADS)

Jaroszkiewicz, George

The interpretation of quantum mechanics (QM) is discussed in terms of the principles and logic of empiricism. First, we list a set of issues that should be settled before any consistent interpretation is attempted. This includes questions such as whether we can use an exophysical perspective or an endophysical perspective, and whether a completely reductionist approach makes sense or are we forced to incorporate emergent laws of physics. We then list the scientific pr nciples that should be strictly adhered to in any debate on QM. We follow this with a list of cautions and warnings about misleading concepts that should be avoided, such as ignoring contextuality and the meaning of scientific truth values. These principles and warning are then used to decide on the issues we first identified, giving us a basis for an interpretation of QM from the perspective of observers and quantum signal states of apparatus, rather than in terms of qu ntum states of systems under observation. Finally, we review a proposed mathematical formalism that encodes this interpretation in terms of quantum registers.

Linear Regression Quantile Mapping (RQM) - A new approach to bias correction with consistent quantile trends

NASA Astrophysics Data System (ADS)

Passow, Christian; Donner, Reik

2017-04-01

Quantile mapping (QM) is an established concept that allows to correct systematic biases in multiple quantiles of the distribution of a climatic observable. It shows remarkable results in correcting biases in historical simulations through observational data and outperforms simpler correction methods which relate only to the mean or variance. Since it has been shown that bias correction of future predictions or scenario runs with basic QM can result in misleading trends in the projection, adjusted, trend preserving, versions of QM were introduced in the form of detrended quantile mapping (DQM) and quantile delta mapping (QDM) (Cannon, 2015, 2016). Still, all previous versions and applications of QM based bias correction rely on the assumption of time-independent quantiles over the investigated period, which can be misleading in the context of a changing climate. Here, we propose a novel combination of linear quantile regression (QR) with the classical QM method to introduce a consistent, time-dependent and trend preserving approach of bias correction for historical and future projections. Since QR is a regression method, it is possible to estimate quantiles in the same resolution as the given data and include trends or other dependencies. We demonstrate the performance of the new method of linear regression quantile mapping (RQM) in correcting biases of temperature and precipitation products from historical runs (1959 - 2005) of the COSMO model in climate mode (CCLM) from the Euro-CORDEX ensemble relative to gridded E-OBS data of the same spatial and temporal resolution. A thorough comparison with established bias correction methods highlights the strengths and potential weaknesses of the new RQM approach. References: A.J. Cannon, S.R. Sorbie, T.Q. Murdock: Bias Correction of GCM Precipitation by Quantile Mapping - How Well Do Methods Preserve Changes in Quantiles and Extremes? Journal of Climate, 28, 6038, 2015 A.J. Cannon: Multivariate Bias Correction of Climate Model Outputs - Matching Marginal Distributions and Inter-variable Dependence Structure. Journal of Climate, 29, 7045, 2016

Sorption of N2 and EGME vapors on some soils, clays, and mineral oxides and determination of sample surface areas by use of sorption data

USGS Publications Warehouse

Chiou, C.T.; Rutherford, D.W.; Manes, M.

1993-01-01

Vapor sorption isotherms of ethylene glycol monoethyl ether (EGME) at room temperature and isotherms of N2 gas at liquid nitrogen temperature were determined for various soils and minerals. The N2 monolayer capacities [Qm (N2)] were calculated from the BET equation and used to determine the surface areas. To examine whether EGME is an appropriate adsorbate for determination of surface areas, the apparent EGME monolayer capacities [Qm (EGME)ap] were also obtained by use of the BET equation. For sand, aluminum oxide, kaolinite, hematite, and synthetic hydrous iron oxide, which are relatively free of organic impurity and expanding/solvating minerals, the Qm (EGME)ap values are in good conformity with the corresponding Qm (N2) values and would give surface areas consistent with BET (N2) values. For other samples (Woodburn soil, a natural hydrous iron oxide, illite, and montmorillonite), the Qm (EGME)ap values overestimate the Qm (N2) values from a moderate to a large extent, depending on the sample. A high-organic-content peat shows a very small BET (N2) surface area; the EGME/ peat isotherm is linear and does not yield a calculation of the surface area. Large discrepancies between results of the two methods for some samples are attributed to the high solubility of polar EGME in soil organic matter and/ or to the cation solvation of EGME with solvating clays. The agreement for other samples is illustrative of the consistency of the BET method when different adsorbates are used, so long as they do not exhibit bulk penetration and/or cation solvation. ?? 1993 American Chemical Society.

A polarizable QM/MM approach to the molecular dynamics of amide groups solvated in water

NASA Astrophysics Data System (ADS)

Schwörer, Magnus; Wichmann, Christoph; Tavan, Paul

2016-03-01

The infrared (IR) spectra of polypeptides are dominated by the so-called amide bands. Because they originate from the strongly polar and polarizable amide groups (AGs) making up the backbone, their spectral positions sensitively depend on the local electric fields. Aiming at accurate computations of these IR spectra by molecular dynamics (MD) simulations, which derive atomic forces from a hybrid quantum and molecular mechanics (QM/MM) Hamiltonian, here we consider the effects of solvation in bulk liquid water on the amide bands of the AG model compound N-methyl-acetamide (NMA). As QM approach to NMA we choose grid-based density functional theory (DFT). For the surrounding MM water, we develop, largely based on computations, a polarizable molecular mechanics (PMM) model potential called GP6P, which features six Gaussian electrostatic sources (one induced dipole, five static partial charge distributions) and, therefore, avoids spurious distortions of the DFT electron density in hybrid DFT/PMM simulations. Bulk liquid GP6P is shown to have favorable properties at the thermodynamic conditions of the parameterization and beyond. Lennard-Jones (LJ) parameters of the DFT fragment NMA are optimized by comparing radial distribution functions in the surrounding GP6P liquid with reference data obtained from a "first-principles" DFT-MD simulation. Finally, IR spectra of NMA in GP6P water are calculated from extended DFT/PMM-MD trajectories, in which the NMA is treated by three different DFT functionals (BP, BLYP, B3LYP). Method-specific frequency scaling factors are derived from DFT-MD simulations of isolated NMA. The DFT/PMM-MD simulations with GP6P and with the optimized LJ parameters then excellently predict the effects of aqueous solvation and deuteration observed in the IR spectra of NMA. As a result, the methods required to accurately compute such spectra by DFT/PMM-MD also for larger peptides in aqueous solution are now at hand.

A polarizable QM/MM approach to the molecular dynamics of amide groups solvated in water

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schwörer, Magnus; Wichmann, Christoph; Tavan, Paul, E-mail: tavan@physik.uni-muenchen.de

2016-03-21

The infrared (IR) spectra of polypeptides are dominated by the so-called amide bands. Because they originate from the strongly polar and polarizable amide groups (AGs) making up the backbone, their spectral positions sensitively depend on the local electric fields. Aiming at accurate computations of these IR spectra by molecular dynamics (MD) simulations, which derive atomic forces from a hybrid quantum and molecular mechanics (QM/MM) Hamiltonian, here we consider the effects of solvation in bulk liquid water on the amide bands of the AG model compound N-methyl-acetamide (NMA). As QM approach to NMA we choose grid-based density functional theory (DFT). Formore » the surrounding MM water, we develop, largely based on computations, a polarizable molecular mechanics (PMM) model potential called GP6P, which features six Gaussian electrostatic sources (one induced dipole, five static partial charge distributions) and, therefore, avoids spurious distortions of the DFT electron density in hybrid DFT/PMM simulations. Bulk liquid GP6P is shown to have favorable properties at the thermodynamic conditions of the parameterization and beyond. Lennard-Jones (LJ) parameters of the DFT fragment NMA are optimized by comparing radial distribution functions in the surrounding GP6P liquid with reference data obtained from a “first-principles” DFT-MD simulation. Finally, IR spectra of NMA in GP6P water are calculated from extended DFT/PMM-MD trajectories, in which the NMA is treated by three different DFT functionals (BP, BLYP, B3LYP). Method-specific frequency scaling factors are derived from DFT-MD simulations of isolated NMA. The DFT/PMM-MD simulations with GP6P and with the optimized LJ parameters then excellently predict the effects of aqueous solvation and deuteration observed in the IR spectra of NMA. As a result, the methods required to accurately compute such spectra by DFT/PMM-MD also for larger peptides in aqueous solution are now at hand.« less

Investigating learners' epistemological framings of quantum mechanics

NASA Astrophysics Data System (ADS)

Dini, Vesal

Classical mechanics challenges students to use their intuitions and experiences as a basis for understanding, in effect to approach learning as "a refinement of everyday thinking'' (Einstein, 1936). Moving on to quantum mechanics (QM), students, like physicists, need to adjust this approach, in particular with respect to the roles that intuitive knowledge and mathematics play in the pursuit of coherent understanding (these are adjustments to aspects of their epistemologies). In this dissertation, I explore how some students manage the epistemological transition. I began this work by recruiting both graduate and undergraduate students, interviewing each subject several times as they moved through coursework in QM. The interviews featured, among other things, how students tried to fit ideas together in mutually consistent ways, including with respect to intuitive knowledge, mathematics and experiment, if at all. I modeled these dynamic cognitive processes as different epistemological framings (i.e., tacit, in-the-moment responses to the question "How should I approach knowledge?''). Through detailed qualitative analyses of students' reasoning and a systematic coding of their interviews, I explored how these coherence seeking related framings impacted their learning. The dissertation supports three main findings: (1) students' patterns of epistemological framing are mostly stable within a given course; (2) students who profess epistemologies aligned with the coordination of coherence seeking framings tend to be more stable in demonstrating them; and (3) students aware that their understanding of QM ultimately anchors in its mathematics tend to produce more coherent explanations and perform better in their courses. These findings are consistent with existing research on student epistemologies in QM and imply that epistemologies, in particular whether and how students seek coherence, require greater attention and emphasis in instruction.

Docking modes of BB-3497 into the PDF active site--a comparison of the pure MM and QM/MM based docking strategies.

PubMed

Kumari, Tripti; Issar, Upasana; Kakkar, Rita

2014-01-01

Peptide deformylase (PDF) has emerged as an important antibacterial drug target. Considerable effort is being directed toward developing peptidic and non-peptidic inhibitors for this metalloprotein. In this work, the known peptidic inhibitor BB-3497 and its various ionization and tautomeric states are evaluated for their inhibition efficiency against PDF using a molecular mechanics (MM) approach as well as a mixed quantum mechanics/molecular mechanics (QM/MM) approach, with an aim to understand the interactions in the binding site. The evaluated Gibbs energies of binding with the mixed QM/MM approach are shown to have the best predictive power. The experimental pose is found to have the most negative Gibbs energy of binding, and also the smallest strain energy. A quantum mechanical evaluation of the active site reveals the requirement of strong chelation by the ligand with the metal ion. The investigated ligand chelates the metal ion through the two oxygens of its reverse hydroxamate moiety, particularly the N-O(-) oxygen, forming strong covalent bonds with the metal ion, which is penta-coordinated. In the uninhibited state, the metal ion is tetrahedrally coordinated, and hence chelation with the inhibitor is associated with an increase of the metal ion coordination. Thus, the strong binding of the ligand at the binding site is accounted for.

High level QM/MM modeling of the formation of the tetrahedral intermediate in the acylation of wild type and K73A mutant TEM-1 class A beta-lactamase.

PubMed

Hermann, Johannes C; Pradon, Juliette; Harvey, Jeremy N; Mulholland, Adrian J

2009-10-29

The breakdown of beta-lactam antibiotics by beta-lactamases is the most important resistance mechanism of gram negative bacteria against these drugs. The reaction mechanism of class A beta-lactamases, the most widespread family of these enzymes, consists of two main steps: acylation of an active site serine by the antibiotic, followed by deacylation and release of the cleaved compound. We have investigated the first step in acylation (the formation of the tetrahedral intermediate) for the reaction of benzylpenicillin in the TEM-1 enzyme using high level combined quantum mechanics/molecular mechanics (QM/MM) methods. Structures were optimized at the B3LYP/6-31+G(d)/CHARMM27 level, with energies for key points calculated up to the ab initio SCS-MP2/aug-cc-pVTZ/CHARMM27 level. The results support a mechanism in which Glu166 removes a proton (via an intervening water molecule) from Ser70, which in turn attacks the beta-lactam of the antibiotic. Depending on the method used, the calculated barriers range from 3 to 12 kcal mol(-1) for this step, consistent with experimental data. We have also modeled this reaction step in a model of the K73A mutant enzyme. The barrier to reaction in this mutant model is found to be slightly higher: the results indicate that Lys73 stabilizes the transition state, in particular deprotonated Ser70, lowering the barrier by about 1.7 kcal mol(-1). This finding may help to explain the conservation of Lys73, in addition to the role we have previously found for it in the later stages of the reaction (Hermann et al. Org. Biomol. Chem. 2006, 4, 206-210).

High Level QM/MM Modeling of the Formation of the Tetrahedral Intermediate in the Acylation of Wild Type and K73A Mutant TEM-1 Class A β-Lactamase

NASA Astrophysics Data System (ADS)

Hermann, Johannes C.; Pradon, Juliette; Harvey, Jeremy N.; Mulholland, Adrian J.

2009-09-01

The breakdown of β-lactam antibiotics by β-lactamases is the most important resistance mechanism of Gram negative bacteria against these drugs. The reaction mechanism of class A β-lactamases, the most widespread family of these enzymes, consists of two main steps: acylation of an active site serine by the antibiotic, followed by deacylation and release of the cleaved compound. We have investigated the first step in acylation (the formation of the tetrahedral intermediate) for the reaction of benzylpenicillin in the TEM-1 enzyme using high level combined quantum mechanics/molecular mechanics (QM/MM) methods. Structures were optimized at the B3LYP/6-31+G(d)/CHARMM27 level, with energies for key points calculated up to the ab initio SCS-MP2/aug-cc-pVTZ/CHARMM27 level. The results support a mechanism in which Glu166 removes a proton (via an intervening water molecule) from Ser70, which in turn attacks the β-lactam of the antibiotic. Depending on the method used, the calculated barriers range from 3 to 12 kcal mol-1 for this step, consistent with experimental data. We have also modeled this reaction step in a model of the K73A mutant enzyme. The barrier to reaction in this mutant model is found to be slightly higher: the results indicate that Lys73 stabilizes the transition state, in particular deprotonated Ser70, lowering the barrier by about 1.7 kcal mol-1. This finding may help to explain the conservation of Lys73, in addition to the role we have previously found for it in the later stages of the reaction ( Hermann et al. Org. Biomol. Chem. 2006, 4, 206 - 210 ).

Mechanistic Insights into Radical-Mediated Oxidation of Tryptophan from ab Initio Quantum Chemistry Calculations and QM/MM Molecular Dynamics Simulations.

PubMed

Wood, Geoffrey P F; Sreedhara, Alavattam; Moore, Jamie M; Wang, John; Trout, Bernhardt L

2016-05-12

An assessment of the mechanisms of (•)OH and (•)OOH radical-mediated oxidation of tryptophan was performed using density functional theory calculations and ab initio plane-wave Quantum Mechanics/Molecular Mechanics (QM/MM) molecular dynamics simulations. For the (•)OH reactions, addition to the pyrrole ring at position 2 is the most favored site with a barrierless reaction in the gas phase. The subsequent degradation of this adduct through a H atom transfer to water was intermittently observed in aqueous-phase molecular dynamics simulations. For the (•)OOH reactions, addition to the pyrrole ring at position 2 is the most favored pathway, in contrast to the situation in the model system ethylene, where concerted addition to the double bond is preferred. From the (•)OOH position 2 adduct QM/MM simulations show that formation of oxy-3-indolanaline occurs readily in an aqueous environment. The observed transformation starts from an initial rupture of the O-O bond followed by a H atom transfer with the accompanying loss of an (•)OH radical to solution. Finally, classical molecular dynamics simulations were performed to equate observed differential oxidation rates of various tryptophan residues in monoclonal antibody fragments. It was found that simple parameters derived from simulation correlate well with the experimental data.

Are mixed explicit/implicit solvation models reliable for studying phosphate hydrolysis? A comparative study of continuum, explicit and mixed solvation models.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kamerlin, Shina C. L.; Haranczyk, Maciej; Warshel, Arieh

2009-05-01

Phosphate hydrolysis is ubiquitous in biology. However, despite intensive research on this class of reactions, the precise nature of the reaction mechanism remains controversial. In this work, we have examined the hydrolysis of three homologous phosphate diesters. The solvation free energy was simulated by means of either an implicit solvation model (COSMO), hybrid quantum mechanical / molecular mechanical free energy perturbation (QM/MM-FEP) or a mixed solvation model in which N water molecules were explicitly included in the ab initio description of the reacting system (where N=1-3), with the remainder of the solvent being implicitly modelled as a continuum. Here, bothmore » COSMO and QM/MM-FEP reproduce Delta Gobs within an error of about 2kcal/mol. However, we demonstrate that in order to obtain any form of reliable results from a mixed model, it is essential to carefully select the explicit water molecules from short QM/MM runs that act as a model for the true infinite system. Additionally, the mixed models tend to be increasingly inaccurate the more explicit water molecules are placed into the system. Thus, our analysis indicates that this approach provides an unreliable way for modelling phosphate hydrolysis in solution.« less

First hyperpolarizability of isomers of pyridinium N-phenoxide betaine dye in solution using the ASEC-FEG method

NASA Astrophysics Data System (ADS)

Torres, E. M.; Georg, H. C.; Fonseca, T. L.; Castro, M. A.

2018-05-01

The linear and nonlinear properties of isomeric forms of pyridinium-N-phenoxide betaine dye were investigated in protic and aprotic solvents using atomistic simulations. We employed the sequential Quantum Mechanics/Molecular Mechanics (S-QM/MM) and the free energy gradient (FEG) methods to optimize the geometry of each isomer in chloroform, acetonitrile, methanol and water. The results show a complex dependence of the first hyperpolarizability with respect to the solvent nature and isomeric form, with a marked effect of conformational changes for para-betaine. Large contrasts of the first hyperpolarizability show a clear distinction between isomeric forms in solution that could be experimentally detected.

What is behind small deviations of quantum mechanics theory from experiments? Observer's mathematics point of view

NASA Astrophysics Data System (ADS)

Khots, Boris; Khots, Dmitriy

2014-12-01

Certain results that have been predicted by Quantum Mechanics (QM) theory are not always supported by experiments. This defines a deep crisis in contemporary physics and, in particular, quantum mechanics. We believe that, in fact, the mathematical apparatus employed within today's physics is a possible reason. In particular, we consider the concept of infinity that exists in today's mathematics as the root cause of this problem. We have created Observer's Mathematics that offers an alternative to contemporary mathematics. This paper is an attempt to relay how Observer's Mathematics may explain some of the contradictions in QM theory results. We consider the Hamiltonian Mechanics, Newton equation, Schrodinger equation, two slit interference, wave-particle duality for single photons, uncertainty principle, Dirac equations for free electron in a setting of arithmetic, algebra, and topology provided by Observer's Mathematics (see www.mathrelativity.com). Certain results and communications pertaining to solution of these problems are provided.

Electron dynamics in complex environments with real-time time dependent density functional theory in a QM-MM framework

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morzan, Uriel N.; Ramírez, Francisco F.; Scherlis, Damián A., E-mail: damian@qi.fcen.uba.ar, E-mail: mcgl@qb.ffyb.uba.ar

2014-04-28

This article presents a time dependent density functional theory (TDDFT) implementation to propagate the Kohn-Sham equations in real time, including the effects of a molecular environment through a Quantum-Mechanics Molecular-Mechanics (QM-MM) hamiltonian. The code delivers an all-electron description employing Gaussian basis functions, and incorporates the Amber force-field in the QM-MM treatment. The most expensive parts of the computation, comprising the commutators between the hamiltonian and the density matrix—required to propagate the electron dynamics—, and the evaluation of the exchange-correlation energy, were migrated to the CUDA platform to run on graphics processing units, which remarkably accelerates the performance of the code.more » The method was validated by reproducing linear-response TDDFT results for the absorption spectra of several molecular species. Two different schemes were tested to propagate the quantum dynamics: (i) a leap-frog Verlet algorithm, and (ii) the Magnus expansion to first-order. These two approaches were confronted, to find that the Magnus scheme is more efficient by a factor of six in small molecules. Interestingly, the presence of iron was found to seriously limitate the length of the integration time step, due to the high frequencies associated with the core-electrons. This highlights the importance of pseudopotentials to alleviate the cost of the propagation of the inner states when heavy nuclei are present. Finally, the methodology was applied to investigate the shifts induced by the chemical environment on the most intense UV absorption bands of two model systems of general relevance: the formamide molecule in water solution, and the carboxy-heme group in Flavohemoglobin. In both cases, shifts of several nanometers are observed, consistently with the available experimental data.« less

Electron dynamics in complex environments with real-time time dependent density functional theory in a QM-MM framework

NASA Astrophysics Data System (ADS)

Morzan, Uriel N.; Ramírez, Francisco F.; Oviedo, M. Belén; Sánchez, Cristián G.; Scherlis, Damián A.; Lebrero, Mariano C. González

2014-04-01

This article presents a time dependent density functional theory (TDDFT) implementation to propagate the Kohn-Sham equations in real time, including the effects of a molecular environment through a Quantum-Mechanics Molecular-Mechanics (QM-MM) hamiltonian. The code delivers an all-electron description employing Gaussian basis functions, and incorporates the Amber force-field in the QM-MM treatment. The most expensive parts of the computation, comprising the commutators between the hamiltonian and the density matrix—required to propagate the electron dynamics—, and the evaluation of the exchange-correlation energy, were migrated to the CUDA platform to run on graphics processing units, which remarkably accelerates the performance of the code. The method was validated by reproducing linear-response TDDFT results for the absorption spectra of several molecular species. Two different schemes were tested to propagate the quantum dynamics: (i) a leap-frog Verlet algorithm, and (ii) the Magnus expansion to first-order. These two approaches were confronted, to find that the Magnus scheme is more efficient by a factor of six in small molecules. Interestingly, the presence of iron was found to seriously limitate the length of the integration time step, due to the high frequencies associated with the core-electrons. This highlights the importance of pseudopotentials to alleviate the cost of the propagation of the inner states when heavy nuclei are present. Finally, the methodology was applied to investigate the shifts induced by the chemical environment on the most intense UV absorption bands of two model systems of general relevance: the formamide molecule in water solution, and the carboxy-heme group in Flavohemoglobin. In both cases, shifts of several nanometers are observed, consistently with the available experimental data.

Electron dynamics in complex environments with real-time time dependent density functional theory in a QM-MM framework.

PubMed

Morzan, Uriel N; Ramírez, Francisco F; Oviedo, M Belén; Sánchez, Cristián G; Scherlis, Damián A; Lebrero, Mariano C González

2014-04-28

This article presents a time dependent density functional theory (TDDFT) implementation to propagate the Kohn-Sham equations in real time, including the effects of a molecular environment through a Quantum-Mechanics Molecular-Mechanics (QM-MM) hamiltonian. The code delivers an all-electron description employing Gaussian basis functions, and incorporates the Amber force-field in the QM-MM treatment. The most expensive parts of the computation, comprising the commutators between the hamiltonian and the density matrix-required to propagate the electron dynamics-, and the evaluation of the exchange-correlation energy, were migrated to the CUDA platform to run on graphics processing units, which remarkably accelerates the performance of the code. The method was validated by reproducing linear-response TDDFT results for the absorption spectra of several molecular species. Two different schemes were tested to propagate the quantum dynamics: (i) a leap-frog Verlet algorithm, and (ii) the Magnus expansion to first-order. These two approaches were confronted, to find that the Magnus scheme is more efficient by a factor of six in small molecules. Interestingly, the presence of iron was found to seriously limitate the length of the integration time step, due to the high frequencies associated with the core-electrons. This highlights the importance of pseudopotentials to alleviate the cost of the propagation of the inner states when heavy nuclei are present. Finally, the methodology was applied to investigate the shifts induced by the chemical environment on the most intense UV absorption bands of two model systems of general relevance: the formamide molecule in water solution, and the carboxy-heme group in Flavohemoglobin. In both cases, shifts of several nanometers are observed, consistently with the available experimental data.

Substrate polarization in enzyme catalysis: QM/MM analysis of the effect of oxaloacetate polarization on acetyl-CoA enolization in citrate synthase.

PubMed

van der Kamp, Marc W; Perruccio, Francesca; Mulholland, Adrian J

2007-11-15

Citrate synthase is an archetypal carbon-carbon bond forming enzyme. It promotes the conversion of oxaloacetate (OAA) to citrate by catalyzing the deprotonation (enolization) of acetyl-CoA, followed by nucleophilic attack of the enolate form of this substrate on OAA to form a citryl-CoA intermediate and subsequent hydrolysis. OAA is strongly bound to the active site and its alpha-carbonyl group is polarized. This polarization has been demonstrated spectroscopically, [(Kurz et al., Biochemistry 1985;24:452-457; Kurz and Drysdale, Biochemistry 1987;26:2623-2627)] and has been suggested to be an important catalytic strategy. Substrate polarization is believed to be important in many enzymes. The first step, formation of the acetyl-CoA enolate intermediate, is thought to be rate-limiting in the mesophilic (pig/chicken) enzyme. We have examined the effects of substrate polarization on this key step using quantum mechanical/molecular mechanical (QM/MM) methods. Free energy profiles have been calculated by AM1/CHARMM27 umbrella sampling molecular dynamics (MD) simulations, together with potential energy profiles. To study the influence of OAA polarization, profiles were calculated with different polarization of the OAA alpha-carbonyl group. The results indicate that OAA polarization influences catalysis only marginally but has a larger effect on intermediate stabilization. Different levels of treatment of OAA are compared (MM or QM), and its polarization in the protein and in water analyzed at the B3LYP/6-31+G(d)/CHARMM27 level. Analysis of stabilization by individual residues shows that the enzyme mainly stabilizes the enolate intermediate (not the transition state) through electrostatic (including hydrogen bond) interactions: these contribute much more than polarization of OAA. (c) 2007 Wiley-Liss, Inc.

Steady-State Linear and Non-linear Optical Spectroscopy of Organic Chromophores and Bio-macromolecules

NASA Astrophysics Data System (ADS)

Marazzi, Marco; Gattuso, Hugo; Monari, Antonio; Assfeld, Xavier

2018-04-01

Bio-macromolecules as DNA, lipid membranes and (poly)peptides are essential compounds at the core of biological systems. The development of techniques and methodologies for their characterization is therefore necessary and of utmost interest, even though difficulties can be experienced due to their intrinsic complex nature. Among these methods, spectroscopies, relying on optical properties are especially important to determine their macromolecular structures and behaviors, as well as the possible interactions and reactivity with external dyes – often drugs or pollutants – that can (photo)sensitize the bio-macromolecule leading to eventual chemical modifications, thus damages. In this review, we will focus on the theoretical simulation of electronic spectroscopies of bio-macromolecules, considering their secondary structure and including their interaction with different kind of (photo)sensitizers. Namely, absorption, emission and electronic circular dichroism (CD) spectra are calculated and compared with the available experimental data. Non-linear properties will be also taken into account by two-photon absorption, a highly promising technique (i) to enhance absorption in the red and infra-red windows and (ii) to enhance spatial resolution. Methodologically, the implications of using implicit and explicit solvent, coupled to quantum and thermal samplings of the phase space, will be addressed. Especially, hybrid quantum mechanics/ molecular mechanics (QM/MM) methods are explored for a comparison with solely QM methods, in order to address the necessity to consider an accurate description of environmental effects on spectroscopic properties of biological systems.

Computational prediction of chemical reactions: current status and outlook.

PubMed

Engkvist, Ola; Norrby, Per-Ola; Selmi, Nidhal; Lam, Yu-Hong; Peng, Zhengwei; Sherer, Edward C; Amberg, Willi; Erhard, Thomas; Smyth, Lynette A

2018-06-01

Over the past few decades, various computational methods have become increasingly important for discovering and developing novel drugs. Computational prediction of chemical reactions is a key part of an efficient drug discovery process. In this review, we discuss important parts of this field, with a focus on utilizing reaction data to build predictive models, the existing programs for synthesis prediction, and usage of quantum mechanics and molecular mechanics (QM/MM) to explore chemical reactions. We also outline potential future developments with an emphasis on pre-competitive collaboration opportunities. Copyright © 2018 Elsevier Ltd. All rights reserved.

QM/MM nonadiabatic dynamics simulations on photoinduced Wolff rearrangements of 1,2,3-thiadiazole

NASA Astrophysics Data System (ADS)

Liu, Xiang-Yang; Fang, Ye-Guang; Xie, Bin-Bin; Fang, Wei-Hai; Cui, Ganglong

2017-06-01

The photoinduced rearrangement reaction mechanism of 1,2,3-thiadiazole remains experimentally elusive. Two possible mechanisms have been proposed to date. The first is a stepwise mechanism via a thiocarbene intermediate; the second is an excited-state concerted rearrangement mechanism. Herein we have adopted both the electronic structure calculations and nonadiabatic dynamics simulations to study the photoinduced rearrangement reactions of 1,2,3-thiadiazole in the S2, S1, and S0 states in solution. On the basis of QM(CASPT2)/MM [quantum mechanics(complete active space self-consistent field second-order perturbation theory)/molecular mechanics] calculations, we have found that (1) the thiocarbene intermediate is not stable; thus, the stepwise mechanism should be unfavorable; (2) the excited-state decay from the S2 via S1 to S0 state is ultrafast and completed within ca. 200 fs; therefore, both the S2 and S1 states should not have a long enough time for the excited-state rearrangements. Instead, we have computationally proposed a modified photoinduced rearrangement mechanism. Upon irradiation, the S2 state is first populated (114.0 kcal/mol), followed by an ultrafast S2 → S1 → S0 excited-state decay along the S-N bond fission, which eventually leads to a very "hot" intermediate with the S-N bond broken (18.3 kcal/mol). Then, thermal rearrangements to thioketene, thiirene, and ethynethiol occur in a concerted asynchronous way. This mechanistic scenario has been verified by full-dimensional trajectory-based nonadiabatic dynamics simulations at the QM(CASPT2)/MM level. Finally, our present computational work provides experimentally interesting mechanistic insights into the photoinduced rearrangement reactions of cyclic and acyclic diazo compounds.

Effects of Atomic-Scale Structure on the Fracture Properties of Amorphous Carbon - Carbon Nanotube Composites

NASA Technical Reports Server (NTRS)

Jensen, Benjamin D.; Wise, Kristopher E.; Odegard, Gregory M.

2015-01-01

The fracture of carbon materials is a complex process, the understanding of which is critical to the development of next generation high performance materials. While quantum mechanical (QM) calculations are the most accurate way to model fracture, the fracture behavior of many carbon-based composite engineering materials, such as carbon nanotube (CNT) composites, is a multi-scale process that occurs on time and length scales beyond the practical limitations of QM methods. The Reax Force Field (ReaxFF) is capable of predicting mechanical properties involving strong deformation, bond breaking and bond formation in the classical molecular dynamics framework. This has been achieved by adding to the potential energy function a bond-order term that varies continuously with distance. The use of an empirical bond order potential, such as ReaxFF, enables the simulation of failure in molecular systems that are several orders of magnitude larger than would be possible in QM techniques. In this work, the fracture behavior of an amorphous carbon (AC) matrix reinforced with CNTs was modeled using molecular dynamics with the ReaxFF reactive forcefield. Care was taken to select the appropriate simulation parameters, which can be different from those required when using traditional fixed-bond force fields. The effect of CNT arrangement was investigated with three systems: a single-wall nanotube (SWNT) array, a multi-wall nanotube (MWNT) array, and a SWNT bundle system. For each arrangement, covalent bonds are added between the CNTs and AC, with crosslink fractions ranging from 0-25% of the interfacial CNT atoms. The SWNT and MWNT array systems represent ideal cases with evenly spaced CNTs; the SWNT bundle system represents a more realistic case because, in practice, van der Waals interactions lead to the agglomeration of CNTs into bundles. The simulation results will serve as guidance in setting experimental processing conditions to optimize the mechanical properties of CNT composites.

Is a Quality Course a Worthy Course? Designing for Value and Worth in Online Courses

ERIC Educational Resources Information Center

Youger, Robin E.; Ahern, Terence C.

2015-01-01

There are many strategies for estimating the effectiveness of instruction. Typically, most methods are based on the student evaluation. Recently a more standardized approach, Quality Matters (QM), has been developed that uses an objectives-based strategy. QM, however, does not account for the learning process, nor for the value and worth of the…

Charge redistribution in QM:QM ONIOM model systems: a constrained density functional theory approach

NASA Astrophysics Data System (ADS)

Beckett, Daniel; Krukau, Aliaksandr; Raghavachari, Krishnan

2017-11-01

The ONIOM hybrid method has found considerable success in QM:QM studies designed to approximate a high level of theory at a significantly reduced cost. This cost reduction is achieved by treating only a small model system with the target level of theory and the rest of the system with a low, inexpensive, level of theory. However, the choice of an appropriate model system is a limiting factor in ONIOM calculations and effects such as charge redistribution across the model system boundary must be considered as a source of error. In an effort to increase the general applicability of the ONIOM model, a method to treat the charge redistribution effect is developed using constrained density functional theory (CDFT) to constrain the charge experienced by the model system in the full calculation to the link atoms in the truncated model system calculations. Two separate CDFT-ONIOM schemes are developed and tested on a set of 20 reactions with eight combinations of levels of theory. It is shown that a scheme using a scaled Lagrange multiplier term obtained from the low-level CDFT model calculation outperforms ONIOM at each combination of levels of theory from 32% to 70%.

Chemical Reaction Rates from Ring Polymer Molecular Dynamics: Zero Point Energy Conservation in Mu + H2 → MuH + H.

PubMed

Pérez de Tudela, Ricardo; Aoiz, F J; Suleimanov, Yury V; Manolopoulos, David E

2012-02-16

A fundamental issue in the field of reaction dynamics is the inclusion of the quantum mechanical (QM) effects such as zero point energy (ZPE) and tunneling in molecular dynamics simulations, and in particular in the calculation of chemical reaction rates. In this work we study the chemical reaction between a muonium atom and a hydrogen molecule. The recently developed ring polymer molecular dynamics (RPMD) technique is used, and the results are compared with those of other methods. For this reaction, the thermal rate coefficients calculated with RPMD are found to be in excellent agreement with the results of an accurate QM calculation. The very minor discrepancies are within the convergence error even at very low temperatures. This exceptionally good agreement can be attributed to the dominant role of ZPE in the reaction, which is accounted for extremely well by RPMD. Tunneling only plays a minor role in the reaction.

The implementation of quality management systems in hospitals: a comparison between three countries

PubMed Central

Wagner, C; Gulácsi, L; Takacs, E; Outinen, M

2006-01-01

Background Is the implementation of Quality Management (QM) in health care proceeding satisfactorily and can national health care policies influence the implementation process? Policymakers and researchers in a country need to know the answer to this question. Cross country comparisons can reveal whether sufficient progress is being made and how this can be stimulated. The objective of the study was to investigate agreement and disparities in the implementation of QMS between The Netherlands, Hungary and Finland with respect to the evaluation model used and the national policy strategy of the three countries. Methods The study has a cross sectional design, based on measurements in 2000. Empirical data about QM-activities in hospitals were gathered by a self-administered questionnaire. The questionnaires were answered by the directors of the hospitals or the quality coordinators. The analyses are based on data from 101 hospitals in the Netherlands, 116 hospitals in Hungary and 59 hospitals in Finland. Outcome measures are the developmental stage of the Quality Management System (QMS), the development within five focal areas, and distinct QM-activities which were listed in the questionnaire. Results A mean of 22 QM-activities per hospital was found in the Netherlands and Finland versus 20 QM-activities in Hungarian hospitals. Only a small number of hospitals has already implemented a QMS (4% in The Netherlands,0% in Hungary and 3% in Finland). More hospitals in the Netherlands are concentrating on quality documents, whereas Finnish hospitals are concentrating on training in QM and guidelines. Cyclic quality improvement activities have been developed in the three countries, but in most hospitals the results were not used for improvements. All three countries pay hardly any attention to patient participation. Conclusion The study demonstrates that the implementation of QM-activities can be measured at national level and that differences between countries can be assessed. The hypothesis that governmental legislation or financial reimbursement can stimulate the implementation of QM-activities, more than voluntary recommendations, could not be confirmed. However, the results show that specific obligations can stimulate the implementation of QM-activities more than general, framework legislation. PMID:16608510

Comment on 'Realism and quantum flux tunneling'

NASA Technical Reports Server (NTRS)

Leggett, A. J.; Garg, Anupam

1987-01-01

A reply is presented to Ballentine's (1987) critique of the Legett and Garg (1985) experiment to discriminate between the experimental predictions of quantum mechanics (QM) and those of a class of macrorealistic theories. Legett and Garg uphold their earlier conclusions on the basis of the fact that the present critique refers to an experiment which was not in fact proposed. It is stressed that the original work involved an analysis according to macrorealism, while the calculations of Ballentine only demonstrate the internal consistency of the formalism of QM when applied to three consecutive actually performed experiments.

Final report of the key comparison APMP.QM-K91: APMP comparison on pH measurement of phthalate buffer

NASA Astrophysics Data System (ADS)

Hioki, Akiharu; Asakai, Toshiaki; Maksimov, Igor; Suzuki, Toshihiro; Miura, Tsutomu; Ketrin, Rosi; Nuryatini; Thanh, Ngo Huy; Truong Chinh, Nguyen; Vospelova, Alena; Bastkowski, Frank; Sander, Beatrice; Matzke, Jessica; Prokunin, Sergey; Frolov, Dmitry; Aprelev, Alexey; Dobrovolskiy, Vladimir; Uysal, Emrah; Liv, Lokman; Velina Lara-Manzano, Judith; Montero-Ruiz, Jazmin; Ortiz-Aparicio, JosÉ Luis; Ticona Canaza, Galia; Anuar Mohd Amin, Khirul; Abd Kadir, Haslina; Bakovets, Nickolay; Wong, Siu-Kay; Lam, Wai-Hing

2017-01-01

The APMP.QM-K91 was organised by TCQM of APMP to test the abilities of the national metrology institutes in the APMP region to measure a pH value of a phthalate buffer. This APMP comparison on pH measurement was proposed by the National Metrology Institute of Japan at the APMP-TCQM meeting held September 22-23, 2014. After approval by TCQM, the comparison has been conducted by NMIJ. The comparison is a key comparison following CCQM-K91. The comparison material was a phthalate buffer of pH around 4.0 and the measurement temperatures were 15 °C, 25 °C and 37 °C. This is the third APMP key comparison on pH measurement and the fifth APMP comparison on pH measurement following APMP.QM-P06 (two phosphate buffers) in 2004, APMP.QM-P09 (a phthalate buffer) in 2006, APMP.QM-K9/APMP.QM-P16 (a phosphate buffer) in 2010-2011 and APMP.QM-K19/APMP.QM-P25 (a borate buffer) in 2013-2014. The results can be used further by any participant to support its CMC claim at least for a phthalate buffer. That claim will concern the pH method employed by the participant during this comparison and will cover the used temperature(s) or the full temperature range between 15°C and 37 °C for the participant which measured pH values at the three temperatures. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Increasing Literacy in Quantitative Methods: The Key to the Future of Canadian Psychology

PubMed Central

Counsell, Alyssa; Cribbie, Robert A.; Harlow, Lisa. L.

2016-01-01

Quantitative methods (QM) dominate empirical research in psychology. Unfortunately most researchers in psychology receive inadequate training in QM. This creates a challenge for researchers who require advanced statistical methods to appropriately analyze their data. Many of the recent concerns about research quality, replicability, and reporting practices are directly tied to the problematic use of QM. As such, improving quantitative literacy in psychology is an important step towards eliminating these concerns. The current paper will include two main sections that discuss quantitative challenges and opportunities. The first section discusses training and resources for students and presents descriptive results on the number of quantitative courses required and available to graduate students in Canadian psychology departments. In the second section, we discuss ways of improving quantitative literacy for faculty, researchers, and clinicians. This includes a strong focus on the importance of collaboration. The paper concludes with practical recommendations for improving quantitative skills and literacy for students and researchers in Canada. PMID:28042199

Increasing Literacy in Quantitative Methods: The Key to the Future of Canadian Psychology.

PubMed

Counsell, Alyssa; Cribbie, Robert A; Harlow, Lisa L

2016-08-01

Quantitative methods (QM) dominate empirical research in psychology. Unfortunately most researchers in psychology receive inadequate training in QM. This creates a challenge for researchers who require advanced statistical methods to appropriately analyze their data. Many of the recent concerns about research quality, replicability, and reporting practices are directly tied to the problematic use of QM. As such, improving quantitative literacy in psychology is an important step towards eliminating these concerns. The current paper will include two main sections that discuss quantitative challenges and opportunities. The first section discusses training and resources for students and presents descriptive results on the number of quantitative courses required and available to graduate students in Canadian psychology departments. In the second section, we discuss ways of improving quantitative literacy for faculty, researchers, and clinicians. This includes a strong focus on the importance of collaboration. The paper concludes with practical recommendations for improving quantitative skills and literacy for students and researchers in Canada.

Quantum Chemical Molecular Dynamics Simulations of 1,3-Dichloropropene Combustion.

PubMed

Ahubelem, Nwakamma; Shah, Kalpit; Moghtaderi, Behdad; Page, Alister J

2015-09-03

Oxidative decomposition of 1,3-dichloropropene was investigated using quantum chemical molecular dynamics (QM/MD) at 1500 and 3000 K. Thermal oxidation of 1,3-dichloropropene was initiated by (1) abstraction of allylic H/Cl by O2 and (2) intra-annular C-Cl bond scission and elimination of allylic Cl. A kinetic analysis shows that (2) is the more dominant initiation pathway, in agreement with QM/MD results. These QM/MD simulations reveal new routes to the formation of major products (H2O, CO, HCl, CO2), which are propagated primarily by the chloroperoxy (ClO2), OH, and 1,3-dichloropropene derived radicals. In particular, intra-annular C-C/C-H bond dissociation reactions of intermediate aldehydes/ketones are shown to play a dominant role in the formation of CO and CO2. Our simulations demonstrate that both combustion temperature and radical concentration can influence the product yield, however not the combustion mechanism.

Effect of material constants on power output in piezoelectric vibration-based generators.

PubMed

Takeda, Hiroaki; Mihara, Kensuke; Yoshimura, Tomohiro; Hoshina, Takuya; Tsurumi, Takaaki

2011-09-01

A possible power output estimation based on material constants in piezoelectric vibration-based generators is proposed. A modified equivalent circuit model of the generator was built and was validated by the measurement results in the generator fabricated using potassium sodium niobate-based and lead zirconate titanate (PZT) ceramics. Subsequently, generators with the same structure using other PZT-based and bismuth-layered structure ferroelectrics ceramics were fabricated and tested. The power outputs of these generators were expressed as a linear functions of the term composed of electromechanical coupling coefficients k(sys)(2) and mechanical quality factors Q*(m) of the generator. The relationship between device constants (k(sys)(2) and Q*(m)) and material constants (k(31)(2) and Q(m)) was clarified. Estimation of the power output using material constants is demonstrated and the appropriate piezoelectric material for the generator is suggested.

Embedded-cluster calculations in a numeric atomic orbital density-functional theory framework.

PubMed

Berger, Daniel; Logsdail, Andrew J; Oberhofer, Harald; Farrow, Matthew R; Catlow, C Richard A; Sherwood, Paul; Sokol, Alexey A; Blum, Volker; Reuter, Karsten

2014-07-14

We integrate the all-electron electronic structure code FHI-aims into the general ChemShell package for solid-state embedding quantum and molecular mechanical (QM/MM) calculations. A major undertaking in this integration is the implementation of pseudopotential functionality into FHI-aims to describe cations at the QM/MM boundary through effective core potentials and therewith prevent spurious overpolarization of the electronic density. Based on numeric atomic orbital basis sets, FHI-aims offers particularly efficient access to exact exchange and second order perturbation theory, rendering the established QM/MM setup an ideal tool for hybrid and double-hybrid level density functional theory calculations of solid systems. We illustrate this capability by calculating the reduction potential of Fe in the Fe-substituted ZSM-5 zeolitic framework and the reaction energy profile for (photo-)catalytic water oxidation at TiO2(110).

Embedded-cluster calculations in a numeric atomic orbital density-functional theory framework

DOE Office of Scientific and Technical Information (OSTI.GOV)

Berger, Daniel, E-mail: daniel.berger@ch.tum.de; Oberhofer, Harald; Reuter, Karsten

2014-07-14

We integrate the all-electron electronic structure code FHI-aims into the general ChemShell package for solid-state embedding quantum and molecular mechanical (QM/MM) calculations. A major undertaking in this integration is the implementation of pseudopotential functionality into FHI-aims to describe cations at the QM/MM boundary through effective core potentials and therewith prevent spurious overpolarization of the electronic density. Based on numeric atomic orbital basis sets, FHI-aims offers particularly efficient access to exact exchange and second order perturbation theory, rendering the established QM/MM setup an ideal tool for hybrid and double-hybrid level density functional theory calculations of solid systems. We illustrate this capabilitymore » by calculating the reduction potential of Fe in the Fe-substituted ZSM-5 zeolitic framework and the reaction energy profile for (photo-)catalytic water oxidation at TiO{sub 2}(110)« less

Cost-Effective Method for Free-Energy Minimization in Complex Systems with Elaborated Ab Initio Potentials.

PubMed

Bistafa, Carlos; Kitamura, Yukichi; Martins-Costa, Marilia T C; Nagaoka, Masataka; Ruiz-López, Manuel F

2018-06-12

We describe a method to locate stationary points in the free-energy hypersurface of complex molecular systems using high-level correlated ab initio potentials. In this work, we assume a combined QM/MM description of the system although generalization to full ab initio potentials or other theoretical schemes is straightforward. The free-energy gradient (FEG) is obtained as the mean force acting on relevant nuclei using a dual level strategy. First, a statistical simulation is carried out using an appropriate, low-level quantum mechanical force-field. Free-energy perturbation (FEP) theory is then used to obtain the free-energy derivatives for the target, high-level quantum mechanical force-field. We show that this composite FEG-FEP approach is able to reproduce the results of a standard free-energy minimization procedure with high accuracy, while simultaneously allowing for a drastic reduction of both computational and wall-clock time. The method has been applied to study the structure of the water molecule in liquid water at the QCISD/aug-cc-pVTZ level of theory, using the sampling from QM/MM molecular dynamics simulations at the B3LYP/6-311+G(d,p) level. The obtained values for the geometrical parameters and for the dipole moment of the water molecule are within the experimental error, and they also display an excellent agreement when compared to other theoretical estimations. The developed methodology represents therefore an important step toward the accurate determination of the mechanism, kinetics, and thermodynamic properties of processes in solution, in enzymes, and in other disordered chemical systems using state-of-the-art ab initio potentials.

Investigating Learners' Epistemological Framings of Quantum Mechanics

ERIC Educational Resources Information Center

Dini, Vesal

2017-01-01

Classical mechanics challenges students to use their intuitions and experiences as a basis for understanding, in effect to approach learning as "a refinement of everyday thinking'' (Einstein, 1936). Moving on to quantum mechanics (QM), students, like physicists, need to adjust this approach, in particular with respect to the roles that…

Quantum mechanical/molecular mechanical and docking study of the novel analogues based on hybridization of common pharmacophores as potential anti-breast cancer agents

PubMed Central

Asadi, Parvin; Khodarahmi, Ghadamali; Farrokhpour, Hossein; Hassanzadeh, Farshid; Saghaei, Lotfollah

2017-01-01

In an attempt to identify some new potential leads as anti-breast cancer agents, novel hybrid compounds were designed by molecular hybridization approach. These derivatives were structurally derived from hybrid benzofuran–imidazole and quinazolinone derivatives, which had shown good cytotoxicity against the breast cancer cell line (MCF-7). Since aromatase enzyme (CYP19) is highly expressed in the MCF-7 cell line, the binding of these novel hybrid compounds to aromatase was investigated using the docking method. In this study, due to the positive charge on the imidazole ring of the designed ligands and also, the presence of heme iron in the active site of the enzyme, it was decided to optimize the ligand inside the protein to obtain more realistic atomic charges for it. Quantum mechanical/molecular mechanical (QM/MM) method was used to obtain more accurate atomic charges of ligand for docking calculations by considering the polarization effects of CYP19 on ligands. It was observed that the refitted charge improved the binding energy of the docked compounds. Also, the results showed that these novel hybrid compounds were adopted properly within the aromatase binding site, thereby suggesting that they could be potential inhibitors of aromatase. The main binding modes in these complexes were through hydrophobic and H bond interactions showing agreement with the basic physicochemical features of known anti aromatase compounds. Finally, the complex structures obtained from the docking study were used for single point QM/MM calculations to obtain more accurate electronic interaction energy, considering the electronic polarization of the ligand by its protein environment. PMID:28626481

Fragment-based Quantum Mechanical/Molecular Mechanical Simulations of Thermodynamic and Kinetic Process of the Ru2+-Ru3+ Self-Exchange Electron Transfer.

PubMed

Zeng, Xiancheng; Hu, Xiangqian; Yang, Weitao

2012-12-11

A fragment-based fractional number of electron (FNE) approach, is developed to study entire electron transfer (ET) processes from the electron donor region to the acceptor region in condensed phase. Both regions are described by the density-fragment interaction (DFI) method while FNE as an efficient ET order parameter is applied to simulate the electron transfer process. In association with the QM/MM energy expression, the DFI-FNE method is demonstrated to describe ET processes robustly with the Ru 2+ -Ru 3+ self-exchange ET as a proof-of-concept example. This method allows for systematic calculations of redox free energies, reorganization energies, and electronic couplings, and the absolute ET rate constants within the Marcus regime.

Can quantile mapping improve precipitation extremes from regional climate models?

NASA Astrophysics Data System (ADS)

Tani, Satyanarayana; Gobiet, Andreas

2015-04-01

The ability of quantile mapping to accurately bias correct regard to precipitation extremes is investigated in this study. We developed new methods by extending standard quantile mapping (QMα) to improve the quality of bias corrected extreme precipitation events as simulated by regional climate model (RCM) output. The new QM version (QMβ) was developed by combining parametric and nonparametric bias correction methods. The new nonparametric method is tested with and without a controlling shape parameter (Qmβ1 and Qmβ0, respectively). Bias corrections are applied on hindcast simulations for a small ensemble of RCMs at six different locations over Europe. We examined the quality of the extremes through split sample and cross validation approaches of these three bias correction methods. This split-sample approach mimics the application to future climate scenarios. A cross validation framework with particular focus on new extremes was developed. Error characteristics, q-q plots and Mean Absolute Error (MAEx) skill scores are used for evaluation. We demonstrate the unstable behaviour of correction function at higher quantiles with QMα, whereas the correction functions with for QMβ0 and QMβ1 are smoother, with QMβ1 providing the most reasonable correction values. The result from q-q plots demonstrates that, all bias correction methods are capable of producing new extremes but QMβ1 reproduces new extremes with low biases in all seasons compared to QMα, QMβ0. Our results clearly demonstrate the inherent limitations of empirical bias correction methods employed for extremes, particularly new extremes, and our findings reveals that the new bias correction method (Qmß1) produces more reliable climate scenarios for new extremes. These findings present a methodology that can better capture future extreme precipitation events, which is necessary to improve regional climate change impact studies.

Quantile Mapping Bias correction for daily precipitation over Vietnam in a regional climate model

NASA Astrophysics Data System (ADS)

Trinh, L. T.; Matsumoto, J.; Ngo-Duc, T.

2017-12-01

In the past decades, Regional Climate Models (RCMs) have been developed significantly, allowing climate simulation to be conducted at a higher resolution. However, RCMs often contained biases when comparing with observations. Therefore, statistical correction methods were commonly employed to reduce/minimize the model biases. In this study, outputs of the Regional Climate Model (RegCM) version 4.3 driven by the CNRM-CM5 global products were evaluated with and without the Quantile Mapping (QM) bias correction method. The model domain covered the area from 90oE to 145oE and from 15oS to 40oN with a horizontal resolution of 25km. The QM bias correction processes were implemented by using the Vietnam Gridded precipitation dataset (VnGP) and the outputs of RegCM historical run in the period 1986-1995 and then validated for the period 1996-2005. Based on the statistical quantity of spatial correlation and intensity distributions, the QM method showed a significant improvement in rainfall compared to the non-bias correction method. The improvements both in time and space were recognized in all seasons and all climatic sub-regions of Vietnam. Moreover, not only the rainfall amount but also some extreme indices such as R10m, R20mm, R50m, CDD, CWD, R95pTOT, R99pTOT were much better after the correction. The results suggested that the QM correction method should be taken into practice for the projections of the future precipitation over Vietnam.

Challenges and promises of integrating knowledge engineering and qualitative methods

NASA Astrophysics Data System (ADS)

Lundberg, C. Gustav; Holm, Gunilla

Our goal is to expose some of the close ties that exist between knowledge engineering (KE) and qualitative methodology (QM). Many key concepts of qualitative research, for example meaning, commonsense, understanding, and everyday life, overlap with central research concerns in artificial intelligence. These shared interests constitute a largely unexplored avenue for interdisciplinary cooperation. We compare and take some steps toward integrating two historically diverse methodologies by exploring the commonalities of KE and QM both from a substantive and a methodological/technical perspective. In the second part of this essay, we address knowledge acquisition problems and procedures. Knowledge acquisition within KE has been based primarily on cognitive psychology/science foundations, whereas knowledge acquisition within QM has a broader foundation in phenomenology, symbolic interactionism, and ethnomethodology. Our discussion and examples are interdisciplinary in nature. We do not suggest that there is a clash between the KE and QM frameworks, but rather that the lack of communication potentially may limit each framework's future development.

Development of the ReaxFFCBN reactive force field for the improved design of liquid CBN hydrogen storage materials.

PubMed

Pai, Sung Jin; Yeo, Byung Chul; Han, Sang Soo

2016-01-21

Liquid CBN (carbon-boron-nitrogen) hydrogen-storage materials such as 3-methyl-1,2-BN-cyclopentane have the advantage of being easily accessible for use in current liquid-fuel infrastructure. To develop practical liquid CBN hydrogen-storage materials, it is of great importance to understand the reaction pathways of hydrogenation/dehydrogenation in the liquid phase, which are difficult to discover by experimental methods. Herein, we developed a reactive force field (ReaxFFCBN) from quantum mechanical (QM) calculations based on density functional theory for the storage of hydrogen in BN-substituted cyclic hydrocarbon materials. The developed ReaxFFCBN provides similar dehydrogenation pathways and energetics to those predicted by QM calculations. Moreover, molecular dynamics (MD) simulations with the developed ReaxFFCBN can predict the stability and dehydrogenation behavior of various liquid CBN hydrogen-storage materials. Our simulations reveal that a unimolecular dehydrogenation mechanism is preferred in liquid CBN hydrogen-storage materials. However, as the temperature in the simulation increases, the contribution of a bimolecular dehydrogenation mechanism also increases. Moreover, our ReaxFF MD simulations show that in terms of thermal stability and dehydrogenation kinetics, liquid CBN materials with a hexagonal structure are more suitable materials than those with a pentagonal structure. We expect that the developed ReaxFFCBN could be a useful protocol in developing novel liquid CBN hydrogen-storage materials.

Computational Insights into the O2-evolving complex of photosystem II

PubMed Central

Sproviero, Eduardo M.; McEvoy, James P.; Gascón, José A.; Brudvig, Gary W.; Batista, Victor S.

2009-01-01

Mechanistic investigations of the water-splitting reaction of the oxygen-evolving complex (OEC) of photosystem II (PSII) are fundamentally informed by structural studies. Many physical techniques have provided important insights into the OEC structure and function, including X-ray diffraction (XRD) and extended X-ray absorption fine structure (EXAFS) spectroscopy as well as mass spectrometry (MS), electron paramagnetic resonance (EPR) spectroscopy and Fourier transform infrared spectroscopy applied in conjunction with mutagenesis studies. However, experimental studies have yet to yield consensus as to the exact configuration of the catalytic metal cluster and its ligation scheme. Computational modeling studies, including density functional (DFT) theory combined with quantum mechanics/molecular mechanics (QM/MM) hybrid methods for explicitly including the influence of the surrounding protein, have proposed chemically satisfactory models of the fully ligated OEC within PSII that are maximally consistent with experimental results. The inorganic core of these models is similar to the crystallographic model upon which they were based but comprises important modifications due to structural refinement, hydration and proteinaceous ligation which improve agreement with a wide range of experimental data. The computational models are useful for rationalizing spectroscopic and crystallographic results and for building a complete structure-based mechanism of water-splitting in PSII as described by the intermediate oxidation states of the OEC. This review summarizes these recent advances in QM/MM modeling of PSII within the context of recent experimental studies. PMID:18483777

Theory of chemical bonds in metalloenzymes XXI. Possible mechanisms of water oxidation in oxygen evolving complex of photosystem II

NASA Astrophysics Data System (ADS)

Yamaguchi, Kizashi; Shoji, Mitsuo; Isobe, Hiroshi; Yamanaka, Shusuke; Kawakami, Takashi; Yamada, Satoru; Katouda, Michio; Nakajima, Takahito

2018-03-01

Possible mechanisms for water cleavage in oxygen evolving complex (OEC) of photosystem II (PSII) have been investigated based on broken-symmetry (BS) hybrid DFT (HDFT)/def2 TZVP calculations in combination with available XRD, XFEL, EXAFS, XES and EPR results. The BS HDFT and the experimental results have provided basic concepts for understanding of chemical bonds of the CaMn4O5 cluster in the catalytic site of OEC of PSII for elucidation of the mechanism of photosynthetic water cleavage. Scope and applicability of the hybrid DFT (HDFT) methods have been examined in relation to relative stabilities of possible nine intermediates such as Mn-hydroxide, Mn-oxo, Mn-peroxo, Mn-superoxo, etc., in order to understand the O-O (O-OH) bond formation in the S3 and/or S4 states of OEC of PSII. The relative stabilities among these intermediates are variable, depending on the weight of the Hartree-Fock exchange term of HDFT. The Mn-hydroxide, Mn-oxo and Mn-superoxo intermediates are found to be preferable in the weak, intermediate and strong electron correlation regimes, respectively. Recent different serial femtosecond X-ray (SFX) results in the S3 state are investigated based on the proposed basic concepts under the assumption of different water-insertion steps for water cleavage in the Kok cycle. The observation of water insertion in the S3 state is compatible with previous large-scale QM/MM results and previous theoretical proposal for the chemical equilibrium mechanism in the S3 state . On the other hand, the no detection of water insertion in the S3 state based on other SFX results is consistent with previous proposal of the O-OH (or O-O) bond formation in the S4 state . Radical coupling and non-adiabatic one-electron transfer (NA-OET) mechanisms for the OO-bond formation are examined using the energy diagrams by QM calculations and by QM(UB3LYP)/MM calculations . Possible reaction pathways for the O-O and O-OH bond formations are also investigated based on two water-inlet pathways for oxygen evolution in OEC of PSII. Future perspectives are discussed in relation to post HDFT calculations of the energy diagrams for elucidation of the mechanism of water oxidation in OEC of PSII.

Generalized trajectory surface-hopping method for internal conversion and intersystem crossing

NASA Astrophysics Data System (ADS)

Cui, Ganglong; Thiel, Walter

2014-09-01

Trajectory-based fewest-switches surface-hopping (FSSH) dynamics simulations have become a popular and reliable theoretical tool to simulate nonadiabatic photophysical and photochemical processes. Most available FSSH methods model internal conversion. We present a generalized trajectory surface-hopping (GTSH) method for simulating both internal conversion and intersystem crossing processes on an equal footing. We consider hops between adiabatic eigenstates of the non-relativistic electronic Hamiltonian (pure spin states), which is appropriate for sufficiently small spin-orbit coupling. This choice allows us to make maximum use of existing electronic structure programs and to minimize the changes to available implementations of the traditional FSSH method. The GTSH method is formulated within the quantum mechanics (QM)/molecular mechanics framework, but can of course also be applied at the pure QM level. The algorithm implemented in the GTSH code is specified step by step. As an initial GTSH application, we report simulations of the nonadiabatic processes in the lowest four electronic states (S0, S1, T1, and T2) of acrolein both in vacuo and in acetonitrile solution, in which the acrolein molecule is treated at the ab initio complete-active-space self-consistent-field level. These dynamics simulations provide detailed mechanistic insight by identifying and characterizing two nonadiabatic routes to the lowest triplet state, namely, direct S1 → T1 hopping as major pathway and sequential S1 → T2 → T1 hopping as minor pathway, with the T2 state acting as a relay state. They illustrate the potential of the GTSH approach to explore photoinduced processes in complex systems, in which intersystem crossing plays an important role.

Comparison Of Reaction Barriers In Energy And Free Energy For Enzyme Catalysis

NASA Astrophysics Data System (ADS)

Andrés Cisneros, G.; Yang, Weitao

Reaction paths on potential energy surfaces obtained from QM/MM calculations of enzymatic or solution reactions depend on the starting structure employed for the path calculations. The free energies associated with these paths should be more reliable for studying reaction mechanisms, because statistical averages are used. To investigate this, the role of enzyme environment fluctuations on reaction paths has been studied with an ab initio QM/MM method for the first step of the reaction catalyzed by 4-oxalocrotonate tautomerase (4OT). Four minimum energy paths (MEPs) are compared, which have been determined with two different methods. The first path (path A) has been determined with a procedure that combines the nudged elastic band (NEB) method and a second order parallel path optimizer recently developed in our group. The second path (path B) has also been determined by the combined procedure, however, the enzyme environment has been relaxed by molecular dynamics (MD) simulations. The third path (path C) has been determined with the coordinate driving (CD) method, using the enzyme environment from path B. We compare these three paths to a previously determined path (path D) determined with the CD method. In all four cases the QM/MM-FE method (Y. Zhang et al., JCP, 112, 3483) was employed to obtain the free energy barriers for all four paths. In the case of the combined procedure, the reaction path is approximated by a small number of images which are optimized to the MEP in parallel, which results in a reduced computational cost. However, this does not allow the FEP calculation on the MEP. In order to perform FEP calculations on these paths, we introduce a modification to the NEB method that enables the addition of as many extra images to the path as needed for the FEP calculations. The calculated potential energy barriers show differences in the activation barrier between the calculated paths of as much as 5.17 kcal/mol. However, the largest free energy barrier difference is 1.58 kcal/mol. These results show the importance of the inclusion of the environment fluctuation in the calculation of enzymatic activation barriers

Solvent electronic polarization effects on a charge transfer excitation studied by the mean-field QM/MM method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakano, Hiroshi; Elements Strategy Initiative for Catalysts and Batteries, Kyoto University, Kyoto 615-8245

2015-12-31

Electronic polarization effects of a medium can have a significant impact on a chemical reaction in condensed phases. We discuss the effects on the charge transfer excitation of a chromophore, N,N-dimethyl-4-nitroaniline, in various solvents using the mean-field QM/MM method with a polarizable force field. The results show that the explicit consideration of the solvent electronic polarization effects is important especially for a solvent with a low dielectric constant when we study the solvatochromism of the chromophore.

Estimation of the Young’s modulus of cellulose Iß by MM3 and quantum mechanics

USDA-ARS?s Scientific Manuscript database

Young’s modulus provides a measure of the resistance to deformation of an elastic material. In this study, modulus estimations for models of cellulose Iß relied on calculations performed with molecular mechanics (MM) and quantum mechanics (QM) programs. MM computations used the second generation emp...

Young’s modulus calculations for cellulose Iß by MM3 and quantum mechanics

USDA-ARS?s Scientific Manuscript database

Quantum mechanics (QM) and molecular mechanics (MM) calculations were performed to elucidate Young’s moduli for a series of cellulose Iß models. Computations using the second generation empirical force field MM3 with a disaccharide cellulose model, 1,4'-O-dimethyl-ß-cellobioside (DMCB), and an analo...

What is behind small deviations of quantum mechanics theory from experiments? Observer's mathematics point of view

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khots, Boris, E-mail: bkhots@cccglobal.com; Khots, Dmitriy, E-mail: dkhots@imathconsulting.com

2014-12-10

Certain results that have been predicted by Quantum Mechanics (QM) theory are not always supported by experiments. This defines a deep crisis in contemporary physics and, in particular, quantum mechanics. We believe that, in fact, the mathematical apparatus employed within today's physics is a possible reason. In particular, we consider the concept of infinity that exists in today's mathematics as the root cause of this problem. We have created Observer's Mathematics that offers an alternative to contemporary mathematics. This paper is an attempt to relay how Observer's Mathematics may explain some of the contradictions in QM theory results. We considermore » the Hamiltonian Mechanics, Newton equation, Schrodinger equation, two slit interference, wave-particle duality for single photons, uncertainty principle, Dirac equations for free electron in a setting of arithmetic, algebra, and topology provided by Observer's Mathematics (see www.mathrelativity.com). Certain results and communications pertaining to solution of these problems are provided.« less

Charge-dependent non-bonded interaction methods for use in quantum mechanical modeling of condensed phase reactions

NASA Astrophysics Data System (ADS)

Kuechler, Erich R.

Molecular modeling and computer simulation techniques can provide detailed insight into biochemical phenomena. This dissertation describes the development, implementation and parameterization of two methods for the accurate modeling of chemical reactions in aqueous environments, with a concerted scientific effort towards the inclusion of charge-dependent non-bonded non-electrostatic interactions into currently used computational frameworks. The first of these models, QXD, modifies interactions in a hybrid quantum mechanical/molecular (QM/MM) mechanical framework to overcome the current limitations of 'atom typing' QM atoms; an inaccurate and non-intuitive practice for chemically active species as these static atom types are dictated by the local bonding and electrostatic environment of the atoms they represent, which will change over the course of the simulation. The efficacy QXD model is demonstrated using a specific reaction parameterization (SRP) of the Austin Model 1 (AM1) Hamiltonian by simultaneously capturing the reaction barrier for chloride ion attack on methylchloride in solution and the solvation free energies of a series of compounds including the reagents of the reaction. The second, VRSCOSMO, is an implicit solvation model for use with the DFTB3/3OB Hamiltonian for biochemical reactions; allowing for accurate modeling of ionic compound solvation properties while overcoming the discontinuous nature of conventional PCM models when chemical reaction coordinates. The VRSCOSMO model is shown to accurately model the solvation properties of over 200 chemical compounds while also providing smooth, continuous reaction surfaces for a series of biologically motivated phosphoryl transesterification reactions. Both of these methods incorporate charge-dependent behavior into the non-bonded interactions variationally, allowing the 'size' of atoms to change in meaningful ways with respect to changes in local charge state, as to provide an accurate, predictive and transferable models for the interactions between the quantum mechanical system and their solvated surroundings.

Observing Quantum Monodromy: AN Energy-Momentum Map Built from Experimentally-Determined Level Energies Obtained from the νb{7} Far-Infrared Band System of Ncncs

NASA Astrophysics Data System (ADS)

Tokaryk, Dennis W.; Ross, Stephen Cary; Winnewisser, Brenda P.; Winnewisser, Manfred; De Lucia, Frank C.; Billinghurst, Brant E.

2016-06-01

The concept of Quantum Monodromy (QM) provides a fresh insight into the structure of rovibrational levels in those flexible molecules for which a bending mode can carry the molecule through the linear configuration. To confirm the existence of QM in a molecule required the fruits of several strands of development: the formulation of the abstract mathematical concept of monodromy, including the exploration of its relevance to systems described by classical mechanics and its manifestation in quantum molecular applications; the development of the required spectroscopic technology and computer-aided assignment; and the development of a theoretical model to apply in fitting to the observed data. We present a timeline for each of these strands, converging in our initial confirmation of QM in NCNCS from pure rotational data alone. In that work a Generalised SemiRigid Bender (GSRB) Hamiltonian was fitted to the experimental rotational structure. Rovibrational energies calculated from the fitted GSRB parameters allowed us to construct an ``Energy-Momentum" map and confirm the presence of QM in NCNCS. In further experimental work at the Canadian Light Source Synchrotron we have identified a network of transitions directly connecting the relevant energy levels and thereby have produced a refined Energy Momentum map for NCNCS from experimental measurements alone. This map extends from the ground vibrational level to well above the potential energy barrier, beautifully illustrating the characteristic signature of QM in a system uncomplicated by interaction with other vibrational modes. B. P. Winnewisser et al., Phys. Rev. Lett. 95, 243002 (2005)

Links between quantum physics and thought.

PubMed

Robson, Barry

2009-01-01

Quantum mechanics (QM) provides a variety of ideas that can assist in developing Artificial Intelligence for healthcare, and opens the possibility of developing a unified system of Best Practice for inference that will embrace both QM and classical inference. Of particular interest is inference in the hyperbolic-complex plane, the counterpart of the normal i-complex plane of basic QM. There are two reasons. First, QM appears to rotate from i-complex Hilbert space to hyperbolic-complex descriptions when observations are made on wave functions as particles, yielding classical results, and classical laws of probability manipulation (e.g. the law of composition of probabilities) then hold, whereas in the i-complex plane they do not. Second, i-complex Hilbert space is not the whole story in physics. Hyperbolic complex planes arise in extension from the Dirac-Clifford calculus to particle physics, in relativistic correction thereby, and in regard to spinors and twisters. Generalization of these forms resemble grammatical constructions and promote the idea that probability-weighted algebraic elements can be used to hold dimensions of syntactic and semantic meaning. It is also starting to look as though when a solution is reached by an inference system in the hyperbolic-complex, the hyperbolic-imaginary values disappear, while conversely hyperbolic-imaginary values are associated with the un-queried state of a system and goal seeking behavior.

Making electronic health records support quality management: A narrative review.

PubMed

Triantafillou, Peter

2017-08-01

Since the 1990s many hospitals in the OECD countries have introduced electronic health record (EHR) systems. A number of studies have examined the factors impinging on EHR implementation. Others have studied the clinical efficacy of EHR. However, only few studies have explored the (intermediary) factors that make EHR systems conducive to quality management (QM). Undertake a narrative review of existing studies in order to identify and discuss the factors conducive to making EHR support three dimensions of QM: clinical outcomes, managerial monitoring and cost-effectiveness. A narrative review of Web of Science, Cochrane, EBSCO, ProQuest, Scopus and three Nordic research databases. most studies do not specify the type of EHR examined. 39 studies were identified for analysis. 10 factors were found to be conducive to make EHR support QM. However, the contribution of EHR to the three specific dimensions of QM varied substantially. Most studies (29) included clinical outcomes. However, only half of these reported EHR to have a positive impact. Almost all the studies (36) dealt with the ability of EHR to enhance managerial monitoring of clinical activities, the far majority of which showed a positive relationship. Finally, only five dealt with cost-effectiveness of which two found positive effects. The findings resonates well with previous reviews, though two factors making EHR support QM seem new, namely: political goals and strategies, and integration of guidelines for clinical conduct. Lacking EHR type specification and diversity in study method imply that there is a strong need for further research on the factors that may make EHR may support QM. Copyright © 2017 Elsevier B.V. All rights reserved.

The in Silico Insight into Carbon Nanotube and Nucleic Acid Bases Interaction.

PubMed

Karimi, Ali Asghar; Ghalandari, Behafarid; Tabatabaie, Seyed Saleh; Farhadi, Mohammad

2016-05-01

To explore practical applications of carbon nanotubes (CNTs) in biomedical fields the properties of their interaction with biomolecules must be revealed. Recent years, the interaction of CNTs with biomolecules is a subject of research interest for practical applications so that previous research explored that CNTs have complementary structure properties with single strand DNA (ssDNA). Hence, the quantum mechanics (QM) method based on ab initio was used for this purpose. Therefore values of binding energy, charge distribution, electronic energy and other physical properties of interaction were studied for interaction of nucleic acid bases and SCNT. In this study, the interaction between nucleic acid bases and a (4, 4) single-walled carbon nanotube (SCNT) were investigated through calculations within quantum mechanics (QM) method at theoretical level of Hartree-Fock (HF) method using 6-31G basis set. Hence, the physical properties such as electronic energy, total dipole moment, charge distributions and binding energy of nucleic acid bases interaction with SCNT were investigated based on HF method. It has been found that the guanine base adsorption is bound stronger to the outer surface of nanotube in comparison to the other bases, consistent with the recent theoretical studies. In the other words, the results explored that guanine interaction with SCNT has optimum level of electronic energy so that their interaction is stable. Also, the calculations illustrated that SCNT interact to nucleic acid bases by noncovalent interaction because of charge distribution an electrostatic area is created in place of interaction. Consequently, small diameter SCNT interaction with nucleic acid bases is noncovalent. Also, the results revealed that small diameter SCNT interaction especially SCNT (4, 4) with nucleic acid bases can be useful in practical application area of biomedical fields such detection and drug delivery.

Chloride Ion Transport by the E. coli CLC Cl-/H+ Antiporter: A Combined Quantum-Mechanical and Molecular-Mechanical Study.

PubMed

Wang, Chun-Hung; Duster, Adam W; Aydintug, Baris O; Zarecki, MacKenzie G; Lin, Hai

2018-01-01

We performed steered molecular dynamics (SMD) and umbrella sampling simulations of Cl - ion migration through the transmembrane domain of a prototypical E. coli CLC Cl - /H + antiporter by employing combined quantum-mechanical (QM) and molecular-mechanical (MM) calculations. The SMD simulations revealed interesting conformational changes of the protein. While no large-amplitude motions of the protein were observed during pore opening, the side chain rotation of the protonated external gating residue Glu148 was found to be critical for full access of the channel entrance by Cl - . Moving the anion into the external binding site (S ext ) induced small-amplitude shifting of the protein backbone at the N-terminal end of helix F. As Cl - traveled through the pore, rigid-body swinging motions of helix R separated it from helix D. Helix R returned to its original position once Cl - exited the channel. Population analysis based on polarized wavefunction from QM/MM calculations discovered significant (up to 20%) charge loss for Cl - along the ion translocation pathway inside the pore. The delocalized charge was redistributed onto the pore residues, especially the functional groups containing π bonds (e.g., the Tyr445 side chain), while the charges of the H atoms coordinating Cl - changed almost negligibly. Potentials of mean force computed from umbrella sampling at the QM/MM and MM levels both displayed barriers at the same locations near the pore entrance and exit. However, the QM/MM PMF showed higher barriers (~10 kcal/mol) than the MM PMF (~2 kcal/mol). Binding energy calculations indicated that the interactions between Cl - and certain pore residues were overestimated by the semi-empirical PM3 Hamiltonian and underestimated by the CHARMM36 force fields, both of which were employed in the umbrella sampling simulations. In particular, CHARMM36 underestimated binding interactions for the functional groups containing π bonds, missing the stabilizations of the Cl - ion due to electron delocalization. The results suggested that it is important to explore these quantum effects for accurate descriptions of the Cl - transport.

Chloride Ion Transport by the E. coli CLC Cl−/H+ Antiporter: A Combined Quantum-Mechanical and Molecular-Mechanical Study

PubMed Central

Wang, Chun-Hung; Duster, Adam W.; Aydintug, Baris O.; Zarecki, MacKenzie G.; Lin, Hai

2018-01-01

We performed steered molecular dynamics (SMD) and umbrella sampling simulations of Cl− ion migration through the transmembrane domain of a prototypical E. coli CLC Cl−/H+ antiporter by employing combined quantum-mechanical (QM) and molecular-mechanical (MM) calculations. The SMD simulations revealed interesting conformational changes of the protein. While no large-amplitude motions of the protein were observed during pore opening, the side chain rotation of the protonated external gating residue Glu148 was found to be critical for full access of the channel entrance by Cl−. Moving the anion into the external binding site (Sext) induced small-amplitude shifting of the protein backbone at the N-terminal end of helix F. As Cl− traveled through the pore, rigid-body swinging motions of helix R separated it from helix D. Helix R returned to its original position once Cl− exited the channel. Population analysis based on polarized wavefunction from QM/MM calculations discovered significant (up to 20%) charge loss for Cl− along the ion translocation pathway inside the pore. The delocalized charge was redistributed onto the pore residues, especially the functional groups containing π bonds (e.g., the Tyr445 side chain), while the charges of the H atoms coordinating Cl− changed almost negligibly. Potentials of mean force computed from umbrella sampling at the QM/MM and MM levels both displayed barriers at the same locations near the pore entrance and exit. However, the QM/MM PMF showed higher barriers (~10 kcal/mol) than the MM PMF (~2 kcal/mol). Binding energy calculations indicated that the interactions between Cl− and certain pore residues were overestimated by the semi-empirical PM3 Hamiltonian and underestimated by the CHARMM36 force fields, both of which were employed in the umbrella sampling simulations. In particular, CHARMM36 underestimated binding interactions for the functional groups containing π bonds, missing the stabilizations of the Cl− ion due to electron delocalization. The results suggested that it is important to explore these quantum effects for accurate descriptions of the Cl− transport. PMID:29594103

Chloride Ion Transport by the E. coli CLC Cl–/H+ Antiporter: A Combined Quantum-Mechanical and Molecular-Mechanical Study

NASA Astrophysics Data System (ADS)

Wang, Chun-Hung; Duster, Adam W.; Aydintug, Baris O.; Zarecki, MacKenzie G.; Lin, Hai

2018-03-01

We performed steered molecular dynamics (SMD) and umbrella sampling simulations of Cl– ion migration through the transmembrane domain of a prototypical E. coli CLC Cl–/H+ antiporter employing combined quantum-mechanical (QM) and molecular-mechanical (MM) calculations. The SMD simulations revealed interesting conformational changes of the protein. While no large-amplitude motions of the protein were observed during pore opening, the side chain rotation of the protonated external gating residue Glu148 was found critical to full access of the channel entrance by Cl–. Moving the anion into the external binding site (Sext) induced small-amplitude shifting of the protein backbone at the N-terminal end of helix F. As Cl– travelled through the pore, rigid-body swinging motions of helix R separated it from helix D. Helix R returned to its original position once Cl– exited the channel. Population analysis based on polarized wavefunction from QM/MM calculations discovered significant (up to 20%) charge loss for Cl– along the ion translocation pathway inside the pore. The delocalized charge was redistributed onto the pore residues, especially the functional groups containing pi bonds (e.g. the Tyr445 side chain), while the charges of the H atoms coordinating Cl– changed almost negligibly. Potentials of mean force computed from umbrella sampling at the QM/MM and MM levels both displayed barriers at the same locations near the pore entrance and exit. However, the QM/MM PMF showed higher barriers ( 10 kcal/mol) than the MM PMF ( 2 kcal/mol). Binding energy calculations indicated that the interactions between Cl– and certain pore residues were overestimated by the semi-empirical PM3 Hamiltonian and underestimated by the CHARMM36 force fields, both of which were employed in the umbrella sampling simulations. In particular, CHARMM36 underestimated binding interactions for the functional groups containing pi bonds, missing the stabilizations of the Cl– ion due to electron delocalization. The results suggested that it is important to explore these quantum effects for accurate descriptions of the Cl– transport.

Testing electronic structure methods for describing intermolecular H...H interactions in supramolecular chemistry.

PubMed

Casadesús, Ricard; Moreno, Miquel; González-Lafont, Angels; Lluch, José M; Repasky, Matthew P

2004-01-15

In this article a wide variety of computational approaches (molecular mechanics force fields, semiempirical formalisms, and hybrid methods, namely ONIOM calculations) have been used to calculate the energy and geometry of the supramolecular system 2-(2'-hydroxyphenyl)-4-methyloxazole (HPMO) encapsulated in beta-cyclodextrin (beta-CD). The main objective of the present study has been to examine the performance of these computational methods when describing the short range H. H intermolecular interactions between guest (HPMO) and host (beta-CD) molecules. The analyzed molecular mechanics methods do not provide unphysical short H...H contacts, but it is obvious that their applicability to the study of supramolecular systems is rather limited. For the semiempirical methods, MNDO is found to generate more reliable geometries than AM1, PM3 and the two recently developed schemes PDDG/MNDO and PDDG/PM3. MNDO results only give one slightly short H...H distance, whereas the NDDO formalisms with modifications of the Core Repulsion Function (CRF) via Gaussians exhibit a large number of short to very short and unphysical H...H intermolecular distances. In contrast, the PM5 method, which is the successor to PM3, gives very promising results. Our ONIOM calculations indicate that the unphysical optimized geometries from PM3 are retained when this semiempirical method is used as the low level layer in a QM:QM formulation. On the other hand, ab initio methods involving good enough basis sets, at least for the high level layer in a hybrid ONIOM calculation, behave well, but they may be too expensive in practice for most supramolecular chemistry applications. Finally, the performance of the evaluated computational methods has also been tested by evaluating the energetic difference between the two most stable conformations of the host(beta-CD)-guest(HPMO) system. Copyright 2003 Wiley Periodicals, Inc. J Comput Chem 25: 99-105, 2004

Tether mutations that restore function and suppress pleiotropic phenotypes of the C. elegans isp-1(qm150) Rieske iron–sulfur protein

PubMed Central

Jafari, Gholamali; Wasko, Brian M.; Tonge, Ashley; Schurman, Nathan; Dong, Cindy; Li, Zhongyu; Peters, Rebecca; Kayser, Ernst-Bernhard; Pitt, Jason N.; Morgan, Phil G.; Sedensky, Margaret M.; Crofts, Antony R.; Kaeberlein, Matt

2015-01-01

Mitochondria play an important role in numerous diseases as well as normative aging. Severe reduction in mitochondrial function contributes to childhood disorders such as Leigh Syndrome, whereas mild disruption can extend the lifespan of model organisms. The Caenorhabditis elegans isp-1 gene encodes the Rieske iron–sulfur protein subunit of cytochrome c oxidoreductase (complex III of the electron transport chain). The partial loss of function allele, isp-1(qm150), leads to several pleiotropic phenotypes. To better understand the molecular mechanisms of ISP-1 function, we sought to identify genetic suppressors of the delayed development of isp-1(qm150) animals. Here we report a series of intragenic suppressors, all located within a highly conserved six amino acid tether region of ISP-1. These intragenic mutations suppress all of the evaluated isp-1(qm150) phenotypes, including developmental rate, pharyngeal pumping rate, brood size, body movement, activation of the mitochondrial unfolded protein response reporter, CO2 production, mitochondrial oxidative phosphorylation, and lifespan extension. Furthermore, analogous mutations show a similar effect when engineered into the budding yeast Rieske iron–sulfur protein Rip1, revealing remarkable conservation of the structure–function relationship of these residues across highly divergent species. The focus on a single subunit as causal both in generation and in suppression of diverse pleiotropic phenotypes points to a common underlying molecular mechanism, for which we propose a “spring-loaded” model. These observations provide insights into how gating and control processes influence the function of ISP-1 in mediating pleiotropic phenotypes including developmental rate, movement, sensitivity to stress, and longevity. PMID:26504246

The Possibility of a New Metaphysics for Quantum Mechanics from Meinong's Theory of Objects

NASA Astrophysics Data System (ADS)

Graffigna, Matías

According to de Ronde it was Bohr's interpretation of Quantum Mechanics (QM) which closed the possibility of understanding physical reality beyond the realm of the actual, so establishing the Orthodox Line of Research. In this sense, it is not the task of any physical theory to look beyond the language and metaphysics supposed by classical physics, in order to account for what QM describes. If one wishes to maintain a realist position (though not nave) regarding physical theories, one seems then to be trapped by an array of concepts that do not allow to understand the main principles involved in the most successful physical theory thus far, mainly: the quantum postulate, the principle of indetermination and the superposition principle. If de Ronde is right in proposing QM can only be completed as a physical theory by the introduction of `new concepts' that admit as real a domain beyond actuality, then a new ontology that goes beyond Aristotelian and Newtonian actualism is needed. It was already in the early 20th century that misunderstood philosopher Alexius von Meinong proposed a Theory of Objects that admits a domain of being beyond existence-actuality. Member of the so called `School of Brentano', Meinong's concerns were oriented to provide an ontology of everything that can be thought of, and at the same time an intentionality theory of how objects are thought of. I wish to argue that in Meinong's theory of objects we find the rudiments of the ontology and the intentionality theory we need to account for QM's basic principles: mainly the possibility of predicating properties of non-entities, or in other words, the possibility of objectively describing a domain of what is, that is different from the domain of actual existence.

3D-QSAR based on quantum-chemical molecular fields: toward an improved description of halogen interactions.

PubMed

Güssregen, Stefan; Matter, Hans; Hessler, Gerhard; Müller, Marco; Schmidt, Friedemann; Clark, Timothy

2012-09-24

Current 3D-QSAR methods such as CoMFA or CoMSIA make use of classical force-field approaches for calculating molecular fields. Thus, they can not adequately account for noncovalent interactions involving halogen atoms like halogen bonds or halogen-π interactions. These deficiencies in the underlying force fields result from the lack of treatment of the anisotropy of the electron density distribution of those atoms, known as the "σ-hole", although recent developments have begun to take specific interactions such as halogen bonding into account. We have now replaced classical force field derived molecular fields by local properties such as the local ionization energy, local electron affinity, or local polarizability, calculated using quantum-mechanical (QM) techniques that do not suffer from the above limitation for 3D-QSAR. We first investigate the characteristics of QM-based local property fields to show that they are suitable for statistical analyses after suitable pretreatment. We then analyze these property fields with partial least-squares (PLS) regression to predict biological affinities of two data sets comprising factor Xa and GABA-A/benzodiazepine receptor ligands. While the resulting models perform equally well or even slightly better in terms of consistency and predictivity than the classical CoMFA fields, the most important aspect of these augmented field-types is that the chemical interpretation of resulting QM-based property field models reveals unique SAR trends driven by electrostatic and polarizability effects, which cannot be extracted directly from CoMFA electrostatic maps. Within the factor Xa set, the interaction of chlorine and bromine atoms with a tyrosine side chain in the protease S1 pocket are correctly predicted. Within the GABA-A/benzodiazepine ligand data set, PLS models of high predictivity resulted for our QM-based property fields, providing novel insights into key features of the SAR for two receptor subtypes and cross-receptor selectivity of the ligands. The detailed interpretation of regression models derived using improved QM-derived property fields thus provides a significant advantage by revealing chemically meaningful correlations with biological activity and helps in understanding novel structure-activity relationship features. This will allow such knowledge to be used to design novel molecules on the basis of interactions additional to steric and hydrogen-bonding features.

Magnetic-Ordering Propagation Vectors of Terbium Hexaboride Revisited

NASA Astrophysics Data System (ADS)

Iwasa, Kazuaki; Iga, Fumitoshi; Moyoshi, Taketo; Nakao, Akiko; Ohhara, Takashi

2018-06-01

The magnetic ordered state of a single-crystal sample of TbB6 has been studied with the high-precision neutron diffraction instrument SENJU installed at BL18 of the Materials and Life Science Facility in J-PARC. We observed new Bragg reflection spots characterized by a propagation vector qM2 = (1/4,1/4,0) below the Néel temperature TN ≈ 20 K, in addition to qM1 = (1/4,1/4,1/2) reported in the literature. Because X-ray Thomson scattering measurements do not detect the qM2 superlattice reflections at 13 K, qM2 is a new magnetic-ordering propagation vector. The magnetic multi-q structure of TbB6 is similar to that of CeB6, whereas the ratio of the qM2 amplitude to that of qM1 is smaller than that in CeB6. The combination of qM1 and qM2 is expected to assist the qL1 = (1/2,0,0) lattice modulation.

[Quality management in private practice. A nationwide survey in Germany].

PubMed

Obermann, K; Müller, P

2007-08-01

Quality management (QM) will soon become mandatory for private practice physicians in Germany. We aimed to assess the knowledge about and state of implementation of QM in German private practices. In cooperation with the Stiftung Gesundheit (Foundation for Health), Hamburg, a stratified sample of 15,383 physicians was requested via e-mail in 2006 to participate in the online survey. The survey covered sources of information and experiences with QM, cost of implementing QM, and general attitudes towards QM in private health care. A total of 787 doctors (5.1% response rate) rendered useful data sets; 16% of doctors had not yet familiarized themselves with QM. The DIN-ISO QM System is by far the best-known system, with 86% of doctors having heard about it. All other systems are known by only 30% or less of the physicians. Only about 20% of private practices have already implemented QM or are about to have it implemented. The cost of QM depends heavily on the system used with DIN-ISO (5600 euros) and EFQM (2800 euros) being the more expensive, while EPA (1800 euros) and QEP (850 euros) are much less costly. All QM systems require roughly the same amount of time from staff to be implemented and maintained. Two thirds of all doctors have not yet decided which QM system to use and contacts during seminars and recommendations from colleagues are most important when selecting a system. The level of satisfaction with QM service providers is generally high. In general, the study revealed a very heterogeneous picture. As with other new technologies or organizational changes there is a group of enthusiastic "early adopters," but we also found a substantial number of physicians (about 25%) who are highly skeptical about implementing QM. They posed a challenge for health policy and service providers alike and careful market segmentation will be needed to cater for the different needs of the different groups of doctors. Moreover, the still rather technical approach towards QM might not be helpful in convincing the clinical and patient-oriented doctors of the need to install systematic and organization-based quality systems.

Structural changes in the oxygen-evolving complex of photosystem II induced by the S 1 to S 2 transition: A combined XRD and QM/MM study

DOE PAGES

Askerka, Mikhail; Wang, Jimin; Brudvig, Gary W.; ...

2014-10-27

The S 1 → S 2 transition of the oxygen-evolving complex (OEC) of photosystem II does not involve the transfer of a proton to the lumen and occurs at cryogenic temperatures. Therefore, it is commonly thought to involve only Mn oxidation without any significant change in the structure of the OEC. Here, we analyze structural changes upon the S 1 → S 2 transition, as revealed by quantum mechanics/molecular mechanics methods and the isomorphous difference Fourier method applied to serial femtosecond X-ray diffraction data. Lastly, we find that the main structural change in the OEC is in the position ofmore » the dangling Mn and its coordination environment.« less

On the Mechanism and Rate of Spontaneous Decomposition of Amino Acids

PubMed Central

Alexandrova, Anastassia N.; Jorgensen, William L.

2011-01-01

Spontaneous decarboxylation of amino acids is among the slowest known reactions; it is much less facile than the cleavage of amide bonds in polypeptides. Establishment of the kinetics and mechanisms for this fundamental reaction is important for gauging the proficiency of enzymes. In the present study, multiple mechanisms for glycine decomposition in water are explored using QM/MM Monte Carlo simulations and free energy perturbation theory. Simple CO2 detachment emerges as the preferred pathway for decarboxylation; it is followed by water-assisted proton transfer to yield the products, CO2 and methylamine. The computed free energy of activation of 45 kcal/mol, and the resulting rate-constant of 1 × 10−21 s−1, can be compared with an extrapolated experimental rate constant of ~2 × 10−17 s−1 at 25 °C. The half-life for the reaction is more than 1 billion years. Furthermore, examination of deamination finds simple NH3-detachment yielding α-lactone to be the favored route, though it is less facile than decarboxylation by kcal/mol. Ab initio and DFT calculations with the CPCM hydration model were also carried out for the reactions; the computed free energies of activation for glycine decarboxylation agree with the QM/MM result, while deamination is predicted to be more favorable. QM/MM calculations were also performed for decarboxylation of alanine; the computed barrier is 2 kcal/mol higher than for glycine in qualitative accord with experiment. PMID:21995727

History of the Hollandia Operation

DTIC Science & Technology

1944-01-01

convoy to reduce the hazard of loss of all of the supplies. The split loading created a considerable problem on the beaches in the effort to locate -and... Pigeon Det Co B (less Det), 442nd Sig Const Bn 993rd QM Service Co 4189th QM Service Co 3522nd QM Trk Co 1 Plat, 2058th QM Trk Co (Avn) 601st QM Graves...deferred. (e) Utilize pigeons insofar as possible, especially for patrol work. (f) 1 Cause radio silence to be observed by all elements of their

Studies of carbon incorporation on the diamond [100] surface during chemical vapor deposition using density functional theory.

PubMed

Cheesman, Andrew; Harvey, Jeremy N; Ashfold, Michael N R

2008-11-13

Accurate potential energy surface calculations are presented for many of the key steps involved in diamond chemical vapor deposition on the [100] surface (in its 2 x 1 reconstructed and hydrogenated form). The growing diamond surface was described by using a large (approximately 1500 atoms) cluster model, with the key atoms involved in chemical steps being described by using a quantum mechanical (QM, density functional theory, DFT) method and the bulk of the atoms being described by molecular mechanics (MM). The resulting hybrid QM/MM calculations are more systematic and/or at a higher level of theory than previous work on this growth process. The dominant process for carbon addition, in the form of methyl radicals, is predicted to be addition to a surface radical site, opening of the adjacent C-C dimer bond, insertion, and ultimate ring closure. Other steps such as insertion across the trough between rows of dimer bonds or addition to a neighboring dimer leading to formation of a reconstruction on the next layer may also contribute. Etching of carbon can also occur; the most likely mechanism involves loss of a two-carbon moiety in the form of ethene. The present higher-level calculations confirm that migration of inserted carbon along both dimer rows and chains should be relatively facile, with barriers of approximately 150 kJ mol (-1) when starting from suitable diradical species, and that this step should play an important role in establishing growth of smooth surfaces.

Cis-trans photoisomerization of azobenzene upon excitation to the S1 state: an ab initio molecular dynamics and QM/MM study

NASA Astrophysics Data System (ADS)

Pederzoli, Marek; Pittner, Jiří; Barbatti, Mario; Lischka, Hans

2012-10-01

The cis-trans isomerization of azobenzene upon S1(n,π*) excitation is studied both in gas phase and in solution. Our study is based on ab initio non-adiabatic dynamics simulations with the non-adiabatic effects included via the fewest-switches surface hopping method with potential-energy surfaces and couplings determined on the fly. The non-adiabatic couplings have been computed based on overlaps of CASSCF wave functions. The solvent is described using classical molecular dynamics employing the quantum mechanics/molecular mechanics (QM/MM) approach. Azobenzene photoisomerization upon S1(n,π*) excitation occurs purely as a rotational motion of the central CNNC moiety. Two non-equivalent rotational pathways, corresponding to clockwise or counterclockwise rotation, are available. The course of the rotational motion is strongly dependent on the initial conditions. The internal conversion occurs via a S0/S1 crossing seam located near the midpoint of both of these rotational pathways. Based on statistical analysis it is shown that the occurrence of one or other pathways can be completely controlled by selecting adequate initial conditions. The effect of the solvent on the reaction mechanism is small. The lifetime of the S1 state is marginally lowered; the effect does not depend on the polarity, but rather on the viscosity of the solvent. The quantum yield is solvent dependent; the simulations in water give smaller quantum yield than those obtained in n-hexane and in gas phase.

Longitudinal Changes in Intermuscular Fat Volume and Quadriceps Muscle Volume in the Thighs of Female Osteoarthritis Initiative Participants

PubMed Central

MacIntyre, Norma J.; Ramadan, Khaled; Inglis, Dean; Maly, Monica R.

2011-01-01

Objectives To quantify rates of change in quadriceps muscle (QM) and intermuscular fat (IMF) volumes over 2-years in women in the Osteoarthritis Initiative (OAI) study and examine group differences between those with radiographic OA (ROA) and those without (non-ROA). Methods The OAI database was queried for women ≥50 years old in the incident and progression cohorts with and without ROA at baseline. Mid-thigh MRI scans (15 contiguous slices, 5 mm slice thickness) of eligible women were randomly selected and anonymized. Image pairs were registered. QM and IMF were segmented in the 12 most proximal matching slices with the segmenter blinded to image time point. Age-adjusted differences in QM and IMF volume changes between groups were tested using ANCOVA. Results 41 women without ROA (mean (SD) age 60.7 (7.6) yrs) and 45 with ROA (mean (SD) age 64.5 (6.7) yrs) were included. Mean QM and IMF volume changes in the non-ROA group were -4.1 (11.1) cm3 and 3.4 (7.1) cm3, respectively, and -5.4 (13.5) cm3 and 3.1 (7.4) cm3 in the ROA group, respectively. Age-adjusted between-group differences in QM and IMF changes were not significant (p>0.05). Conclusions Two-year changes in QM and IMF volume appear consistent with ageing and do not seem to be related to OA status. Direct comparison with a control cohort without OA risk factors could confirm this. Since group assignment was based on baseline data, there may have been women in the non-ROA group who developed radiographic OA over follow-up resulting in some overlap between groups. PMID:21905259

76 FR 65751 - Notice of intent to grant exclusive license

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-24

... the invention described and claimed in MFS-32870-1 ``Greener Electro-Mechanical Slide Valve'' to QM Power, Inc, having its principal place of business in Lee's Summit, MO. The intellectual property rights...

Spoilt for choice - A comparison of downscaling approaches for hydrological impact studies

NASA Astrophysics Data System (ADS)

Rössler, Ole; Fischer, Andreas; Kotlarski, Sven; Keller, Denise; Liniger, Mark; Weingartner, Rolf

2017-04-01

With the increasing number of available climate downscaling approaches, users are often faced with the luxury problem of which downscaling method to apply in a climate change impact assessment study. In Switzerland, for instance, the new generation of local scale climate scenarios CH2018 will be based on quantile mapping (QM), replacing the previous delta change (DC) method. Parallel to those two methods, a multi-site weather generator (WG) was developed to meet specific user needs. The question poses which downscaling method is the most suitable for a given application. Here, we analyze the differences of the three approaches in terms of hydro-meteorological responses in the Swiss pre-Alps in terms of mean values as well as indices of extremes. The comparison of the three different approaches was carried out in the frame of a hydrological impact assessment study that focused on different runoff characteristics and their related meteorological indices in the meso-scale catchment of the river Thur ( 1700 km2), Switzerland. For this purpose, we set up the hydrological model WaSiM-ETH under present (1980-2009) and under future conditions (2070-2099), assuming the SRES A1B emission scenario. Input to the three downscaling approaches were 10 GCM-RCM simulations of the ENSEMBLES project, while eight meteorological station observations served as the reference. All station data, observed and downscaled, were interpolated to obtain meteorological fields of temperature and precipitation required by the hydrological model. For the present-day reference period we evaluated the ability of each downscaling method to reproduce today's hydro-meteorological patterns. In the scenario runs, we focused on the comparison of change signals for each hydro-meteorological parameter generated by the three downscaling techniques. The evaluation exercise reveals that QM and WG perform equally well in representing present day average conditions, but that QM outperforms WG in reproducing indices related to extreme conditions like the number of drought events or multi-day rain sums. In terms of mean monthly discharge changes, the three downscaling methods reveal notable differences: DC shows the strongest (in summer) and less pronounced (in winter) change signal. Regarding some extreme features of runoff like frequency of droughts and the low flow level, DC shows similar change signals compared to QM and WG. This was unexpected as DC is commonly reported to fail in terms of projecting extreme changes. In contrast, QM mostly shows the strongest change signals for the 10 different extreme related indices, due to its ability to pick up more features of the climate change signals from the RCM. This indicates that DC and also WG miss some aspects, especially for flood related indices. Hence, depending on the target variable of interest, DC and QM typically provide the full range of change signals, while WG mostly lies in between both method. However, it offers the great advantage of multiple realizations combined with inter-variable consistency.

THE COMPLETE, TEMPERATURE RESOLVED EXPERIMENTAL SPECTRUM OF METHYL FORMATE (HCOOCH{sub 3}) BETWEEN 214.6 AND 265.4 GHz

DOE Office of Scientific and Technical Information (OSTI.GOV)

McMillan, James P.; Fortman, Sarah M.; Neese, Christopher F.

2016-05-20

Because methyl formate (HCOOCH{sub 3}) is abundant in the interstellar medium and has a strong, complex spectrum, it is a major contributor to the list of identified astrophysical lines. Because of its spectral complexity, with many low lying torsional and vibrational states, the quantum mechanical (QM) analysis of its laboratory spectrum is challenging and thus incomplete. As a result it is assumed that methyl formate is also one of the major contributors to the lists of unassigned lines in astrophysical spectra. This paper provides a characterization, without the need for QM analysis, of the spectrum of methyl formate between 214.6more » and 265.4 GHz for astrophysically significant temperatures. The experimental basis for this characterization is a set of 425 spectra, with absolute intensity calibration, recorded between 248 and 408 K. Analysis of these spectra makes possible the calculation of the Complete Experimental Spectrum of methyl formate as a function of temperature. Of the 7132 strongest lines reported in this paper, 2523 are in the QM catalogs. Intensity differences of 5%–10% from those calculated via QM models were also found. Results are provided in a frequency point-by-point catalog that is well suited for the simulation of overlapped spectra. The common astrophysical line frequency, line strength, and lower state energy catalog is also provided.« less

The Complete, Temperature Resolved Experimental Spectrum of Methyl Formate (HCOOCH3) between 214.6 and 265.4 GHz

NASA Astrophysics Data System (ADS)

McMillan, James P.; Fortman, Sarah M.; Neese, Christopher F.; De Lucia, Frank C.

2016-05-01

Because methyl formate (HCOOCH3) is abundant in the interstellar medium and has a strong, complex spectrum, it is a major contributor to the list of identified astrophysical lines. Because of its spectral complexity, with many low lying torsional and vibrational states, the quantum mechanical (QM) analysis of its laboratory spectrum is challenging and thus incomplete. As a result it is assumed that methyl formate is also one of the major contributors to the lists of unassigned lines in astrophysical spectra. This paper provides a characterization, without the need for QM analysis, of the spectrum of methyl formate between 214.6 and 265.4 GHz for astrophysically significant temperatures. The experimental basis for this characterization is a set of 425 spectra, with absolute intensity calibration, recorded between 248 and 408 K. Analysis of these spectra makes possible the calculation of the Complete Experimental Spectrum of methyl formate as a function of temperature. Of the 7132 strongest lines reported in this paper, 2523 are in the QM catalogs. Intensity differences of 5%-10% from those calculated via QM models were also found. Results are provided in a frequency point-by-point catalog that is well suited for the simulation of overlapped spectra. The common astrophysical line frequency, line strength, and lower state energy catalog is also provided.

Novel mutant of Escherichia coli asparaginase II to reduction of the glutaminase activity in treatment of acute lymphocytic leukemia by molecular dynamics simulations and QM-MM studies.

PubMed

Ardalan, Noeman; Mirzaie, Sako; Sepahi, Abbas Akhavan; Khavari-Nejad, Ramazan Ali

2018-03-01

L-Asparaginases (ASNase) belong to a family of amidohydrolases, have both asparaginase and glutaminase activity. Acute lymphocytic leukemia (ALL) is an outrageous disease worldwide. Bacterial ASNase has been used for the treatment of ALL. Glutaminase activity of enzyme causes some side effect and it is not essential for anticancer activity. The aim of this study was engineering of Escherichia coli asparaginase II to find a mutant with reduced glutaminase activity by molecular docking, molecular dynamics (MD) and QM-MM (Quantum mechanics molecular dynamics) simulations. Residues with low free energy of binding to Asn and high free binding energy to Gln were chosen for mutagenesis. Then, a mutant with higher glutaminase free binding energy was selected for further studies. Additionally, the MD simulation and QM-MM computation of wild type (WT) were employed and the selected mutated ASNase were analyzed and discussed. Our data showed that V27T is a good candidate to reduction the glutaminase activity, while has no remarkable effect on asparaginase activity of the enzyme. The simulation analysis revealed that V27T mutant is more stable than WT and mutant simulation was successful completely. QM-MM results confirmed the successfulness of our mutagenesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Excited state free energy calculations of Cy3 in different environments

NASA Astrophysics Data System (ADS)

Sawangsang, Pilailuk; Buranachai, Chittanon; Punwong, Chutintorn

2015-05-01

Cy3, a cyanine dye, is one of the most widely used dyes in investigating the structure and dynamics of biomolecules by means of fluorescence methods. However, Cy3 fluorescence emission is strongly competed by trans-cis isomerization, whose efficiency is dictated by the isomerization energy barrier and the environment of Cy3. The fluorescence quantum yield of Cy3 is very low when the dye is free in homogeneous solution but it is considerably enhanced in an environment that rigidifies the structure, e.g. when it is attached to a DNA strand. In this work, the barriers for isomerization on the excited state of free Cy3, and Cy3 attached to single- and double-stranded DNA in methanol, are presented. The free energy and subsequently the isomerization barrier calculations are performed using the umbrella sampling technique with the weighted histogram analysis method. The hybrid quantum mechanics/molecular mechanics (QM/MM) approach is employed to provide the potential energy surfaces for the excited state dynamics simulations in umbrella sampling. The semiempirical floating occupation molecular orbital configuration interaction method is used for electronic excited state calculations of the QM region (Cy3). From the free energy calculations, the barrier of Cy3 attached to the single-stranded DNA is highest, in agreement with previously reported experimental results. This is likely due to the stacking interaction between Cy3 and DNA. Such a stacking interaction is likely associated with steric hindrance that prevents the rotation around the conjugated bonds of Cy3. If Cy3 experiences high steric hindrance, it has a higher isomerization barrier and thus the efficiency of fluorescence emission increases.

Particle in a Box: An Experiential Environment for Learning Introductory Quantum Mechanics

ERIC Educational Resources Information Center

Anupam, Aditya; Gupta, Ridhima; Naeemi, Azad; JafariNaimi, Nassim

2018-01-01

Quantum mechanics (QMs) is a foundational subject in many science and engineering fields. It is difficult to teach, however, as it requires a fundamental revision of the assumptions and laws of classical physics and probability. Furthermore, introductory QM courses and texts predominantly focus on the mathematical formulations of the subject and…

Reduction of α,β-Unsaturated Ketones by Old Yellow Enzymes: Mechanistic Insights from Quantum Mechanics/Molecular Mechanics Calculations.

PubMed

Lonsdale, Richard; Reetz, Manfred T

2015-11-25

Enoate reductases catalyze the reduction of activated C═C bonds with high enantioselectivity. The oxidative half-reaction, which involves the addition of a hydride and a proton to opposite faces of the C═C bond, has been studied for the first time by hybrid quantum mechanics/molecular mechanics (QM/MM). The reduction of 2-cyclohexen-1-one by YqjM from Bacillus subtilis was selected as the model system. Two-dimensional QM/MM (B3LYP-D/OPLS2005) reaction pathways suggest that the hydride and proton are added as distinct steps, with the former step preceding the latter. Furthermore, we present interesting insights into the reactivity of this enzyme, including the weak binding of the substrate in the active site, the role of the two active site histidine residues for polarization of the substrate C═O bond, structural details of the transition states to hydride and proton transfer, and the role of Tyr196 as proton donor. The information presented here will be useful for the future design of enantioselective YqjM mutants for other substrates.

A Local-Realistic Model of Quantum Mechanics Based on a Discrete Spacetime

NASA Astrophysics Data System (ADS)

Sciarretta, Antonio

2018-01-01

This paper presents a realistic, stochastic, and local model that reproduces nonrelativistic quantum mechanics (QM) results without using its mathematical formulation. The proposed model only uses integer-valued quantities and operations on probabilities, in particular assuming a discrete spacetime under the form of a Euclidean lattice. Individual (spinless) particle trajectories are described as random walks. Transition probabilities are simple functions of a few quantities that are either randomly associated to the particles during their preparation, or stored in the lattice nodes they visit during the walk. QM predictions are retrieved as probability distributions of similarly-prepared ensembles of particles. The scenarios considered to assess the model comprise of free particle, constant external force, harmonic oscillator, particle in a box, the Delta potential, particle on a ring, particle on a sphere and include quantization of energy levels and angular momentum, as well as momentum entanglement.

Use of quality measurement across US dental delivery systems: a qualitative analysis.

PubMed

Alrqiq, Hosam M; Edelstein, Burton L

2016-03-01

Dentistry is increasingly challenged by payers and the public to demonstrate quality measurement (QM) activities that substantiate value. Unknown is how various components of the US oral health-care financing and delivery systems have adopted QM. The objective of this study is to explore QM activities by US dental delivery, management, financing, and related organizations. Using a structured interview guide based on a novel conceptual framework that incorporates factors influencing QM intention, adoption, and implementation, 19 key informant interviews were conducted. Informants represented safety net delivery programs (health center, nonprofit mobile, hospital-based, Veterans Administration, and tribal dental programs), private delivery organizations (private practice, closed panel HMO, and for-profit mobile dental programs), training programs that deliver care (dental and dental therapy programs), management organizations (private and Medicaid group practice management companies), care financing organizations (Medicaid managed care plan, state Medicaid program, dental benefits companies), and dental quality organizations (institute and dental professional organization). Interviews were transcribed and analyzed qualitatively. Informants report wide variation in the intensity of QM efforts with organizational leadership cited as most influential. Motivation to adopt QM efforts is more often internal than imposed. Data management and information technology both facilitate and limit QM activities. QM activities are associated with operational improvements including use of guidelines and refinements of mission. Organizational type and size appear to influence QM programs. The current status of QM is highly variable across dental organizations because organizational leadership, needs, and requirements vary according to mission and structure. © 2015 American Association of Public Health Dentistry.

Hydrogen Donor-Acceptor Fluctuations from Kinetic Isotope Effects: A Phenomenological Model

PubMed Central

Roston, Daniel; Cheatum, Christopher M.; Kohen, Amnon

2012-01-01

Kinetic isotope effects (KIEs) and their temperature dependence can probe the structural and dynamic nature of enzyme-catalyzed proton or hydride transfers. The molecular interpretation of their temperature dependence requires expensive and specialized QM/MM calculations to provide a quantitative molecular understanding. Currently available phenomenological models use a non-adiabatic assumption that is not appropriate for most hydride and proton-transfer reactions, while others require more parameters than the experimental data justify. Here we propose a phenomenological interpretation of KIEs based on a simple method to quantitatively link the size and temperature dependence of KIEs to a conformational distribution of the catalyzed reaction. The present model assumes adiabatic hydrogen tunneling, and by fitting experimental KIE data, the model yields a population distribution for fluctuations of the distance between donor and acceptor atoms. Fits to data from a variety of proton and hydride transfers catalyzed by enzymes and their mutants, as well as non-enzymatic reactions, reveal that steeply temperature-dependent KIEs indicate the presence of at least two distinct conformational populations, each with different kinetic behaviors. We present the results of these calculations for several published cases and discuss how the predictions of the calculations might be experimentally tested. The current analysis does not replace molecular quantum mechanics/molecular mechanics (QM/MM) investigations, but it provides a fast and accessible way to quantitatively interpret KIEs in the context of a Marcus-like model. PMID:22857146

A computational study to identify the key residues of peroxisome proliferator-activated receptor gamma in the interactions with its antagonists.

PubMed

Sharifi, Tayebeh; Ghayeb, Yousef

2018-05-01

Peroxisome proliferator-activated receptors (PPARs) compose a family of nuclear receptors, PPARα, PPARβ, and PPARγ, which mediate the effects of lipidic ligands at the transcriptional level. Among these, the PPARγ has been known to regulate adipocyte differentiation, fatty acid storage and glucose metabolism, and is a target of antidiabetic drugs. In this work, the interactions between PPARγ and its six known antagonists were investigated using computational methods such as molecular docking, molecular dynamics (MD) simulations, and the hybrid quantum mechanics/molecular mechanics (QM/MM). The binding energies evaluated by molecular docking varied between -22.59 and -35.15 kJ mol - 1 . In addition, MD simulations were performed to investigate the binding modes and PPARγ conformational changes upon binding of antagonists. Analysis of the root-mean-square fluctuations (RMSF) of backbone atoms shows that H3 of PPARγ has a higher mobility in the absence of antagonists and moderate conformational changes were observed. The interaction energies between antagonists and each PPARγ residue involved in the interactions were studied by QM/MM calculations. These calculations reveal that antagonists with different structures show different interaction energies with the same residue of PPARγ. Therefore, it can be concluded that the key residues vary depending on the structure of the ligand, which binds to PPARγ.

QM/MM Calculation of the Enzyme Catalytic Cycle Mechanism for Copper- and Zinc-Containing Superoxide Dismutase.

PubMed

Lintuluoto, Masami; Yamada, Chiaki; Lintuluoto, Juha M

2017-08-03

The entire enzyme catalytic mechanism including the electron and the proton transfers of the copper- and zinc-containing extracellular superoxide dismutase (SOD3) was investigated by using QM/MM method. In the first step, the electron transfer from O 2 ·- to SOD3 occurred without the bond formation between the donor and the acceptor and formed the triplet oxygen molecule and reduced SOD3. In the reduced SOD3, the distorted tetrahedral structure of Cu(I) atom was maintained. The reduction of Cu(II) atom induced the protonation of His113, which bridges between the Cu(II) and Zn(II) atoms in the resting state. Since the protonation of His113 broke the bond between Cu(I) and His113, three-coordinated Cu(I) was formed. Further, we suggest the binding of O 2 ·- formed hydrogen peroxide and the resting state after both the Cu reduction and the protonation of His113. The protonation of His113 caused the conformational change of Arg186 located at the entrance of the reactive site. The electrostatic potential surface around the reactive site showed that Arg186 plays an important role as electrostatic guidance for the negatively charged substrates only after the protonation of His113. The rotation of Arg186 switched the proton supply routes via Glu108 or Glu179 for transferring two protons from the bulk solvent.

Molecular simulation of water and hydration effects in different environments: challenges and developments for DFTB based models.

PubMed

Goyal, Puja; Qian, Hu-Jun; Irle, Stephan; Lu, Xiya; Roston, Daniel; Mori, Toshifumi; Elstner, Marcus; Cui, Qiang

2014-09-25

We discuss the description of water and hydration effects that employs an approximate density functional theory, DFTB3, in either a full QM or QM/MM framework. The goal is to explore, with the current formulation of DFTB3, the performance of this method for treating water in different chemical environments, the magnitude and nature of changes required to improve its performance, and factors that dictate its applicability to reactions in the condensed phase in a QM/MM framework. A relatively minor change (on the scale of kBT) in the O-H repulsive potential is observed to substantially improve the structural properties of bulk water under ambient conditions; modest improvements are also seen in dynamic properties of bulk water. This simple change also improves the description of protonated water clusters, a solvated proton, and to a more limited degree, a solvated hydroxide. By comparing results from DFTB3 models that differ in the description of water, we confirm that proton transfer energetics are adequately described by the standard DFTB3/3OB model for meaningful mechanistic analyses. For QM/MM applications, a robust parametrization of QM-MM interactions requires an explicit consideration of condensed phase properties, for which an efficient sampling technique was developed recently and is reviewed here. The discussions help make clear the value and limitations of DFTB3 based simulations, as well as the developments needed to further improve the accuracy and transferability of the methodology.

Prequantum classical statistical field theory: background field as a source of everything?

NASA Astrophysics Data System (ADS)

Khrennikov, Andrei

2011-07-01

Prequantum classical statistical field theory (PCSFT) is a new attempt to consider quantum mechanics (QM) as an emergent phenomenon, cf. with De Broglie's "double solution" approach, Bohmian mechanics, stochastic electrodynamics (SED), Nelson's stochastic QM and its generalization by Davidson, 't Hooft's models and their development by Elze. PCSFT is a comeback to a purely wave viewpoint on QM, cf. with early Schrodinger. There is no quantum particles at all, only waves. In particular, photons are simply wave-pulses of the classical electromagnetic field, cf. SED. Moreover, even massive particles are special "prequantum fields": the electron field, the neutron field, and so on. PCSFT claims that (sooner or later) people will be able to measure components of these fields: components of the "photonic field" (the classical electromagnetic field of low intensity), electronic field, neutronic field, and so on. At the moment we are able to produce quantum correlations as correlations of classical Gaussian random fields. In this paper we are interested in mathematical and physical reasons of usage of Gaussian fields. We consider prequantum signals (corresponding to quantum systems) as composed of a huge number of wave-pulses (on very fine prequantum time scale). We speculate that the prequantum background field (the field of "vacuum fluctuations") might play the role of a source of such pulses, i.e., the source of everything.

A computational study of ultrafast acid dissociation and acid-base neutralization reactions. I. The model.

PubMed

Maurer, Patrick; Thomas, Vibin; Rivard, Ugo; Iftimie, Radu

2010-07-28

Ultrafast, time-resolved investigations of acid-base neutralization reactions have recently been performed using systems containing the photoacid 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt (HPTS) and various Bronsted bases. Two conflicting neutralization mechanisms have been formulated by Mohammed et al. [Science 310, 83 (2005)] and Siwick et al. [J. Am. Chem. Soc. 129, 13412 (2007)] for the same acid-base system. Herein an ab initio molecular dynamics based computational model is formulated, which is able to investigate the validity of the proposed mechanisms in the general context of ground-state acid-base neutralization reactions. Our approach consists of using 2,4,6-tricyanophenol (exp. pKa congruent with 1) as a model for excited-state HPTS( *) (pKa congruent with 1.4) and carboxylate ions for the accepting base. We employ our recently proposed dipole-field/quantum mechanics (QM) treatment [P. Maurer and R. Iftimie, J. Chem. Phys. 132, 074112 (2010)] of the proton donor and acceptor molecules. This approach allows one to tune the free energy of neutralization to any desired value as well as model initial nonequilibrium hydration effects caused by a sudden increase in acidity, making it possible to achieve a more realistic comparison with experimental data than could be obtained via a full-QM treatment of the entire system. It is demonstrated that the dipole-field/QM model reproduces correctly key properties of the 2,4,6-tricyanophenol acid molecule including gas-phase proton dissociation energies and dipole moments, and condensed-phase hydration structure and pKa values.

An Overview of the Transactional Interpretation of Quantum Mechanics

NASA Astrophysics Data System (ADS)

Cramer, John G.

1988-02-01

The transactional interpretation of quantum mechanics (TI) is summarized and various points concerning the TI and its relation to the Copenhagen interpretation (CI) are considered. Questions concerning mapping the TI onto the CI, of advanced waves as solutions to proper wave equations, of collapse and the QM formalism, and of the relation of quantum mechanical interpretations to experimental tests and results are discussed.

Toward molecular mechanism of xenon anesthesia: a link to studies of xenon complexes with small aromatic molecules.

PubMed

Andrijchenko, Natalya N; Ermilov, Alexander Yu; Khriachtchev, Leonid; Räsänen, Markku; Nemukhin, Alexander V

2015-03-19

The present study illustrates the steps toward understanding molecular mechanism of xenon anesthesia by focusing on a link to the structures and spectra of intermolecular complexes of xenon with small aromatic molecules. A primary cause of xenon anesthesia is attributed to inhibition of N-methyl-D-aspartate (NMDA) receptors by an unknown mechanism. Following the results of quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) calculations we report plausible xenon action sites in the ligand binding domain of the NMDA receptor, which are due to interaction of xenon atoms with aromatic amino-acid residues. We rely in these calculations on computational protocols adjusted in combined experimental and theoretical studies of intermolecular complexes of xenon with phenol. Successful reproduction of vibrational shifts in molecular species upon complexation with xenon measured in low-temperature matrices allowed us to select a proper functional form in density functional theory (DFT) approach for use in QM subsystems, as well as to calibrate force field parameters for MD simulations. The results of molecular modeling show that xenon atoms can compete with agonists for a place in the corresponding protein cavity, thus indicating their active role in anesthetic action.

Early History of BELL'S Theorem Theory and Experiment

NASA Astrophysics Data System (ADS)

Clauser, John F.

Before 1980 it was unfashionable for a physicist to admit that he either did not understand and/or doubted the Truth and/or Orthodoxy of Quantum Mechanics (QM). Contemporary wisdom deemed it impossible that it may lead to incorrect predictions. Thus, it was foolish to suggest that it warranted further testing. Said wisdom proclaimed that nothing would ever be gained by any such pursuit. Bohr had won his debates with Einstein. Von Neumann had proven all other interpretations wrong. That was the end to it! Only an iconoclast dared think otherwise. Here I provide a brief history of some of my encounters with a few fellow iconoclasts, past denizens of a QM doubter's subculture.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fortman, Sarah M.; Neese, Christopher F.; De Lucia, Frank C.

The results of an experimental approach to the identification and characterization of the astrophysical weed vinyl cyanide in the 210-270 GHz region are reported. This approach is based on spectrally complete, intensity-calibrated spectra taken at more than 400 different temperatures in the 210-270 GHz region and is used to produce catalogs in the usual astrophysical format: line frequency, line strength, and lower state energy. As in our earlier study of ethyl cyanide, we also include the results of a frequency point-by-point analysis, which is especially well suited for characterizing weak lines and blended lines in crowded spectra. This study showsmore » substantial incompleteness in the quantum-mechanical (QM) models used to calculate astrophysical catalogs, primarily due to their omission of many low-lying vibrational states of vinyl cyanide, but also due to the exclusion of perturbed rotational transitions. Unlike ethyl cyanide, the QM catalogs for vinyl cyanide include analyses of perturbed excited vibrational states, whose modeling is more challenging. Accordingly, we include an empirical study of the frequency accuracy of these QM models. We observe modest frequency differences for some vibrationally excited lines.« less

Progress in the implementation of Quality Management in Dutch health care: 1995-2000.

PubMed

Sluijs, Emmy M; Wagner, Cordula

2003-06-01

Policymakers and researchers in all countries like to know whether the implementation of Quality Management (QM) in health care is proceeding satisfactorily. Longitudinal surveys can reveal whether sufficient progress is being made. The main objective of the study was to investigate the progress in QM in Dutch health care organizations during the period 1995-2000. A second objective was to explore whether the progress in QM was related to subsectors of care and/or to cultural characteristics of health care organizations. The study has a descriptive longitudinal design, based on repeat measurements in 1995 and 2000. Empirical data about QM activities in health care organizations were gathered using a questionnaire. The analyses are based on data from the 474 health care organizations that participated in the study in 1995 and 2000. Participants in the study were organizations from all subsectors of health care, including providers of home care, nursing homes, hospitals, and other care sectors. Outcome measures are 46 distinct QM activities, which were listed in the questionnaire. Two-thirds of the organizations had made progress in the implementation of QM activities. A mean of 25 QM activities per organization was found in 2000 compared with 20 in 1995. More care providers had set up a client council and had carried out patient satisfaction surveys. Home care organizations had made twice as much progress as many other health care organizations. However, nearly one-third of the health care organizations showed a decline in QM activities. Patient organizations were less often involved in the development of quality criteria and protocols. Progress in QM was weakly related to the dedicated and flexible attitude of employees and a non-hierarchical decision-making structure. The study demonstrates that the implementation of QM activities can be monitored at the national level and that differences between subsectors of care can be assessed. The decline in QM activities in one-third of the organizations needs to be researched further.

Quantum Mechanics Studies of Fuel Cell Catalysts and Proton Conducting Ceramics with Validation by Experiment

NASA Astrophysics Data System (ADS)

Tsai, Ho-Cheng

We carried out quantum mechanics (QM) studies aimed at improving the performance of hydrogen fuel cells. In part I, The challenge was to find a replacement for the Pt cathode that would lead to improved performance for the Oxygen Reduction Reaction (ORR) while remaining stable under operational conditions and decreasing cost. Our design strategy was to find an alloy with composition Pt3M that would lead to surface segregation such that the top layer would be pure Pt, with the second and subsequent layers richer in M. Under operating conditions we expect the surface to have significant O and/or OH chemisorbed on the surface; we searched for M that would remain segregated under these conditions. Using QM we examined surface segregation for 28 Pt3M alloys, where M is a transition metal. We found that only Pt3Os and Pt3Ir showed significant surface segregation when O and OH are chemisorbed on the catalyst surfaces. This result indicates that Pt3Os and Pt 3Ir favor formation of a Pt-skin surface layer structure that would resist the acidic electrolyte corrosion during fuel cell operation environments. We chose to focus on Os because the phase diagram for Pt-Ir indicated that Pt-Ir could not form a homogeneous alloy at lower temperature. To determine the performance for ORR, we used QM to examine intermediates, reaction pathways, and reaction barriers involved in the processes for which protons from the anode reactions react with O2 to form H2O. These QM calculations used our Poisson-Boltzmann implicit solvation model include the effects of the solvent (water with dielectric constant 78 with pH 7 at 298K). We also carried out similar QM studies followed by experimental validation for the Os/Pt core-shell catalyst fabricated by the underpotential deposition (UPD) method. The QM results indicated that the RDS for ORR is a compromise between the OOH formation step (0.37 eV for Pt, 0.23 eV for Pt2ML/Os core-shell) and H2O formation steps (0.32 eV for Pt, 0.22 eV for Pt2ML /Os core-shell). We found that Pt2ML/Os has the highest activity (compared to pure Pt and to the Pt3Os alloy) because the 0.37 eV barrier decreases to 0.23 eV. To understand what aspects of the core shell structure lead to this improved performance, we considered the effect on ORR of compressing the alloy slab to the dimensions of pure Pt. However this had the same RDS barrier 0.37 eV. Experimental materials characterization proves the core-shell feature of our catalyst. In part II, we used QM calculations to study methane stream reforming on a Ni-alloy catalyst surfaces for solid oxide fuel cell (SOFC) application. SOFC has wide fuel adaptability but the coking and sulfur poisoning will reduce its stability. We carried out QM calculations on surface segregation and found that the most stable configuration for Ni4Fe has a Fe atom distribution of (0%, 50%, 25%, 25%, 0%) starting at the bottom layer. We calculated that the binding of C atoms on the Ni4Fe surface is 142.9 Kcal/mol, which is about 10 Kcal/mol weaker compared to the pure Ni surface. This result confirms the experimental observation. The reaction energy barriers for CH x decomposition and C binding on various alloy surface, Ni4X (X=Fe, Co, Mn, and Mo), showed Ni4Fe, Ni4Co, and Fe4Mn all have better coking resistance than pure Ni, but that only Ni4Fe and Fe4Mn have (slightly) improved activity compared to pure Ni. In part III, we used QM to examine the proton transport in doped perovskite-ceramics. Here we used a 2x2x2 supercell of perovskite with composition Ba8X 7M1(OH)1O23 where X=Ce or Zr and M=Y, Gd, or Dy. Thus in each case a 4+ X is replace by a 3 + M plus a proton on one O. Here we predicted the barriers for proton diffusion allowing both includes intra-octahedron and inter-octahedra proton transfer. Without any restriction, we only observed the inter-octahedra proton transfer with similar energy barrier as previous computational work but 0.2 eV higher than experimental result for Y doped zirconate. For one restriction in our calculations is that the Odonor-Oacceptor atoms were kept at fixed distances, we found that the barrier difference between cerates/zirconates with various dopants are only 0.02~0.03 eV. To fully address performance one would need to examine proton transfer at grain boundaries, which will require larger scale ReaxFF reactive dynamics for systems with millions of atoms. The QM calculations used here will be used to train the ReaxFF force field. (Abstract shortened by UMI.).

Scientific and Engineering Studies, Compiled 1985. Signal Processing Studies.

DTIC Science & Technology

1985-01-01

of Marcum QM(ab) QM-function, ref. 8 qM(u),qM(u) Auxiliary functions, ( 115 ) viii TR 7045 OPERATING CHARACTERISTICS OF CROSSCORRELATOR WITH OR WITHOUT...preparation for that result, we use the shorthand notation qM(u) = QM (2r(-- /2 , (2u+w)1+ 2) q =(u) . QM r , (-2- ( 115 ) 40 TR 7045 where the QM...rJ- [r2+2w(1+)-+w)w)2u] for u < 0 Ph(U) = (117) -• exp r2q 3(u)+2w(l+w)q 2 (u)-(l+w)2uql(u)] for u > 0 where ( 115 ) has been used; the upper line

Heterogeneous nucleation of polymorphs on polymer surfaces: polymer-molecule interactions using a Coulomb and van der Waals model.

PubMed

Wahlberg, Nanna; Madsen, Anders Ø; Mikkelsen, Kurt V

2018-06-09

The nucleation processes of acetaminophen on poly(methyl methacrylate) and poly(vinyl acetate) have been investigated and the mechanisms of the processes are studied. This is achieved by a combination of theoretical models and computational investigations within the framework of a modified QM/MM method; a Coulomb-van der Waals model. We have combined quantum mechanical computations and electrostatic models at the atomistic level for investigating the stability of different orientations of acetaminophen on the polymer surfaces. Based on the Coulomb-van der Waals model, we have determined the most stable orientation to be a flat orientation, and the strongest interaction is seen between poly(vinyl acetate) and the molecule in a flat orientation in vacuum.

The Complete, Temperature Resolved Experimental Spectrum of Methanol (CH3OH) between 560 and 654 GHz

NASA Astrophysics Data System (ADS)

Fortman, Sarah M.; Neese, Christopher F.; De Lucia, Frank C.

2014-02-01

The complete spectrum of methanol (CH3OH) has been characterized over a range of astrophysically significant temperatures in the 560.4-654.0 GHz spectral region. Absolute intensity calibration and analysis of 166 experimental spectra recorded over a slow 248-398 K temperature ramp provide a means for the simulation of the complete spectrum of methanol as a function of temperature. These results include contributions from vt = 3 and other higher states that are difficult to model via quantum mechanical (QM) techniques. They also contain contributions from the 13C isotopologue in terrestrial abundance. In contrast to our earlier work on semi-rigid species, such as ethyl cyanide and vinyl cyanide, significant intensity differences between these experimental values and those calculated by QM methods were found for many of the lines. Analysis of these differences shows the difficulty of the calculation of dipole matrix elements in the context of the internal rotation of the methanol molecule. These results are used to both provide catalogs in the usual line frequency, linestrength, and lower state energy format, as well as in a frequency point-by-point catalog that is particularly well suited for the characterization of blended lines.

Two-dimensional free-energy surface on the exchange reaction of alkyl chloride/chloride using the QM/MM-MC method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ohisa, M.; Yamataka, H.; Dupuis, Michel

2007-12-05

Two-dimensional free-energy surfaces are calculated for alkyl chloride/chloride exchange/inversion reactions: Cl- + RCl (R = Me and t-Bu) surrounded by one hundred H2O molecules as a model of solvent. The methodology of free-energy calculation by perturbation theory based on a mixed-Hamiltonian model (QM/MM) combined with Monte Carlo sampling of the solvent configurations was used to obtain the changes in solvation free energy. We devised a special procedure to analyze the two-dimensional free-energy surfaces to gain unique insight into the differences in the reaction mechanisms between the two systems. The inversion reaction path for R = t-Bu on the free-energy surfacemore » is found to proceed in an asynchronous way within a concerted framework via the ion-pair region. This is in contrast to the R = Me system that proceeds as a typical SN2 reaction. This work was supported by the U.S. Department of Energy's (DOE) Office of Basic Energy Sciences, Chemical Sciences program. The Pacific Northwest National Laboratory is operated by Battelle for DOE.« less

Report of the key comparison APMP.QM-K19. APMP comparison on pH measurement of borate buffer

NASA Astrophysics Data System (ADS)

Hioki, Akiharu; Asakai, Toshiaki; Maksimov, Igor; Suzuki, Toshihiro; Miura, Tsutomu; Obromsook, Krairerk; Tangpaisarnkul, Nongluck; Rodruangthum, Patumporn; Wong, Siu-Kay; Lam, Wai-Hing; Zakaria, Osman; Anuar Mohd. Amin, Khirul; Thanh, Ngo Huy; Máriássy, Michal; Vyskocil, Leos; Hankova, Zuzana; Fisicaro, Paola; Stoica, Daniela; Singh, Nahar; Soni, Daya; Ticona Canaza, Galia; Kutovoy, Viatcheslav; Barbieri Gonzaga, Fabiano; Dias, Júlio Cesar; Vospelova, Alena; Bakovets, Nickolay; Zhanasbayeva, Bibinur

2015-01-01

The APMP.QM-K19 was organised by TCQM of APMP to test the abilities of the national metrology institutes in the APMP region to measure a pH value of a borate buffer. This APMP comparison on pH measurement was proposed by the National Metrology Institute of Japan (NMIJ) and the National Institute of Metrology (Thailand) (NIMT) at the APMP-TCQM meeting held 26-27 November 2012. After approval by TCQM, the comparison has been conducted by NMIJ and NIMT. The comparison is a key comparison following CCQM-K19 and CCQM-K19.1. The comparison material was a borate buffer of pH around 9.2 and the measurement temperatures were 15 °C, 25 °C and 37 °C. This is the second APMP key comparison on pH measurement and the fourth APMP comparison on pH measurement following APMP.QM-P06 (two phosphate buffers) in 2004, APMP.QM-P09 (a phthalate buffer) in 2006 and APMP.QM-K9/APMP.QM-P16 (a phosphate buffer) in 2010-2011. The results can be used further by any participant to support its CMC claim at least for a borate buffer. That claim will concern the pH method employed by the participant during this comparison and will cover the used temperature(s) or the full temperature range between 15°C and 37 °C for the participant which measured pH values at the three temperatures. Main text. To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Recent advances in QM/MM free energy calculations using reference potentials.

PubMed

Duarte, Fernanda; Amrein, Beat A; Blaha-Nelson, David; Kamerlin, Shina C L

2015-05-01

Recent years have seen enormous progress in the development of methods for modeling (bio)molecular systems. This has allowed for the simulation of ever larger and more complex systems. However, as such complexity increases, the requirements needed for these models to be accurate and physically meaningful become more and more difficult to fulfill. The use of simplified models to describe complex biological systems has long been shown to be an effective way to overcome some of the limitations associated with this computational cost in a rational way. Hybrid QM/MM approaches have rapidly become one of the most popular computational tools for studying chemical reactivity in biomolecular systems. However, the high cost involved in performing high-level QM calculations has limited the applicability of these approaches when calculating free energies of chemical processes. In this review, we present some of the advances in using reference potentials and mean field approximations to accelerate high-level QM/MM calculations. We present illustrative applications of these approaches and discuss challenges and future perspectives for the field. The use of physically-based simplifications has shown to effectively reduce the cost of high-level QM/MM calculations. In particular, lower-level reference potentials enable one to reduce the cost of expensive free energy calculations, thus expanding the scope of problems that can be addressed. As was already demonstrated 40 years ago, the usage of simplified models still allows one to obtain cutting edge results with substantially reduced computational cost. This article is part of a Special Issue entitled Recent developments of molecular dynamics. Copyright © 2014. Published by Elsevier B.V.

Total Quality Management in Higher Education: Clearing the Hurdles. A Survey on Strategies for Implementing Quality Management Practices in Higher Education. A GOAL/QPC Application Report.

ERIC Educational Resources Information Center

Seymour, Daniel

Based on a survey of Quality Management (QM) practitioners at 21 colleges, this study presents the 10 most difficult implementation hurdles to QM in higher education and a set of hurdle-clearing strategies. The hurdles are: (1) lack of time to implement QM; (2) perception that QM is something for janitorial and housing staffs but not applicable to…

Rate coefficients from quantum and quasi-classical cumulative reaction probabilities for the S(1D) + H2 reaction

NASA Astrophysics Data System (ADS)

Jambrina, P. G.; Lara, Manuel; Menéndez, M.; Launay, J.-M.; Aoiz, F. J.

2012-10-01

Cumulative reaction probabilities (CRPs) at various total angular momenta have been calculated for the barrierless reaction S(1D) + H2 → SH + H at total energies up to 1.2 eV using three different theoretical approaches: time-independent quantum mechanics (QM), quasiclassical trajectories (QCT), and statistical quasiclassical trajectories (SQCT). The calculations have been carried out on the widely used potential energy surface (PES) by Ho et al. [J. Chem. Phys. 116, 4124 (2002), 10.1063/1.1431280] as well as on the recent PES developed by Song et al. [J. Phys. Chem. A 113, 9213 (2009), 10.1021/jp903790h]. The results show that the differences between these two PES are relatively minor and mostly related to the different topologies of the well. In addition, the agreement between the three theoretical methodologies is good, even for the highest total angular momenta and energies. In particular, the good accordance between the CRPs obtained with dynamical methods (QM and QCT) and the statistical model (SQCT) indicates that the reaction can be considered statistical in the whole range of energies in contrast with the findings for other prototypical barrierless reactions. In addition, total CRPs and rate coefficients in the range of 20-1000 K have been calculated using the QCT and SQCT methods and have been found somewhat smaller than the experimental total removal rates of S(1D).

Estimation of Streamflow Characteristics for Charles M. Russell National Wildlife Refuge, Northeastern Montana

USGS Publications Warehouse

Sando, Steven K.; Morgan, Timothy J.; Dutton, DeAnn M.; McCarthy, Peter M.

2009-01-01

Charles M. Russell National Wildlife Refuge (CMR) encompasses about 1.1 million acres (including Fort Peck Reservoir on the Missouri River) in northeastern Montana. To ensure that sufficient streamflow remains in the tributary streams to maintain the riparian corridors, the U.S. Fish and Wildlife Service is negotiating water-rights issues with the Reserved Water Rights Compact Commission of Montana. The U.S. Geological Survey, in cooperation with the U.S. Fish and Wildlife Service, conducted a study to gage, for a short period, selected streams that cross CMR, and analyze data to estimate long-term streamflow characteristics for CMR. The long-term streamflow characteristics of primary interest include the monthly and annual 90-, 80-, 50-, and 20-percent exceedance streamflows and mean streamflows (Q.90, Q.80, Q.50, Q.20, and QM, respectively), and the 1.5-, 2-, and 2.33- year peak flows (PK1.5, PK2, and PK2.33, respectively). The Regional Adjustment Relationship (RAR) was investigated for estimating the monthly and annual Q.90, Q.80, Q.50, Q.20, and QM, and the PK1.5, PK2, and PK2.33 for the short-term CMR gaging stations (hereinafter referred to as CMR stations). The RAR was determined to provide acceptable results for estimating the long-term Q.90, Q.80, Q.50, Q.20, and QM on a monthly basis for the months of March through June, and also on an annual basis. For the months of September through January, the RAR regression equations did not provide acceptable results for any long-term streamflow characteristic. For the month of February, the RAR regression equations provided acceptable results for the long-term Q.50 and QM, but poor results for the long-term Q.90, Q.80, and Q.20. For the months of July and August, the RAR provided acceptable results for the long-term Q.50, Q.20, and QM, but poor results for the long-term Q.90 and Q.80. Estimation coefficients were developed for estimating the long-term streamflow characteristics for which the RAR did not provide acceptable results. The RAR also was determined to provide acceptable results for estimating the PK1.5., PK2, and PK2.33 for the three CMR stations that lacked suitable peak-flow records. Methods for estimating streamflow characteristics at ungaged sites also were derived. Regression analyses that relate individual streamflow characteristics to various basin and climatic characteristics for gaging stations were performed to develop regression equations to estimate streamflow characteristics at ungaged sites. Final equations for the annual Q.50, Q.20, and QM are reported. Acceptable equations also were developed for estimating QM for the months of February, March, April, June, and July, and Q.50, Q.20, and QM on an annual basis. However, equations for QM for the months of February, March, April, June, and July were determined to be less consistent and reliable than the use of estimation coefficients applied to the regression equation results for the annual QM. Acceptable regression equations also were developed for the PK1.5, PK2, and PK2.33.

Hydrolytically degradable poly(ethylene glycol) hydrogel scaffolds with tunable degradation and mechanical properties

PubMed Central

Zustiak, Silviya P.

2011-01-01

The objective of this work was to create three-dimensional (3D) hydrogel matrices with defined mechanical properties, as well as tunable degradability for use in applications involving protein delivery and cell encapsulation. Thus, we report the synthesis and characterization of a novel hydrolytically degradable poly(ethylene glycol) (PEG) hydrogel composed of PEG vinyl sulfone (PEG-VS) cross-linked with PEG-diester-dithiol. Unlike previously reported degradable PEG-based hydrogels, these materials are homogeneous in structure, fully hydrophilic and have highly specific cross-linking chemistry. We characterized hydrogel degradation and associated trends in mechanical properties, i.e., storage modulus (G′), swelling ratio (QM), and mesh size (ξ). Degradation time and the monitored mechanical properties of the hydrogel correlated with cross-linker molecular weight, cross-linker functionality, and total polymer density; these properties changed predictably as degradation proceeded (G′ decreased, whereas QM and ξ increased) until the gels reached complete degradation. Balb/3T3 fibroblast adhesion and proliferation within the 3D hydrogel matrices were also verified. In sum, these unique properties indicate that the reported degradable PEG hydrogels are well poised for specific applications in protein and cell delivery to repair soft tissue. PMID:20355705

Non Kolmogorov Probability Models Outside Quantum Mechanics

NASA Astrophysics Data System (ADS)

Accardi, Luigi

2009-03-01

This paper is devoted to analysis of main conceptual problems in the interpretation of QM: reality, locality, determinism, physical state, Heisenberg principle, "deterministic" and "exact" theories, laws of chance, notion of event, statistical invariants, adaptive realism, EPR correlations and, finally, the EPR-chameleon experiment.

Quantum-Like Models for Decision Making in Psychology and Cognitive Science

NASA Astrophysics Data System (ADS)

Khrennikov, Andrei.

2009-02-01

We show that (in contrast to rather common opinion) the domain of applications of the mathematical formalism of quantum mechanics is not restricted to physics. This formalism can be applied to the description of various quantum-like (QL) information processing. In particular, the calculus of quantum (and more general QL) probabilities can be used to explain some paradoxical statistical data which was collected in psychology and cognitive science. The main lesson of our study is that one should sharply distinguish the mathematical apparatus of QM from QM as a physical theory. The domain of application of the mathematical apparatus is essentially wider than quantum physics. Quantum-like representation algorithm, formula of total probability, interference of probabilities, psychology, cognition, decision making.

Testing local-realism and macro-realism under generalized dichotomic measurements

NASA Astrophysics Data System (ADS)

Das, Debarshi; Mal, Shiladitya; Home, Dipankar

2018-04-01

Generalized quantum measurements with two outcomes are fully characterized by two real parameters, dubbed as sharpness parameter and biasedness parameter and they can be linked with different aspects of the experimental setup. It is known that sharpness parameter characterizes precision of the measurements and decreasing sharpness parameter of the measurements reduces the possibility of probing quantum features like quantum mechanical (QM) violation of local-realism (LR) or macro-realism (MR). Here we investigate the effect of biasedness together with that of sharpness of measurements and find a trade-off between those two parameters in the context of probing QM violations of LR and MR. Interestingly, we also find that the above mentioned trade-off is more robust in the latter case.

[Quality management (TQM) in public health-care (PHC): principles for cost-performance calculations and cost reductions with better quality].

PubMed

Bergholz, W

2008-11-01

In many high-tech industries, quality management (QM) has enabled improvements of quality by a factor of 100 or more, in combination with significant cost reductions. Compared to this, the application of QM methods in health care is in its initial stages. It is anticipated that stringent process management, embedded in an effective QM system will lead to significant improvements in health care in general and in the German public health service in particular. Process management is an ideal platform for controlling in the health care sector, and it will significantly improve the leverage of controlling to bring down costs. Best practice sharing in industry has led to quantum leap improvements. Process management will enable best practice sharing also in the public health service, in spite of the highly diverse portfolio of services that the public health service offers in different German regions. Finally, it is emphasised that "technical" QM, e.g., on the basis of the ISO 9001 standard is not sufficient to reach excellence. It is necessary to integrate soft factors, such as patient or employee satisfaction, and leadership quality into the system. The EFQM model for excellence can serve as proven tool to reach this goal.

Qualitative research within trials: developing a standard operating procedure for a clinical trials unit

PubMed Central

2013-01-01

Background Qualitative research methods are increasingly used within clinical trials to address broader research questions than can be addressed by quantitative methods alone. These methods enable health professionals, service users, and other stakeholders to contribute their views and experiences to evaluation of healthcare treatments, interventions, or policies, and influence the design of trials. Qualitative data often contribute information that is better able to reform policy or influence design. Methods Health services researchers, including trialists, clinicians, and qualitative researchers, worked collaboratively to develop a comprehensive portfolio of standard operating procedures (SOPs) for the West Wales Organisation for Rigorous Trials in Health (WWORTH), a clinical trials unit (CTU) at Swansea University, which has recently achieved registration with the UK Clinical Research Collaboration (UKCRC). Although the UKCRC requires a total of 25 SOPs from registered CTUs, WWORTH chose to add an additional qualitative-methods SOP (QM-SOP). Results The qualitative methods SOP (QM-SOP) defines good practice in designing and implementing qualitative components of trials, while allowing flexibility of approach and method. Its basic principles are that: qualitative researchers should be contributors from the start of trials with qualitative potential; the qualitative component should have clear aims; and the main study publication should report on the qualitative component. Conclusions We recommend that CTUs consider developing a QM-SOP to enhance the conduct of quantitative trials by adding qualitative data and analysis. We judge that this improves the value of quantitative trials, and contributes to the future development of multi-method trials. PMID:23433341

Analytical bound-state solutions of the Schrödinger equation for the Manning-Rosen plus Hulthén potential within SUSY quantum mechanics

NASA Astrophysics Data System (ADS)

Ahmadov, A. I.; Naeem, Maria; Qocayeva, M. V.; Tarverdiyeva, V. A.

2018-01-01

In this paper, the bound-state solution of the modified radial Schrödinger equation is obtained for the Manning-Rosen plus Hulthén potential by using new developed scheme to overcome the centrifugal part. The energy eigenvalues and corresponding radial wave functions are defined for any l≠0 angular momentum case via the Nikiforov-Uvarov (NU) and supersymmetric quantum mechanics (SUSY QM) methods. Thanks to both methods, equivalent expressions are obtained for the energy eigenvalues, and the expression of radial wave functions transformations to each other is presented. The energy levels and the corresponding normalized eigenfunctions are represented in terms of the Jacobi polynomials for arbitrary l states. A closed form of the normalization constant of the wave functions is also found. It is shown that, the energy eigenvalues and eigenfunctions are sensitive to nr radial and l orbital quantum numbers.

Mechanistic aspects of thioflavin-T self-aggregation and DNA binding: evidence for dimer attack on DNA grooves.

PubMed

Biancardi, A; Biver, T; Burgalassi, A; Mattonai, M; Secco, F; Venturini, M

2014-10-07

Thioflavin-T (TFT) is a fluorescent marker widely employed in biomedical research but the mechanism of its binding to polynucleotides has been poorly understood. This paper presents a study of the mechanisms of TFT self-aggregation and binding to DNA. Relaxation kinetics of TFT solutions show that the cyanine undergoes dimerization followed by dimer isomerisation. The interaction of TFT with DNA has been investigated using static methods, such as spectrophotometric and spectrofluorometric titrations under different conditions (salt content, temperature), fluorescence quenching, viscometric experiments and the T-jump relaxation method. The combined use of these techniques enabled us to show that the TFT monomer undergoes intercalation between the DNA base pairs and external binding according to a branched mechanism. Moreover, it has also been observed that, under dye excess conditions, the TFT dimer binds to the DNA grooves. The molecular structures of intercalated TFT and the groove-bound TFT dimer are obtained by performing QM/MM MD simulations.

How are substrate binding and catalysis affected by mutating Glu127 and Arg161 in prolyl-4-hydroxylase? A QM/MM and MD study.

NASA Astrophysics Data System (ADS)

Timmins, Amy; de Visser, Sam P.

2017-11-01

Prolyl-4-hydroxylase is a vital enzyme for human physiology involved in the biosynthesis of 4-hydroxyproline, an essential component for collagen formation. The enzyme performs a unique stereo- and regioselective hydroxylation at the C4 position of proline despite the fact that the C5 hydrogen atom should be thermodynamically easier to abstract. To gain insight into the mechanism and find the origin of this regioselectivity, we have done a quantum mechanics/molecular mechanics (QM/MM) study on wildtype and mutant structures. In a previous study [Timmins, Saint-André and de Visser, J. Am. Chem. Soc. 2017] we identified several active site residues critical for substrate binding and positioning. In particular, the Glu127 and Arg161 were shown to form multiple hydrogen bonding and ion-dipole interactions with substrate and could thereby affect the regio- and stereoselectivity of the reaction. In this work, we decided to test that hypothesis and report a QM/MM and molecular dynamics (MD) study on prolyl-4-hydroxylase and several active site mutants where Glu127 or Arg161 are mutated for Asp, Gln or Lys. Thus, the R161D and R161Q mutants give very high barriers for hydrogen atom abstraction from any proline C–H bond and therefore will be inactive. The R161K mutant, by contrast, sees the regio- and stereoselectivity of the reaction change but still is expected to hydroxylate proline at room temperature. By contrast, the Glu127 mutants E127D and E127Q show possible changes in regioselectivity with the former being more probable to react compared to the latter.

Computational Insights into an Enzyme-Catalyzed [4+2] Cycloaddition

PubMed Central

2017-01-01

The enzyme SpnF, involved in the biosynthesis of spinosyn A, catalyzes a formal [4+2] cycloaddition of a 22-membered macrolactone, which may proceed as a concerted [4+2] Diels–Alder reaction or a stepwise [6+4] cycloaddition followed by a Cope rearrangement. Quantum mechanics/molecular mechanics (QM/MM) calculations combined with free energy simulations show that the Diels–Alder pathway is favored in the enzyme environment. OM2/CHARMM free energy simulations for the SpnF-catalyzed reaction predict a free energy barrier of 22 kcal/mol for the concerted Diels–Alder process and provide no evidence of a competitive stepwise pathway. Compared with the gas phase, the enzyme lowers the Diels–Alder barrier significantly, consistent with experimental observations. Inspection of the optimized geometries indicates that the enzyme may prearrange the substrate within the active site to accelerate the [4+2] cycloaddition and impede the [6+4] cycloaddition through interactions with active-site residues. Judging from partial charge analysis, we find that the hydrogen bond between the Thr196 residue of SpnF and the substrate C15 carbonyl group contributes to the enhancement of the rate of the Diels–Alder reaction. QM/MM simulations show that the substrate can easily adopt a reactive conformation in the active site of SpnF because interconversion between the C5–C6 s-trans and s-cis conformers is facile. Our QM/MM study suggests that the enzyme SpnF does behave as a Diels-Alderase. PMID:29131960

Thiol Versus Hydroxamate as Zinc Binding Group In HDAC Inhibition: An Ab Initio QM/MM Molecular Dynamics Study

PubMed Central

Gong, Wenjing; Wu, Ruibo; Zhang, Yingkai

2015-01-01

Zinc-dependent histone deacetylases (HDACs) play a critical role in transcriptional repression and gene silencing, and are among the most attractive targets for the development of new therapeutics against cancer and various other diseases. Two HDAC inhibitors have been approved by FDA as anti-cancer drugs: one is SAHA whose hydroxamate is directly bound to zinc, the other is FK228 whose active form may use thiol as the zinc binding group. In spite of extensive studies, it remains to be ambiguous regarding how thiol and hydroxamate are bound to the zinc active site of HDACs. In this work, our computational approaches center on Born-Oppenheimer ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics with umbrella sampling, which allow for modeling of the zinc active site with reasonable accuracy while properly including dynamics and effects of protein environment. Meanwhile, an improved short-long effective function (SLEF2) to describe non-bonded interactions between zinc and other atoms has been employed in initial MM equilibrations. Our ab initio QM/MM MD simulations have confirmed that hydroxamate is neutral when it is bound to HDAC8, and found that thiol is deprotonated when directly bound to zinc in the HDAC active site. By comparing thiol and hydroxamate, our results elucidated the differences in their binding environment in the HDAC active sites, and emphasized the importance of the linker design to achieve more specific binding towards class IIa HDACs. PMID:26452222

Thiol versus hydroxamate as zinc binding group in HDAC inhibition: An ab initio QM/MM molecular dynamics study.

PubMed

Gong, Wenjing; Wu, Ruibo; Zhang, Yingkai

2015-11-15

Zinc-dependent histone deacetylases (HDACs) play a critical role in transcriptional repression and gene silencing, and are among the most attractive targets for the development of new therapeutics against cancer and various other diseases. Two HDAC inhibitors have been approved by FDA as anti-cancer drugs: one is SAHA whose hydroxamate is directly bound to zinc, the other is FK228 whose active form may use thiol as the zinc binding group. In spite of extensive studies, it remains to be ambiguous regarding how thiol and hydroxamate are bound to the zinc active site of HDACs. In this work, our computational approaches center on Born-Oppenheimer ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics with umbrella sampling, which allow for modeling of the zinc active site with reasonable accuracy while properly including dynamics and effects of protein environment. Meanwhile, an improved short-long effective function (SLEF2) to describe non-bonded interactions between zinc and other atoms has been employed in initial MM equilibrations. Our ab initio QM/MM MD simulations have confirmed that hydroxamate is neutral when it is bound to HDAC8, and found that thiol is deprotonated when directly bound to zinc in the HDAC active site. By comparing thiol and hydroxamate, our results elucidated the differences in their binding environment in the HDAC active sites, and emphasized the importance of the linker design to achieve more specific binding toward class IIa HDACs. © 2015 Wiley Periodicals, Inc.

[Health insurance dentists' subjective perceptions of quality when implementing quality management in practice - results from a nationwide survey].

PubMed

Kettler, Nele; Chenot, Regine; Jordan, A Rainer

2015-01-01

Statutory health insurance dentists working in private practice have a duty to maintain and improve the quality of dental care. An individual practice's approach to quality management (QM) can be made to reflect the practice's philosophy on quality and standards and can be adapted to the specific requirements of the practice setting they are meant to serve. This study set out to collect data on the subjective perceptions of quality that exist among German dentists, and to canvass their views on the process and benefits of implementing QM systems. In doing so, this study aimed to identify the incentives and obstacles that currently exist in relation to the implementation and further development of practice-based QM systems. As part of a nationally representative cross-sectional study, a random sample of 2,084 dentists was asked to complete a questionnaire on perceptions of quality and QM. The response rate was 40.3 % (n=838). The study's primary end point was defined as the surveyed dentists' interpretative description of quality. The study's secondary end point was defined as the dentists' subjective evaluations of the benefits of QM in the day-to-day management of their own practices. Responses to open-ended questions were analysed using content analysis, while quantitative questions were analysed using descriptive univariate analysis. When analysing respondents' subjective perceptions of quality (primary end point), the following dimensions were revealed as highly significant: patient (mentioned by 31.4 % of the responders), quality of treatment (29.5 %) and staff (14.8 %). As far as the benefits of QM in the day-to-day management of the respondent's own practices (secondary end point) were concerned, these appeared to be linked to the ease of implementation of the organizational tools offered by QM systems: managing emergencies, team meetings and procedural check lists were ranked as "can be implemented to a reasonable degree" and "can be fully implemented" by 82.3 %, 80.2 % and 79.9 % of respondents, respectively. There appeared to be a disconnect between the respondents' subjective perceptions of quality and the benefits of QM as part of day-to-day practice management, with QM systems failing to reflect the respondents' subjective views on quality. The perceptions of QM among German statutory health insurance dentists are generally positive but marked by a disconnect between aspects of quality currently measured by QM systems and the dentists' views on what is required in order to assess quality standards in relation to the dimensions "patient", "quality of treatment" and "staff". A targeted review of the tools offered by QM systems may lead to improved ease of implementation. If QM is to form an integral part of clinical practice, all future developments need to consider the dentists' subjective perceptions of quality and their attitudes towards QM. Copyright © 2015. Published by Elsevier GmbH.

Computationally Efficient Multiscale Reactive Molecular Dynamics to Describe Amino Acid Deprotonation in Proteins

PubMed Central

2016-01-01

An important challenge in the simulation of biomolecular systems is a quantitative description of the protonation and deprotonation process of amino acid residues. Despite the seeming simplicity of adding or removing a positively charged hydrogen nucleus, simulating the actual protonation/deprotonation process is inherently difficult. It requires both the explicit treatment of the excess proton, including its charge defect delocalization and Grotthuss shuttling through inhomogeneous moieties (water and amino residues), and extensive sampling of coupled condensed phase motions. In a recent paper (J. Chem. Theory Comput.2014, 10, 2729−273725061442), a multiscale approach was developed to map high-level quantum mechanics/molecular mechanics (QM/MM) data into a multiscale reactive molecular dynamics (MS-RMD) model in order to describe amino acid deprotonation in bulk water. In this article, we extend the fitting approach (called FitRMD) to create MS-RMD models for ionizable amino acids within proteins. The resulting models are shown to faithfully reproduce the free energy profiles of the reference QM/MM Hamiltonian for PT inside an example protein, the ClC-ec1 H+/Cl– antiporter. Moreover, we show that the resulting MS-RMD models are computationally efficient enough to then characterize more complex 2-dimensional free energy surfaces due to slow degrees of freedom such as water hydration of internal protein cavities that can be inherently coupled to the excess proton charge translocation. The FitRMD method is thus shown to be an effective way to map ab initio level accuracy into a much more computationally efficient reactive MD method in order to explicitly simulate and quantitatively describe amino acid protonation/deprotonation in proteins. PMID:26734942

Computationally Efficient Multiscale Reactive Molecular Dynamics to Describe Amino Acid Deprotonation in Proteins.

PubMed

Lee, Sangyun; Liang, Ruibin; Voth, Gregory A; Swanson, Jessica M J

2016-02-09

An important challenge in the simulation of biomolecular systems is a quantitative description of the protonation and deprotonation process of amino acid residues. Despite the seeming simplicity of adding or removing a positively charged hydrogen nucleus, simulating the actual protonation/deprotonation process is inherently difficult. It requires both the explicit treatment of the excess proton, including its charge defect delocalization and Grotthuss shuttling through inhomogeneous moieties (water and amino residues), and extensive sampling of coupled condensed phase motions. In a recent paper (J. Chem. Theory Comput. 2014, 10, 2729-2737), a multiscale approach was developed to map high-level quantum mechanics/molecular mechanics (QM/MM) data into a multiscale reactive molecular dynamics (MS-RMD) model in order to describe amino acid deprotonation in bulk water. In this article, we extend the fitting approach (called FitRMD) to create MS-RMD models for ionizable amino acids within proteins. The resulting models are shown to faithfully reproduce the free energy profiles of the reference QM/MM Hamiltonian for PT inside an example protein, the ClC-ec1 H(+)/Cl(-) antiporter. Moreover, we show that the resulting MS-RMD models are computationally efficient enough to then characterize more complex 2-dimensional free energy surfaces due to slow degrees of freedom such as water hydration of internal protein cavities that can be inherently coupled to the excess proton charge translocation. The FitRMD method is thus shown to be an effective way to map ab initio level accuracy into a much more computationally efficient reactive MD method in order to explicitly simulate and quantitatively describe amino acid protonation/deprotonation in proteins.

Solution NMR Refinement of a Metal Ion Bound Protein Using Metal Ion Inclusive Restrained Molecular Dynamics Methods

PubMed Central

Chakravorty, Dhruva K.; Wang, Bing; Lee, Chul Won; Guerra, Alfredo J.; Giedroc, David P.; Merz, Kenneth M.

2013-01-01

Correctly calculating the structure of metal coordination sites in a protein during the process of nuclear magnetic resonance (NMR) structure determination and refinement continues to be a challenging task. In this study, we present an accurate and convenient means by which to include metal ions in the NMR structure determination process using molecular dynamics (MD) constrained by NMR-derived data to obtain a realistic and physically viable description of the metal binding site(s). This method provides the framework to accurately portray the metal ions and its binding residues in a pseudo-bond or dummy-cation like approach, and is validated by quantum mechanical/molecular mechanical (QM/MM) MD calculations constrained by NMR-derived data. To illustrate this approach, we refine the zinc coordination complex structure of the zinc sensing transcriptional repressor protein Staphylococcus aureus CzrA, generating over 130 ns of MD and QM/MM MD NMR-data compliant sampling. In addition to refining the first coordination shell structure of the Zn(II) ion, this protocol benefits from being performed in a periodically replicated solvation environment including long-range electrostatics. We determine that unrestrained (not based on NMR data) MD simulations correlated to the NMR data in a time-averaged ensemble. The accurate solution structure ensemble of the metal-bound protein accurately describes the role of conformational dynamics in allosteric regulation of DNA binding by zinc and serves to validate our previous unrestrained MD simulations of CzrA. This methodology has potentially broad applicability in the structure determination of metal ion bound proteins, protein folding and metal template protein-design studies. PMID:23609042

Final report of the SIM.QM-S7 supplementary comparison, trace metals in drinking water

NASA Astrophysics Data System (ADS)

Yang, Lu; Nadeau, Kenny; Gedara Pihillagawa, Indu; Meija, Juris; Grinberg, Patricia; Mester, Zoltan; Valle Moya, Edith; Solís González, Faviola Alejandra; del Rocio Arvizu Torres, María; Yañez Muñoz, Oscar; Velina Lara-Manzano, Judith; Mazzitello, Gisela; Prina, Pedro; Acosta, Osvaldo; Napoli, Romina; Pérez Zambra, Ramiro; Ferreira, Elizabeth; Dobrovolskiy, Vladimir; Aprelev, Aleksei; Stakheev, Aleksei; Frolov, Dmitriy; Gusev, Leonid; Ivanova, Veronika; Näykki, Teemu; Sara-Aho, Timo; Venegas Padilla, Jimmy; Acuña Cubillo, Carlos; Bremmer, Dwyte; Freemantle, Ruel; Taebunpakul, Sutthinun; Tangpaisarnkul, Nongluck; Rodruangthum, Patumporn; Kaewkhomdee, Nattikarn; Thiengmanee, Usana; Tangjit, Tararat; Buzoianu, Mirella; Alejandro Ahumada Forigua, Diego; Abella Gamba, Johanna Paola; Alfredo Chavarro Medina, Luis; Sobina, Egor; Tabatchikova, Tatyana; Alexopoulos, Charalambos; Kakoulides, Elias; Delgado, Mabel; Flores, Liliana; Knox, Saira; Siewlal, Kester; Maharaj, Avinash

2018-01-01

SIM.QM-S7 was performed to assess the analytical capabilities of National Metrology Institutes (NMIs) and Designated Institutes (DIs) of SIM members (or other regions) for the accurate determination of trace metals in drinking water. The study was proposed by the coordinating laboratories National Research Council Canada (NRC) and Centro Nacional de Metrologia (CENAM) as an activity of Inorganic Analysis Working Group (IAWG) of Consultative Committee for Amount of Substance - Metrology in Chemistry and Biology (CCQM). Participants included 16 NMIs/DIs from 15 countries. No measurement method was prescribed by the coordinating laboratories. Therefore, NMIs used measurement methods of their choice. However, the majority of NMIs/DIs used ICP-MS. This SIM.QM-S7 Supplementary Comparison provides NMIs/DIs with the needed evidence for CMC claims for trace elements in fresh waters and similar matrices. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Computational QM/MM Study of the Reaction Mechanism of Human Glutathione S-Transferase A3-3

NASA Astrophysics Data System (ADS)

Calvaresi, Matteo; Stenta, Marco; Altoè, Piero; Bottoni, Andrea; Garavelli, Marco; Spinelli, Domenico

2007-12-01

Human Glutathione S-Transferase A3-3(hGSTA3-3) is the most efficient human steroid double-bond isomerase enzyme. It catalyzes the double bond isomerization of Δ5-androstene-3,17-dione (Δ5-AD) and Δ5-pregnene-3,20-dione (Δ5-PD). The isomerization products are the precursors of the steroid hormones testosterone and progesterone. We have carried out a QM/MM study to elucidate some interesting aspects of the enzyme catalytic mechanism. In particular, we have analyzed either a concerted or a stepwise reaction path. Moreover, we have attempted to rationalize the electrostatic effects on the catalytic activity of the residues surrounding the active site. Specifically, we have performed a "finger print" analysis to determine the electrostatic contribution of each aminoacid residue to the global electrostatic term, thus ranking the effect of the various aminoacids in the course of the reaction. In this way, we have highlighted the most important terms affecting the stabilization-destabilization of the enzyme.

A Direct, Quantitative Connection between Molecular Dynamics Simulations and Vibrational Probe Line Shapes.

PubMed

Xu, Rosalind J; Blasiak, Bartosz; Cho, Minhaeng; Layfield, Joshua P; Londergan, Casey H

2018-05-17

A quantitative connection between molecular dynamics simulations and vibrational spectroscopy of probe-labeled systems would enable direct translation of experimental data into structural and dynamical information. To constitute this connection, all-atom molecular dynamics (MD) simulations were performed for two SCN probe sites (solvent-exposed and buried) in a calmodulin-target peptide complex. Two frequency calculation approaches with substantial nonelectrostatic components, a quantum mechanics/molecular mechanics (QM/MM)-based technique and a solvatochromic fragment potential (SolEFP) approach, were used to simulate the infrared probe line shapes. While QM/MM results disagreed with experiment, SolEFP results matched experimental frequencies and line shapes and revealed the physical and dynamic bases for the observed spectroscopic behavior. The main determinant of the CN probe frequency is the exchange repulsion between the probe and its local structural neighbors, and there is a clear dynamic explanation for the relatively broad probe line shape observed at the "buried" probe site. This methodology should be widely applicable to vibrational probes in many environments.

Experimental nonlocal steering of Bohmian trajectories.

PubMed

Xiao, Ya; Kedem, Yaron; Xu, Jin-Shi; Li, Chuan-Feng; Guo, Guang-Can

2017-06-26

Interpretations of quantum mechanics (QM), or proposals for underlying theories, that attempt to present a definite realist picture, such as Bohmian mechanics, require strong non-local effects. Naively, these effects would violate causality and contradict special relativity. However if the theory agrees with QM the violation cannot be observed directly. Here, we demonstrate experimentally such an effect: we steer the velocity and trajectory of a Bohmian particle using a remote measurement. We use a pair of photons and entangle the spatial transverse position of one with the polarization of the other. The first photon is sent to a double-slit-like apparatus, where its trajectory is measured using the technique of Weak Measurements. The other photon is projected to a linear polarization state. The choice of polarization state, and the result, steer the first photon in the most intuitive sense of the word. The effect is indeed shown to be dramatic, while being easy to visualize. We discuss its strength and what are the conditions for it to occur.

Quantum correlations and dynamics from classical random fields valued in complex Hilbert spaces

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khrennikov, Andrei

2010-08-15

One of the crucial differences between mathematical models of classical and quantum mechanics (QM) is the use of the tensor product of the state spaces of subsystems as the state space of the corresponding composite system. (To describe an ensemble of classical composite systems, one uses random variables taking values in the Cartesian product of the state spaces of subsystems.) We show that, nevertheless, it is possible to establish a natural correspondence between the classical and the quantum probabilistic descriptions of composite systems. Quantum averages for composite systems (including entangled) can be represented as averages with respect to classical randommore » fields. It is essentially what Albert Einstein dreamed of. QM is represented as classical statistical mechanics with infinite-dimensional phase space. While the mathematical construction is completely rigorous, its physical interpretation is a complicated problem. We present the basic physical interpretation of prequantum classical statistical field theory in Sec. II. However, this is only the first step toward real physical theory.« less

Exciton transport in the PE545 complex: insight from atomistic QM/MM-based quantum master equations and elastic network models

NASA Astrophysics Data System (ADS)

Pouyandeh, Sima; Iubini, Stefano; Jurinovich, Sandro; Omar, Yasser; Mennucci, Benedetta; Piazza, Francesco

2017-12-01

In this paper, we work out a parameterization of environmental noise within the Haken-Strobl-Reinenker (HSR) model for the PE545 light-harvesting complex, based on atomic-level quantum mechanics/molecular mechanics (QM/MM) simulations. We use this approach to investigate the role of various auto- and cross-correlations in the HSR noise tensor, confirming that site-energy autocorrelations (pure dephasing) terms dominate the noise-induced exciton mobility enhancement, followed by site energy-coupling cross-correlations for specific triplets of pigments. Interestingly, several cross-correlations of the latter kind, together with coupling-coupling cross-correlations, display clear low-frequency signatures in their spectral densities in the 30-70 cm-1 region. These slow components lie at the limits of validity of the HSR approach, which requires that environmental fluctuations be faster than typical exciton transfer time scales. We show that a simple coarse-grained elastic-network-model (ENM) analysis of the PE545 protein naturally spotlights collective normal modes in this frequency range that represent specific concerted motions of the subnetwork of cysteines covalenty linked to the pigments. This analysis strongly suggests that protein scaffolds in light-harvesting complexes are able to express specific collective, low-frequency normal modes providing a fold-rooted blueprint of exciton transport pathways. We speculate that ENM-based mixed quantum classical methods, such as Ehrenfest dynamics, might be promising tools to disentangle the fundamental designing principles of these dynamical processes in natural and artificial light-harvesting structures.

Variational Identification of Markovian Transition States

NASA Astrophysics Data System (ADS)

Martini, Linda; Kells, Adam; Covino, Roberto; Hummer, Gerhard; Buchete, Nicolae-Viorel; Rosta, Edina

2017-07-01

We present a method that enables the identification and analysis of conformational Markovian transition states from atomistic or coarse-grained molecular dynamics (MD) trajectories. Our algorithm is presented by using both analytical models and examples from MD simulations of the benchmark system helix-forming peptide Ala5 , and of larger, biomedically important systems: the 15-lipoxygenase-2 enzyme (15-LOX-2), the epidermal growth factor receptor (EGFR) protein, and the Mga2 fungal transcription factor. The analysis of 15-LOX-2 uses data generated exclusively from biased umbrella sampling simulations carried out at the hybrid ab initio density functional theory (DFT) quantum mechanics/molecular mechanics (QM/MM) level of theory. In all cases, our method automatically identifies the corresponding transition states and metastable conformations in a variationally optimal way, with the input of a set of relevant coordinates, by accurately reproducing the intrinsic slowest relaxation rate of each system. Our approach offers a general yet easy-to-implement analysis method that provides unique insight into the molecular mechanism and the rare but crucial (i.e., rate-limiting) transition states occurring along conformational transition paths in complex dynamical systems such as molecular trajectories.

A new mathematical solution for predicting char activation reactions

USGS Publications Warehouse

Rafsanjani, H.H.; Jamshidi, E.; Rostam-Abadi, M.

2002-01-01

The differential conservation equations that describe typical gas-solid reactions, such as activation of coal chars, yield a set of coupled second-order partial differential equations. The solution of these coupled equations by exact analytical methods is impossible. In addition, an approximate or exact solution only provides predictions for either reaction- or diffusion-controlling cases. A new mathematical solution, the quantize method (QM), was applied to predict the gasification rates of coal char when both chemical reaction and diffusion through the porous char are present. Carbon conversion rates predicted by the QM were in closer agreement with the experimental data than those predicted by the random pore model and the simple particle model. ?? 2002 Elsevier Science Ltd. All rights reserved.

Risk Mitigation Testing with the BepiColombo MPO SADA

NASA Astrophysics Data System (ADS)

Zemann, J.; Heinrich, B.; Skulicz, A.; Madsen, M.; Weisenstein, W.; Modugno, F.; Althaus, F.; Panhofer, T.; Osterseher, G.

2013-09-01

A Solar Array (SA) Drive Assembly (SADA) for the BepiColombo mission is being developed and qualified at RUAG Space Zürich (RSSZ). The system is consisting of the Solar Array Drive Mechanism (SADM) and the Solar Array Drive Electronics (SADE) which is subcontracted to RUAG Space Austria (RSA).This paper deals with the risk mitigation activities and the lesson learnt from this development. In specific following topics substantiated by bread board (BB) test results will be addressed in detail:Slipring Bread Board Test: Verification of lifetime and electrical performance of carbon brush technology Potentiometer BB Tests: Focus on lifetime verification (> 650000 revolution) and accuracy requirement SADM EM BB Test: Subcomponent (front-bearing and gearbox) characterization; complete test campaign equivalent to QM test.EM SADM/ SADE Combined Test: Verification of combined performance (accuracy, torque margin) and micro-vibration testing of SADA systemSADE Bread Board Test: Parameter optimization; Test campaign equivalent to QM testThe main improvements identified in frame of BB testing and already implemented in the SADM EM/QM and SADE EQM are:• Improved preload device for gearbox• Improved motor ball-bearing assembly• Position sensor improvements• Calibration process for potentiometer• SADE motor controller optimization toachieve required running smoothness• Overall improvement of test equipment.

Simulation of Electronic Circular Dichroism of Nucleic Acids: From the Structure to the Spectrum.

PubMed

Padula, Daniele; Jurinovich, Sandro; Di Bari, Lorenzo; Mennucci, Benedetta

2016-11-14

We present a quantum mechanical (QM) simulation of the electronic circular dichroism (ECD) of nucleic acids (NAs). The simulation combines classical molecular dynamics, to obtain the structure and its temperature-dependent fluctuations, with a QM excitonic model to determine the ECD. The excitonic model takes into account environmental effects through a polarizable embedding and uses a refined approach to calculate the electronic couplings in terms of full transition densities. Three NAs with either similar conformations but different base sequences or similar base sequences but different conformations have been investigated and the results were compared with experimental observations; a good agreement was seen in all cases. A detailed analysis of the nature of the ECD bands in terms of their excitonic composition was also carried out. Finally, a comparison between the QM and the DeVoe models clearly revealed the importance of including fluctuations of the excitonic parameters and of accurately determining the electronic couplings. This study demonstrates the feasibility of the ab initio simulation of the ECD spectra of NAs, that is, without the need of experimental structural or electronic data. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Applications of Quality Management in Language Education

ERIC Educational Resources Information Center

Heyworth, Frank

2013-01-01

This review examines applications of quality management (QM) in language education. QM approaches have been adapted from methodologies developed in industrial and commercial settings, and these are briefly described. Key aspects of QM in language education are the definition of purpose, descriptions of principles and practice, including various…

Gene Transduction and Cell Entry Pathway of Fiber-Modified Adenovirus Type 5 Vectors Carrying Novel Endocytic Peptide Ligands Selected on Human Tracheal Glandular Cells

PubMed Central

Gaden, Florence; Franqueville, Laure; Magnusson, Maria K.; Hong, Saw See; Merten, Marc D.; Lindholm, Leif; Boulanger, Pierre

2004-01-01

Monolayers of cystic fibrosis transmembrane conductance regulator (CFTR)-deficient human tracheal glandular cells (CF-KM4) were subjected to phage biopanning, and cell-internalized phages were isolated and sequenced, in order to identify CF-KM4-specific peptide ligands that would confer upon adenovirus type 5 (Ad5) vector a novel cell target specificity and/or higher efficiency of gene delivery into airway cells of patients with cystic fibrosis (CF). Three different ligands, corresponding to prototypes of the most represented families of phagotopes recovered from intracellular phages, were designed and individually inserted into Ad5-green fluorescent protein (GFP) (AdGFP) vectors at the extremities of short fiber shafts (seven repeats [R7]) terminated by scissile knobs. Only one vector, carrying the decapeptide GHPRQMSHVY (abbreviated as QM10), showed an enhanced gene transduction of CF-KM4 cells compared to control nonliganded vector with fibers of the same length (AdGFP-R7-knob). The enhancement in gene transfer efficiency was not specific to CF-KM4 cells but was observed in other mammalian cell lines tested. The QM10-liganded vector was referred to as AdGFP-QM10-knob in its knobbed version and as AdGFP-QM10 in its proteolytically deknobbed version. AdGFP-QM10 was found to transduce cells with a higher efficiency than its knob-bearing version, AdGFP-QM10-knob. Consistent with this, competition experiments indicated that the presence of knob domains was not an absolute requirement for cell attachment of the QM10-liganded vector and that the knobless AdGFP-QM10 used alternative cell-binding domains on its capsid, including penton base capsomer, via a site(s) different from its RGD motifs. The QM10-mediated effect on gene transduction seemed to take place at the step of endocytosis in both quantitative and qualitative manners. Virions of AdGFP-QM10 were endocytosed in higher numbers than virions of the control vector and were directed to a compartment different from the early endosomes targeted by members of species C Ad. AdGFP-QM10 was found to accumulate in late endosomal and low-pH compartments, suggesting that QM10 acted as an endocytic ligand of the lysosomal pathway. These results validated the concept of detargeting and retargeting Ad vectors via our deknobbing system and redirecting Ad vectors to an alternative endocytic pathway via a peptide ligand inserted in the fiber shaft domain. PMID:15194799

Multistructural microiteration technique for geometry optimization and reaction path calculation in large systems.

PubMed

Suzuki, Kimichi; Morokuma, Keiji; Maeda, Satoshi

2017-10-05

We propose a multistructural microiteration (MSM) method for geometry optimization and reaction path calculation in large systems. MSM is a simple extension of the geometrical microiteration technique. In conventional microiteration, the structure of the non-reaction-center (surrounding) part is optimized by fixing atoms in the reaction-center part before displacements of the reaction-center atoms. In this method, the surrounding part is described as the weighted sum of multiple surrounding structures that are independently optimized. Then, geometric displacements of the reaction-center atoms are performed in the mean field generated by the weighted sum of the surrounding parts. MSM was combined with the QM/MM-ONIOM method and applied to chemical reactions in aqueous solution or enzyme. In all three cases, MSM gave lower reaction energy profiles than the QM/MM-ONIOM-microiteration method over the entire reaction paths with comparable computational costs. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Quantifying the mechanism of phosphate monoester hydrolysis in aqueous solution by evaluating the relevant ab initio QM/MM free-energy surfaces.

PubMed

Plotnikov, Nikolay V; Prasad, B Ram; Chakrabarty, Suman; Chu, Zhen T; Warshel, Arieh

2013-10-24

Understanding the nature of the free-energy surfaces for phosphate hydrolysis is a prerequisite for understanding the corresponding key chemical reactions in biology. Here, the challenge has been to move to careful ab initio QM/MM (QM(ai)/MM) free-energy calculations, where obtaining converging results is very demanding and computationally expensive. This work describes such calculations, focusing on the free-energy surface for the hydrolysis of phosphate monoesters, paying special attention to the comparison between the one water (1W) and two water (2W) paths for the proton-transfer (PT) step. This issue has been explored before by energy minimization with implicit solvent models and by nonsystematic QM/MM energy minimization, as well as by nonsystematic free-energy mapping. However, no study has provided the needed reliable 2D (3D) surfaces that are necessary for reaching concrete conclusions. Here we report a systematic evaluation of the 2D (3D) free-energy maps for several relevant systems, comparing the results of QM(ai)/MM and QM(ai)/implicit solvent surfaces, and provide an advanced description of the relevant energetics. It is found that the 1W path for the hydrolysis of the methyl diphosphate (MDP) trianion is 6-9 kcal/mol higher than that the 2W path. This difference becomes slightly larger in the presence of the Mg(2+) ion because this ion reduces the pKa of the conjugated acid form of the phosphate oxygen that accepts the proton. Interestingly, the BLYP approach (which has been used extensively in some studies) gives a much smaller difference between the 1W and 2W activation barriers. At any rate, it is worth pointing out that the 2W transition state for the PT is not much higher that the common plateau that serves as the starting point of both the 1W and 2W PT paths. Thus, the calculated catalytic effects of proteins based on the 2W PT mechanistic model are not expected to be different from the catalytic effects predicted using the 1W PT mechanistic model, which was calibrated on the observed barrier in solution and in which the TS charge distribution was similar to the that of the plateau (as was done in all of our previous EVB studies).

The Heisenberg Microscope: A Powerful Instructional Tool for Promoting Meta-Cognitive and Meta-Scientific Thinking on Quantum Mechanics and the "Nature of Science"

ERIC Educational Resources Information Center

Hadzidaki, Pandora

2008-01-01

In this paper, we present a multi-dimensional study concerning Heisenberg's "gamma ray microscope", a thought experiment, which is intimately connected with the historical development of quantum mechanics (QM), and also with the most disputed interpretations of quantum theory. In this study: (a) we investigate how philosophers of science read and…

Characterization of free-standing InAs quantum membranes by standing wave hard x-ray photoemission spectroscopy

NASA Astrophysics Data System (ADS)

Conti, G.; Nemšák, S.; Kuo, C.-T.; Gehlmann, M.; Conlon, C.; Keqi, A.; Rattanachata, A.; Karslıoǧlu, O.; Mueller, J.; Sethian, J.; Bluhm, H.; Rault, J. E.; Rueff, J. P.; Fang, H.; Javey, A.; Fadley, C. S.

2018-05-01

Free-standing nanoribbons of InAs quantum membranes (QMs) transferred onto a (Si/Mo) multilayer mirror substrate are characterized by hard x-ray photoemission spectroscopy (HXPS) and by standing-wave HXPS (SW-HXPS). Information on the chemical composition and on the chemical states of the elements within the nanoribbons was obtained by HXPS and on the quantitative depth profiles by SW-HXPS. By comparing the experimental SW-HXPS rocking curves to x-ray optical calculations, the chemical depth profile of the InAs(QM) and its interfaces were quantitatively derived with ångström precision. We determined that (i) the exposure to air induced the formation of an InAsO4 layer on top of the stoichiometric InAs(QM); (ii) the top interface between the air-side InAsO4 and the InAs(QM) is not sharp, indicating that interdiffusion occurs between these two layers; (iii) the bottom interface between the InAs(QM) and the native oxide SiO2 on top of the (Si/Mo) substrate is abrupt. In addition, the valence band offset (VBO) between the InAs(QM) and the SiO2/(Si/Mo) substrate was determined by HXPS. The value of VBO = 0.2 ± 0.04 eV is in good agreement with literature results obtained by electrical characterization, giving a clear indication of the formation of a well-defined and abrupt InAs/SiO2 heterojunction. We have demonstrated that HXPS and SW-HXPS are non-destructive, powerful methods for characterizing interfaces and for providing chemical depth profiles of nanostructures, quantum membranes, and 2D layered materials.

Recent advances in QM/MM free energy calculations using reference potentials☆

PubMed Central

Duarte, Fernanda; Amrein, Beat A.; Blaha-Nelson, David; Kamerlin, Shina C.L.

2015-01-01

Background Recent years have seen enormous progress in the development of methods for modeling (bio)molecular systems. This has allowed for the simulation of ever larger and more complex systems. However, as such complexity increases, the requirements needed for these models to be accurate and physically meaningful become more and more difficult to fulfill. The use of simplified models to describe complex biological systems has long been shown to be an effective way to overcome some of the limitations associated with this computational cost in a rational way. Scope of review Hybrid QM/MM approaches have rapidly become one of the most popular computational tools for studying chemical reactivity in biomolecular systems. However, the high cost involved in performing high-level QM calculations has limited the applicability of these approaches when calculating free energies of chemical processes. In this review, we present some of the advances in using reference potentials and mean field approximations to accelerate high-level QM/MM calculations. We present illustrative applications of these approaches and discuss challenges and future perspectives for the field. Major conclusions The use of physically-based simplifications has shown to effectively reduce the cost of high-level QM/MM calculations. In particular, lower-level reference potentials enable one to reduce the cost of expensive free energy calculations, thus expanding the scope of problems that can be addressed. General significance As was already demonstrated 40 years ago, the usage of simplified models still allows one to obtain cutting edge results with substantially reduced computational cost. This article is part of a Special Issue entitled Recent developments of molecular dynamics. PMID:25038480

Challenges of using quality improvement methods in nursing homes that "need improvement".

PubMed

Rantz, Marilyn J; Zwygart-Stauffacher, Mary; Flesner, Marcia; Hicks, Lanis; Mehr, David; Russell, Teresa; Minner, Donna

2012-10-01

Qualitatively describe the adoption of strategies and challenges experienced by intervention facilities participating in a study targeted to improve quality of care in nursing homes "in need of improvement". To describe how staff use federal quality indicator/quality measure (QI/QM) scores and reports, quality improvement methods and activities, and how staff supported and sustained the changes recommended by their quality improvement teams. A randomized, two-group, repeated-measures design was used to test a 2-year intervention for improving quality of care and resident outcomes in facilities in "need of improvement". Intervention group (n = 29) received an experimental multilevel intervention designed to help them: (1) use quality-improvement methods, (2) use team and group process for direct-care decision-making, (3) focus on accomplishing the basics of care, and (4) maintain more consistent nursing and administrative leadership committed to communication and active participation of staff in decision-making. A qualitative analysis revealed a subgroup of homes likely to continue quality improvement activities and readiness indicators of homes likely to improve: (1) a leadership team (nursing home administrator, director of nurses) interested in learning how to use their federal QI/QM reports as a foundation for improving resident care and outcomes; (2) one of the leaders to be a "change champion" and make sure that current QI/QM reports are consistently printed and shared monthly with each nursing unit; (3) leaders willing to involve all staff in the facility in educational activities to learn about the QI/QM process and the reports that show how their facility compares with others in the state and nation; (4) leaders willing to plan and continuously educate new staff about the MDS and federal QI/QM reports and how to do quality improvement activities; (5) leaders willing to continuously involve all staff in quality improvement committee and team activities so they "own" the process and are responsible for change. Results of this qualitative analysis can help allocate expert nurse time to facilities that are actually ready to improve. Wide-spread adoption of this intervention is feasible and could be enabled by nursing home medical directors in collaborative practice with advanced practice nurses. Copyright © 2012 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.

Contribution to systematic education of quality management in Slovak health care.

PubMed

Rusnakova, V; Bacharova, L

2001-01-01

Of the study was to contribute to quality improvement initiatives in Slovak health services through systematic approach to the education and training in quality management (QM). Consequently, the main objectives were to analyse the content of the education in QM abroad, to conduct an audit of perceived training needs in Slovakia, and to propose the design of QM training programme to be applied within CME scheme based on the study results. Triangular method in the design of the study was implemented. Review of relevant information, data from the questionnaire and semi-structured interview in the sample of 67 Slovak trainees from Health Management School and School of Public Health--were adopted in complementary fashion. Highlighted in the survey are positive attitudes to training in quality management documented by the median score higher than 6 in all tested areas, on scale 0-10. No significant differences in profession groups as physicians, nurses, HC managers or among training institutions involved were displayed. However, potential obstacles were identified in deeper study using interviews. The absence of knowledge and skills in management in general and in quality management approaches especially are observed. Typically, the role of strategic planning is undermined. The large scale of quality management approaches is converted to problems of accreditation. Barriers to participative culture, innovation, devolution of accountability, resistance to change and to team based management are authentic findings as well. Drawn from the study were related to: fostering managers--"transformational leaders" for locally driven decision making in health care policy and practice; need of training activities for the continuing education in quality with respect to specific target groups interests and their level of knowledge in management; content of training oriented towards combination of rational utilization of information, critical analytical skills and planning for quality with human resource development-interpersonal skills, team building (soft skills), not just reduction of quality management tools to hard techniques (statistics, ISO norms); methods of education, where the usage of experiential learning methods, participative training inclusive action learning is highlighted; team training complemented with individual professional development support inclusive a coaching and mentoring scheme. AS IMPLICATIONS: Four types of CME training: Basic Module QM, Training for QM teams, Training Trainers Scheme and Guiding through Accreditation and Quality Award were proposed. (Tab. 9, Ref. 38.)

Structural dynamics and quantum mechanical aspects of shikonin derivatives as CREBBP bromodomain inhibitors.

PubMed

Mitra, Sarmistha; Dash, Raju

2018-05-04

The Proteins involved in the chemical modification of lysine residues in histone, is currently being excessively focused as the therapeutic target for the treatment of cell related diseases like cancer. Among these proteins, the epigenetic reader, CREB-binding protein (CREBBP) bromodomain is one of the most prominent targets for effective anticancer drug design, which is responsible for the reorganization of acetylated histone lysine residues. Therefore, this study employed an integrative approach of structure based drug design, in combination with Molecular Dynamics (MD) and QM/MM study to identify as well as to describe the binding mechanism of two shikonin derivatives, acetylshikonin and propionylshikonin as inhibitors of CREBBP bromodomain. Here induced fit docking strategy was employed to explore the important intrinsic interactions of ligands with CREBBP bromodomain, consistently molecular dynamics simulation with two different methods and binding energy calculations by MM-GBSA and MM-PBSA were adopted to determine the stability of intermolecular interactions between protein and ligands. The results showed that both these derivatives made direct contacts with the important conserved residues of the active site, where propionylshikonin demonstrated stronger binding and stability than acetylshikonin, according to molecular dynamics simulation and binding free energy calculations. Further, QM/MM energy calculation was employed to study the chemical reactivity of the propionylshikonin and also to describe the mechanism of non bonded interactions between the propionylshikonin and CREBBP bromodomain. Though this study demands in vitro and in vivo experiments to evaluate the efficiency of the compound, these insights would assist to design more potent CREBBP bromodomain inhibitor, guiding the site of modification of propionylshikonin moiety for designing selective inhibitors. Copyright © 2018 Elsevier Inc. All rights reserved.

Do SiO 2 and carbon-doped SiO 2 nanoparticles melt? Insights from QM/MD simulations and ramifications regarding carbon nanotube growth

NASA Astrophysics Data System (ADS)

Page, Alister J.; Chandrakumar, K. R. S.; Irle, Stephan; Morokuma, Keiji

2011-05-01

Quantum chemical molecular dynamics (QM/MD) simulations of pristine and carbon-doped SiO 2 nanoparticles have been performed between 1000 and 3000 K. At temperatures above 1600 K, pristine nanoparticle SiO 2 decomposes rapidly, primarily forming SiO. Similarly, carbon-doped nanoparticle SiO 2 decomposes at temperatures above 2000 K, primarily forming SiO and CO. Analysis of the physical states of these pristine and carbon-doped SiO 2 nanoparticles indicate that they remain in the solid phase throughout decomposition. This process is therefore one of sublimation, as the liquid phase is never entered. Ramifications of these observations with respect to presently debated mechanisms of carbon nanotube growth on SiO 2 nanoparticles will be discussed.

Quantum mechanics/molecular mechanics structural models of the oxygen-evolving complex of photosystem II.

PubMed

Sproviero, Eduardo M; Gascón, José A; McEvoy, James P; Brudvig, Gary W; Batista, Victor S

2007-04-01

The annual production of 260 Gtonnes of oxygen, during the process of photosynthesis, sustains life on earth. Oxygen is produced in the thylakoid membranes of green-plant chloroplasts and the internal membranes of cyanobacteria by photocatalytic water oxidation at the oxygen-evolving complex (OEC) of photosystem II (PSII). Recent breakthroughs in X-ray crystallography and advances in quantum mechanics/molecular mechanics (QM/MM) hybrid methods have enabled the construction of chemically sensible models of the OEC of PSII. The resulting computational structural models suggest the complete ligation of the catalytic center by amino acid residues, water, hydroxide and chloride, as determined from the intrinsic electronic properties of the oxomanganese core and the perturbational influence of the surrounding protein environment. These structures are found to be consistent with available mechanistic data, and are also compatible with X-ray diffraction models and extended X-ray absorption fine structure measurements. It is therefore conjectured that these OEC models are particularly relevant for the elucidation of the catalytic mechanism of water oxidation.

Analysis of Peer Review Comments: QM Recommendations and Feedback Intervention Theory

ERIC Educational Resources Information Center

Schwegler, Andria F.; Altman, Barbara W.

2015-01-01

Because feedback is a critical component of the continuous improvement cycle of the Quality Matters (QM) peer review process, the present research analyzed the feedback that peer reviewers provided to course developers after a voluntary, nonofficial QM peer review of online courses. Previous research reveals that the effects of feedback on…

Clinical Decision Support-based Quality Measurement (CDS-QM) Framework: Prototype Implementation, Evaluation, and Future Directions

PubMed Central

Kukhareva, Polina V; Kawamoto, Kensaku; Shields, David E; Barfuss, Darryl T; Halley, Anne M; Tippetts, Tyler J; Warner, Phillip B; Bray, Bruce E; Staes, Catherine J

2014-01-01

Electronic quality measurement (QM) and clinical decision support (CDS) are closely related but are typically implemented independently, resulting in significant duplication of effort. While it seems intuitive that technical approaches could be re-used across these two related use cases, such reuse is seldom reported in the literature, especially for standards-based approaches. Therefore, we evaluated the feasibility of using a standards-based CDS framework aligned with anticipated EHR certification criteria to implement electronic QM. The CDS-QM framework was used to automate a complex national quality measure (SCIP-VTE-2) at an academic healthcare system which had previously relied on time-consuming manual chart abstractions. Compared with 305 manually-reviewed reference cases, the recall of automated measurement was 100%. The precision was 96.3% (CI:92.6%-98.5%) for ascertaining the denominator and 96.2% (CI:92.3%-98.4%) for the numerator. We therefore validated that a standards-based CDS-QM framework can successfully enable automated QM, and we identified benefits and challenges with this approach. PMID:25954389

Substituents on Quinone Methides Strongly Modulate Formation and Stability of Their Nucleophilic Adducts

PubMed Central

Weinert, Emily E.; Dondi, Ruggero; Colloredo-Melz, Stefano; Frankenfield, Kristen N.; Mitchell, Charles H.; Freccero, Mauro; Rokita, Steven E.

2008-01-01

Electronic perturbation of quinone methides (QM) greatly influences their stability and in turn alters the kinetics and product profile of QM reaction with deoxynucleosides. Consistent with the electron deficient nature of this reactive intermediate, electron-donating substituents are stabilizing and electron-withdrawing substituents are destabilizing. For example, a dC N3-QM adduct is made stable over the course of observation (7 days) by the presence of an electron-withdrawing ester group that inhibits QM regeneration. Conversely, a related adduct with an electron donating methyl group is very labile and regenerates its QM with a half-life of approximately 5 hr. The generality of these effects is demonstrated with a series of alternative quinone methide precursors (QMP) containing a variety of substituents attached at different positions with respect to the exocyclic methylene. The rates of nucleophilic addition to substituted QMs measured by laser flash photolysis similarly span five orders of magnitude with electron rich species reacting most slowly and electron deficient species reacting most quickly. The reversibility of QM reaction can now be predictably adjusted for any desired application. PMID:16953635

Adaptive switching of interaction potentials in the time domain: an extended Lagrangian approach tailored to transmute force field to QM/MM simulations and back.

PubMed

Böckmann, Marcus; Doltsinis, Nikos L; Marx, Dominik

2015-06-09

An extended Lagrangian formalism that allows for a smooth transition between two different descriptions of interactions during a molecular dynamics simulation is presented. This time-adaptive method is particularly useful in the context of multiscale simulation as it provides a sound recipe to switch on demand between different hierarchical levels of theory, for instance between ab initio ("QM") and force field ("MM") descriptions of a given (sub)system in the course of a molecular dynamics simulation. The equations of motion can be integrated straightforwardly using the usual propagators, such as the Verlet algorithm. First test cases include a bath of harmonic oscillators, of which a subset is switched to a different force constant and/or equilibrium position, as well as an all-MM to QM/MM transition in a hydrogen-bonded water dimer. The method is then applied to a smectic 8AB8 liquid crystal and is shown to be able to switch dynamically a preselected 8AB8 molecule from an all-MM to a QM/MM description which involves partition boundaries through covalent bonds. These examples show that the extended Lagrangian approach is not only easy to implement into existing code but that it is also efficient and robust. The technique moreover provides easy access to a conserved energy quantity, also in cases when Nosé-Hoover chain thermostatting is used throughout dynamical switching. A simple quadratic driving potential proves to be sufficient to guarantee a smooth transition whose time scale can be easily tuned by varying the fictitious mass parameter associated with the auxiliary variable used to extend the Lagrangian. The method is general and can be applied to time-adaptive switching on demand between two different levels of theory within the framework of hybrid scale-bridging simulations.

Optical Signal Processing for ASW

DTIC Science & Technology

1963-05-01

considered here. In the initial 1. Weissbein, L. , and O’Brien, S. J., "Attenuation of Thermal Radiation with Phototropic Colorants, " Contract DA-129-QM...COORDINATE Fig. A-1 Energy Diagram of Phototropic Mechanisms Included in Category ii can assume that the A--B conversion of a single local system

Simulating Protein Mediated Hydrolysis of ATP and Other Nucleoside Triphosphates by Combining QM/MM Molecular Dynamics with Advances in Metadynamics

PubMed Central

2017-01-01

The protein mediated hydrolysis of nucleoside triphosphates such as ATP or GTP is one of the most important and challenging biochemical reactions in nature. The chemical environment (water structure, catalytic metal, and amino acid residues) adjacent to the hydrolysis site contains hundreds of atoms, usually greatly limiting the amount of the free energy sampling that one can achieve from computationally demanding electronic structure calculations such as QM/MM simulations. Therefore, the combination of QM/MM molecular dynamics with the recently developed transition-tempered metadynamics (TTMetaD), an enhanced sampling method that can provide a high-quality free energy estimate at an early stage in a simulation, is an ideal approach to address the biomolecular nucleoside triphosphate hydrolysis problem. In this work the ATP hydrolysis process in monomeric and filamentous actin is studied as an example application of the combined methodology. The performance of TTMetaD in these demanding QM/MM simulations is compared with that of the more conventional well-tempered metadynamics (WTMetaD). Our results show that TTMetaD exhibits much better exploration of the hydrolysis reaction free energy surface in two key collective variables (CVs) during the early stages of the QM/MM simulation than does WTMetaD. The TTMetaD simulations also reveal that a key third degree of freedom, the O–H bond-breaking and proton transfer from the lytic water, must be biased for TTMetaD to converge fully. To perturb the NTP hydrolysis dynamics to the least extent and to properly focus the MetaD free energy sampling, we also adopt here the recently developed metabasin metadynamics (MBMetaD) to construct a self-limiting bias potential that only applies to the lytic water after its nucleophilic attack of the phosphate of ATP. With these new, state-of-the-art enhanced sampling metadynamics techniques, we present an effective and accurate computational strategy for combining QM/MM molecular dynamics simulation with free energy sampling methodology, including a means to analyze the convergence of the calculations through robust numerical criteria. PMID:28345907

Simulating Protein Mediated Hydrolysis of ATP and Other Nucleoside Triphosphates by Combining QM/MM Molecular Dynamics with Advances in Metadynamics.

PubMed

Sun, Rui; Sode, Olaseni; Dama, James F; Voth, Gregory A

2017-05-09

The protein mediated hydrolysis of nucleoside triphosphates such as ATP or GTP is one of the most important and challenging biochemical reactions in nature. The chemical environment (water structure, catalytic metal, and amino acid residues) adjacent to the hydrolysis site contains hundreds of atoms, usually greatly limiting the amount of the free energy sampling that one can achieve from computationally demanding electronic structure calculations such as QM/MM simulations. Therefore, the combination of QM/MM molecular dynamics with the recently developed transition-tempered metadynamics (TTMetaD), an enhanced sampling method that can provide a high-quality free energy estimate at an early stage in a simulation, is an ideal approach to address the biomolecular nucleoside triphosphate hydrolysis problem. In this work the ATP hydrolysis process in monomeric and filamentous actin is studied as an example application of the combined methodology. The performance of TTMetaD in these demanding QM/MM simulations is compared with that of the more conventional well-tempered metadynamics (WTMetaD). Our results show that TTMetaD exhibits much better exploration of the hydrolysis reaction free energy surface in two key collective variables (CVs) during the early stages of the QM/MM simulation than does WTMetaD. The TTMetaD simulations also reveal that a key third degree of freedom, the O-H bond-breaking and proton transfer from the lytic water, must be biased for TTMetaD to converge fully. To perturb the NTP hydrolysis dynamics to the least extent and to properly focus the MetaD free energy sampling, we also adopt here the recently developed metabasin metadynamics (MBMetaD) to construct a self-limiting bias potential that only applies to the lytic water after its nucleophilic attack of the phosphate of ATP. With these new, state-of-the-art enhanced sampling metadynamics techniques, we present an effective and accurate computational strategy for combining QM/MM molecular dynamics simulation with free energy sampling methodology, including a means to analyze the convergence of the calculations through robust numerical criteria.

Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines.

PubMed

Hylsová, Michaela; Carbain, Benoit; Fanfrlík, Jindřich; Musilová, Lenka; Haldar, Susanta; Köprülüoğlu, Cemal; Ajani, Haresh; Brahmkshatriya, Pathik S; Jorda, Radek; Kryštof, Vladimír; Hobza, Pavel; Echalier, Aude; Paruch, Kamil; Lepšík, Martin

2017-01-27

We present comprehensive testing of solvent representation in quantum mechanics (QM)-based scoring of protein-ligand affinities. To this aim, we prepared 21 new inhibitors of cyclin-dependent kinase 2 (CDK2) with the pyrazolo[1,5-a]pyrimidine core, whose activities spanned three orders of magnitude. The crystal structure of a potent inhibitor bound to the active CDK2/cyclin A complex revealed that the biphenyl substituent at position 5 of the pyrazolo[1,5-a]pyrimidine scaffold was located in a previously unexplored pocket and that six water molecules resided in the active site. Using molecular dynamics, protein-ligand interactions and active-site water H-bond networks as well as thermodynamics were probed. Thereafter, all the inhibitors were scored by the QM approach utilizing the COSMO implicit solvent model. Such a standard treatment failed to produce a correlation with the experiment (R 2  = 0.49). However, the addition of the active-site waters resulted in significant improvement (R 2  = 0.68). The activities of the compounds could thus be interpreted by taking into account their specific noncovalent interactions with CDK2 and the active-site waters. In summary, using a combination of several experimental and theoretical approaches we demonstrate that the inclusion of explicit solvent effects enhance QM/COSMO scoring to produce a reliable structure-activity relationship with physical insights. More generally, this approach is envisioned to contribute to increased accuracy of the computational design of novel inhibitors. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

How Many Conformations Need To Be Sampled To Obtain Converged QM/MM Energies? The Curse of Exponential Averaging.

PubMed

Ryde, Ulf

2017-11-14

Combined quantum mechanical and molecular mechanical (QM/MM) calculations is a popular approach to study enzymatic reactions. They are often based on a set of minimized structures obtained on snapshots from a molecular dynamics simulation to include some dynamics of the enzyme. It has been much discussed how the individual energies should be combined to obtain a final estimate of the energy, but the current consensus seems to be to use an exponential average. Then, the question is how many snapshots are needed to reach a reliable estimate of the energy. In this paper, I show that the question can be easily be answered if it is assumed that the energies follow a Gaussian distribution. Then, the outcome can be simulated based on a single parameter, σ, the standard deviation of the QM/MM energies from the various snapshots, and the number of required snapshots can be estimated once the desired accuracy and confidence of the result has been specified. Results for various parameters are presented, and it is shown that many more snapshots are required than is normally assumed. The number can be reduced by employing a cumulant approximation to second order. It is shown that most convergence criteria work poorly, owing to the very bad conditioning of the exponential average when σ is large (more than ∼7 kJ/mol), because the energies that contribute most to the exponential average have a very low probability. On the other hand, σ serves as an excellent convergence criterion.

Using Quality Management as a Bridge in Educating for Sustainability in a Business School

ERIC Educational Resources Information Center

Rusinko, Cathy A.

2005-01-01

Purpose: To demonstrate how quality management (QM), a widely accepted management paradigm, can be used to advance education for sustainability in the business curriculum. Design/methodology/approach: The assumptions of QM and environmental sustainability are explored. A class exercise is developed that uses QM tools--and in particular, Deming's…

The Development of QM-Fudan Higher Education Online Course Quality Standards: Some Results and Analysis

ERIC Educational Resources Information Center

Ding, Yan; Gao, Yaping; Lu, Fang

2017-01-01

This paper aims to examine whether and how the US-based Quality Matters (QM) Higher Education Rubric-Design Standards for Online and Blended Courses apply to the Chinese higher education environment. Suitability and matchability of QM Standards are respectively examined through a questionnaire and course reviews at Fudan University, a leading…

Polarizable molecular mechanics studies of Cu(I)/Zn(II) superoxide dismutase: bimetallic binding site and structured waters.

PubMed

Gresh, Nohad; El Hage, Krystel; Perahia, David; Piquemal, Jean-Philip; Berthomieu, Catherine; Berthomieu, Dorothée

2014-11-05

The existence of a network of structured waters in the vicinity of the bimetallic site of Cu/Zn-superoxide dismutase (SOD) has been inferred from high-resolution X-ray crystallography. Long-duration molecular dynamics (MD) simulations could enable to quantify the lifetimes and possible interchanges of these waters between themselves as well as with a ligand diffusing toward the bimetallic site. The presence of several charged or polar ligands makes it necessary to resort to second-generation polarizable potentials. As a first step toward such simulations, we benchmark in this article the accuracy of one such potential, sum of interactions between fragments Ab initio computed (SIBFA), by comparisons with quantum mechanics (QM) computations. We first consider the bimetallic binding site of a Cu/Zn-SOD, in which three histidines and a water molecule are bound to Cu(I) and three histidines and one aspartate are bound to Zn(II). The comparisons are made for different His6 complexes with either one or both cations, and either with or without Asp and water. The total net charges vary from zero to three. We subsequently perform preliminary short-duration MD simulations of 296 waters solvating Cu/Zn-SOD. Six representative geometries are selected and energy-minimized. Single-point SIBFA and QM computations are then performed in parallel on model binding sites extracted from these six structures, each of which totals 301 atoms including the closest 28 waters from the Cu metal site. The ranking of their relative stabilities as given by SIBFA is identical to the QM one, and the relative energy differences by both approaches are fully consistent. In addition, the lowest-energy structure, from SIBFA and QM, has a close overlap with the crystallographic one. The SIBFA calculations enable to quantify the impact of polarization and charge transfer in the ranking of the six structures. Five structural waters, which connect Arg141 and Glu131, are endowed with very high dipole moments (2.7-3.0 Debye), equal and larger than the one computed by SIBFA in ice-like arrangements (2.7 D). Copyright © 2014 Wiley Periodicals, Inc.

Investigation into the Use of the Concept Laser QM System as an In-Situ Research and Evaluation Tool

NASA Technical Reports Server (NTRS)

Bagg, Stacey

2014-01-01

The NASA Marshall Space Flight Center (MSFC) is using a Concept Laser Fusing (Cusing) M2 powder bed additive manufacturing system for the build of space flight prototypes and hardware. NASA MSFC is collecting and analyzing data from the M2 QM Meltpool and QM Coating systems for builds. This data is intended to aide in understanding of the powder-bed additive manufacturing process, and in the development of a thermal model for the process. The QM systems are marketed by Concept Laser GmbH as in-situ quality management modules. The QM Meltpool system uses both a high-speed near-IR camera and a photodiode to monitor the melt pool generated by the laser. The software determines from the camera images the size of the melt pool. The camera also measures the integrated intensity of the IR radiation, and the photodiode gives an intensity value based on the brightness of the melt pool. The QM coating system uses a high resolution optical camera to image the surface after each layer has been formed. The objective of this investigation was to determine the adequacy of the QM Meltpool system as a research instrument for in-situ measurement of melt pool size and temperature and its applicability to NASA's objectives in (1) Developing a process thermal model and (2) Quantifying feedback measurements with the intent of meeting quality requirements or specifications. Note that Concept Laser markets the system only as capable of giving an indication of changes between builds, not as an in-situ research and evaluation tool. A secondary objective of the investigation is to determine the adequacy of the QM Coating system as an in-situ layer-wise geometry and layer quality evaluation tool.

Carbinolamine Formation and Dehydration in a DNA Repair Enzyme Active Site

PubMed Central

Dodson, M. L.; Walker, Ross C.; Lloyd, R. Stephen

2012-01-01

In order to suggest detailed mechanistic hypotheses for the formation and dehydration of a key carbinolamine intermediate in the T4 pyrimidine dimer glycosylase (T4PDG) reaction, we have investigated these reactions using steered molecular dynamics with a coupled quantum mechanics–molecular mechanics potential (QM/MM). We carried out simulations of DNA abasic site carbinolamine formation with and without a water molecule restrained to remain within the active site quantum region. We recovered potentials of mean force (PMF) from thirty replicate reaction trajectories using Jarzynski averaging. We demonstrated feasible pathways involving water, as well as those independent of water participation. The water–independent enzyme–catalyzed reaction had a bias–corrected Jarzynski–average barrier height of approximately for the carbinolamine formation reaction and ) for the reverse reaction at this level of representation. When the proton transfer was facilitated with an intrinsic quantum water, the barrier height was approximately in the forward (formation) reaction and for the reverse. In addition, two modes of unsteered (free dynamics) carbinolamine dehydration were observed: in one, the quantum water participated as an intermediate proton transfer species, and in the other, the active site protonated glutamate hydrogen was directly transferred to the carbinolamine oxygen. Water–independent unforced proton transfer from the protonated active site glutamate carboxyl to the unprotonated N–terminal amine was also observed. In summary, complex proton transfer events, some involving water intermediates, were studied in QM/MM simulations of T4PDG bound to a DNA abasic site. Imine carbinolamine formation was characterized using steered QM/MM molecular dynamics. Dehydration of the carbinolamine intermediate to form the final imine product was observed in free, unsteered, QM/MM dynamics simulations, as was unforced acid-base transfer between the active site carboxylate and the N–terminal amine. PMID:22384015

Proton storage site in bacteriorhodopsin: new insights from QM/MM simulations of microscopic pKa and infrared spectra

PubMed Central

Goyal, Puja; Ghosh, Nilanjan; Phatak, Prasad; Clemens, Maike; Gaus, Michael; Elstner, Marcus; Cui, Qiang

2011-01-01

Identifying the group that acts as the proton storage/loading site is a challenging but important problem for understanding the mechanism of proton pumping in biomolecular proton pumps, such as bacteriorhodopsin (bR) and cytochrome c oxidase. Recent experimental studies of bR propelled the idea that the proton storage/release group (PRG) in bR is not an amino acid but a water cluster embedded in the protein. We argue that this idea is at odds with our knowledge of protein electrostatics, since invoking the water cluster as PRG would require the protein to raise the pKa of a hydronium by almost 11 pKa units, which is difficult considering known cases of pKa shifts in proteins. Our recent QM/MM simulations suggested an alternative “intermolecular proton bond” model in which the stored proton is shared between two conserved Glu residues (194 and 204). Here we show that this model leads to microscopic pKa values consistent with available experimental data and the functional requirement of a PRG. Extensive QM/MM simulations also show that, independent of a number of technical issues, such as the influence of QM region size, starting x-ray structure and nuclear quantum effects, the “intermolecular proton bond” model is qualitatively consistent with available spectroscopic data. Potential of mean force calculations show explicitly that the stored proton strongly prefers the pair of Glu residues over the water cluster. The results and analyses help highlight the importance of considering protein electrostatics and provide arguments for why the “intermolecular proton bond” model is likely applicable to PRG in biomolecular proton pumps in general. PMID:21761868

Quality Management in Higher Education: Review and Perspectives

ERIC Educational Resources Information Center

Papanthymou, Anastasia; Darra, Maria

2017-01-01

This paper is a review which presents a summary of 52 studies from 2006 to 2016 in Quality Management (QM) within Higher Education Institutes (HEIs). The aim of this paper is to submit evidence regarding the level of QM in HEIs, particularly in developing countries, and also to enhance the research in the field of QM. The findings reveal that from…

The Binding Mode Prediction and Similar Ligand Potency in the Active Site of Vitamin D Receptor with QM/MM Interaction, MESP, and MD Simulation.

PubMed

Selvaraman, Nagamani; Selvam, Saravana Kumar; Muthusamy, Karthikeyan

2016-08-01

Non-secosteroidal ligands are well-known vitamin D receptor (VDR) agonists. In this study, we described a combined QM/MM to define the protein-ligand interaction energy a strong positive correlation in both QM-MM interaction energy and binding free energy against the biological activity. The molecular dynamics simulation study was performed, and specific interactions were extensively studied. The molecular docking results and surface analysis shed light on steric and electrostatic complementarities of these non-secosteroidal ligands to VDR. Finally, the drug likeness properties were also calculated and found within the acceptable range. The results show that bulky group substitutions in side chain decrease the VDR activity, whereas a small substitution increased it. Functional analyses of H393A and H301A mutations substantiate their roles in the VDR agonistic and antagonistic activities. Apart from the His393 and His301, two other amino acids in the hinge region viz. Ser233 and Arg270 acted as an electron donor/acceptor specific to the agonist in the distinct ligand potency. The results from this study disclose the binding mechanism of VDR agonists and structural modifications required to improve the selectivity. © 2016 John Wiley & Sons A/S.

Strain effects and intermixing at the Si surface: Importance of long-range elastic corrections in first-principles calculations

DOE PAGES

Béland, Laurent Karim; Machado-Charry, Eduardo; Pochet, Pascal; ...

2014-10-06

Here we investigate Ge mixing at the Si(001) surface and characterize the 2 N Si(001) reconstruction by means of hybrid quantum and molecular mechanics calculations (QM/MM). Avoiding fake elastic dampening, this scheme allows to correctly take into account long range deformation induced by reconstructed and defective surfaces. We focus in particular on the dimer vacancy line (DVL) and its interaction with Ge adatoms. We first show that calculated formation energies for these defects are highly dependent on the choice of chemical potential and that the latter must be chosen carefully. Characterizing the effect of the DVL on the deformation field,more » we also find that the DVL favors Ge segregation in the fourth layer close to the DVL. Using the activation-relaxation technique (ART nouveau) and QM/MM, we show that a complex diffusion path permits the substitution of the Ge atom in the fourth layer, with barriers compatible with mixing observed at intermediate temperature. We also show that the use of QM/MM results in much more signi cant corrections at the saddle points (up to 0.5 eV) that at minima, demonstrating its importance for describing kinetics correctly.« less

Modelling zwitterions in solution: 3-fluoro-γ-aminobutyric acid (3F-GABA).

PubMed

Cao, Jie; Bjornsson, Ragnar; Bühl, Michael; Thiel, Walter; van Mourik, Tanja

2012-01-02

The conformations and relative stabilities of folded and extended 3-fluoro-γ-aminobutyric acid (3F-GABA) conformers were studied using explicit solvation models. Geometry optimisations in the gas phase with one or two explicit water molecules favour folded and neutral structures containing intramolecular NH···O-C hydrogen bonds. With three or five explicit water molecules zwitterionic minima are obtained, with folded structures being preferred over extended conformers. The stability of folded versus extended zwitterionic conformers increases on going from a PCM continuum solvation model to the microsolvated complexes, though extended structures become less disfavoured with the inclusion of more water molecules. Full explicit solvation was studied with a hybrid quantum-mechanical/molecular-mechanical (QM/MM) scheme and molecular dynamics simulations, including more than 6000 TIP3P water molecules. According to free energies obtained from thermodynamic integration at the PM3/MM level and corrected for B3LYP/MM total energies, the fully extended conformer is more stable than folded ones by about -4.5 kJ mol(-1). B3LYP-computed (3)J(F,H) NMR spin-spin coupling constants, averaged over PM3/MM-MD trajectories, agree best with experiment for this fully extended form, in accordance with the original NMR analysis. The seeming discrepancy between static PCM calculations and experiment noted previously is now resolved. That the inexpensive semiempirical PM3 method performs so well for this archetypical zwitterion is encouraging for further QM/MM studies of biomolecular systems. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Dynamics of Protonated Peptide Ion Collisions with Organic Surfaces: Consonance of Simulation and Experiment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pratihar, Subha; Barnes, George L.; Laskin, Julia

In this Perspective mass spectrometry experiments and chemical dynamics simulations are described which have explored the atomistic dynamics of protonated peptide ions, peptide-H+, colliding with organic surfaces. These studies have investigated surface-induced dissociation (SID) for which peptide-H+ fragments upon collision with the surface, peptide-H+ physisorption on the surface, soft landing (SL), and peptide-H+ reaction with the surface, reactive landing (RL). The simulations include QM+MM and QM/MM direct dynamics. For collisions with self-assembled monolayer (SAM) surfaces there is quite good agreement between experiment and simulation in the efficiency of energy transfer to the peptide-H+ ion’s internal degrees of freedom. Both themore » experiments and simulations show two mechanisms for peptide-H+ fragmentation, i.e. shattering and statistical, RRKM dynamics. Mechanisms for SL are probed in simulations of collisions of protonated dialanine with a perfluorinated SAM surface. RL has been studied experimentally for a number of peptide-H+ + surface systems, and qualitative agreement between simulation and experiment is found for two similar systems.« less

Does an Emphasis on the Concept of Quantum States Enhance Students' Understanding of Quantum Mechanics?

NASA Astrophysics Data System (ADS)

Greca, Ileana Maria; Freire, Olival

Teaching physics implies making choices. In the case of teaching quantum physics, besides an educational choice - the didactic strategy - another choice must be made, an epistemological one, concerning the interpretation of quantum theory itself. These two choices are closely connected. We have chosen a didactic strategy that privileges the phenomenological-conceptual approach, with emphasis upon quantum features of the systems, instead of searching for classical analogies. This choice has led us to present quantum theory associated with an orthodox, yet realistic, interpretation of the concept of quantum state, considered as the key concept of quantum theory, representing the physical reality of a system, independent of measurement processes. The results of the mplementation of this strategy, with three groups of engineering students, showed that more than a half of them attained a reasonable understanding of the basics of quantum mechanics (QM) for this level. In addition, a high degree of satisfaction was attained with the classes as 80% of the students of the experimental groups claimed to have liked it and to be interested in learning more about QM.

On Mathematical Modeling Of Quantum Systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Achuthan, P.; Dept. of Mathematics, Indian Institute of Technology, Madras, 600 036; Narayanankutty, Karuppath

2009-07-02

The world of physical systems at the most fundamental levels is replete with efficient, interesting models possessing sufficient ability to represent the reality to a considerable extent. So far, quantum mechanics (QM) forming the basis of almost all natural phenomena, has found beyond doubt its intrinsic ingenuity, capacity and robustness to stand the rigorous tests of validity from and through appropriate calculations and experiments. No serious failures of quantum mechanical predictions have been reported, yet. However, Albert Einstein, the greatest theoretical physicist of the twentieth century and some other eminent men of science have stated firmly and categorically that QM,more » though successful by and large, is incomplete. There are classical and quantum reality models including those based on consciousness. Relativistic quantum theoretical approaches to clearly understand the ultimate nature of matter as well as radiation have still much to accomplish in order to qualify for a final theory of everything (TOE). Mathematical models of better, suitable character as also strength are needed to achieve satisfactory explanation of natural processes and phenomena. We, in this paper, discuss some of these matters with certain apt illustrations as well.« less

Multi-Scale Computational Enzymology: Enhancing Our Understanding of Enzymatic Catalysis

PubMed Central

Gherib, Rami; Dokainish, Hisham M.; Gauld, James W.

2014-01-01

Elucidating the origin of enzymatic catalysis stands as one the great challenges of contemporary biochemistry and biophysics. The recent emergence of computational enzymology has enhanced our atomistic-level description of biocatalysis as well the kinetic and thermodynamic properties of their mechanisms. There exists a diversity of computational methods allowing the investigation of specific enzymatic properties. Small or large density functional theory models allow the comparison of a plethora of mechanistic reactive species and divergent catalytic pathways. Molecular docking can model different substrate conformations embedded within enzyme active sites and determine those with optimal binding affinities. Molecular dynamics simulations provide insights into the dynamics and roles of active site components as well as the interactions between substrate and enzymes. Hybrid quantum mechanical/molecular mechanical (QM/MM) can model reactions in active sites while considering steric and electrostatic contributions provided by the surrounding environment. Using previous studies done within our group, on OvoA, EgtB, ThrRS, LuxS and MsrA enzymatic systems, we will review how these methods can be used either independently or cooperatively to get insights into enzymatic catalysis. PMID:24384841

Lung toxicity and tumor promotion by hydroxylated derivatives of 2,6-di-tert-butyl-4-methylphenol (BHT) and 2-tert-butyl-4-methyl-6-iso-propylphenol: correlation with quinone methide reactivity.

PubMed

Kupfer, Rene; Dwyer-Nield, Lori D; Malkinson, Alvin M; Thompson, John A

2002-08-01

Acute pulmonary toxicity and tumor promotion by the food additive 2,6-di-tert-butyl-4-methylphenol (BHT) in mice are well documented. These effects have been attributed to either of two quinone methides, 2,6-di-tert-butyl-4-methylenecyclohexa-2,5-dienone (BHT-QM) formed through direct oxidation of BHT by pulmonary cytochrome P450 or a quinone methide formed by hydroxylation of a tert-butyl group of BHT (to form BHTOH) followed by oxidation of this metabolite to BHTOH-QM. BHTOH-QM is a more reactive electrophile compared to BHT-QM due to intramolecular interactions of the side-chain hydroxyl with the carbonyl oxygen. To further examine this bioactivation pathway, an analogue of BHTOH was prepared, 2-tert-butyl-6-(1'-hydroxy-1'-methyl)ethyl-4-methylphenol (BPPOH), that is structurally very similar to BHTOH but forms a quinone methide (BPPOH-QM) capable of more efficient intramolecular hydrogen bonding and, therefore, higher electrophilicity than BHTOH-QM. BPPOH-QM was synthesized and its reactivity with water, methanol, and glutathione determined to be >10-fold higher than that of BHTOH-QM. The conversions of BPPOH and BHTOH to quinone methides in lung microsomes from male BALB/cByJ mice were quantitatively similar, but in vivo the former was pneumotoxic at one-half of the dose required for the latter and one-eighth of the dose required for BHT, as determined by increased lung weight:body weight ratios following a single i.p. injection. Similar differences were found in the doses of BHT, BHTOH, or BPPOH required for tumor promotion after a single initiating dose of 3-methylcholanthrene followed by three weekly injections of the phenol. The downregulaton of calpain II, previously shown to accompany lung tumor promotion by BHT and BHTOH, also occurred with BPPOH. The correlation between biologic activities of these phenols and the reactivities of their corresponding quinone methides provides additional support for the role of BHTOH-QM as the principal metabolite responsible for the effects of BHT on mouse lung.

Muscular Activity and Fatigue in Lower-Limb and Trunk Muscles during Different Sit-To-Stand Tests.

PubMed

Roldán-Jiménez, Cristina; Bennett, Paul; Cuesta-Vargas, Antonio I

2015-01-01

Sit-to-stand (STS) tests measure the ability to get up from a chair, reproducing an important component of daily living activity. As this functional task is essential for human independence, STS performance has been studied in the past decades using several methods, including electromyography. The aim of this study was to measure muscular activity and fatigue during different repetitions and speeds of STS tasks using surface electromyography in lower-limb and trunk muscles. This cross-sectional study recruited 30 healthy young adults. Average muscle activation, percentage of maximum voluntary contraction, muscle involvement in motion and fatigue were measured using surface electrodes placed on the medial gastrocnemius (MG), biceps femoris (BF), vastus medialis of the quadriceps (QM), the abdominal rectus (AR), erector spinae (ES), rectus femoris (RF), soleus (SO) and the tibialis anterior (TA). Five-repetition STS, 10-repetition STS and 30-second STS variants were performed. MG, BF, QM, ES and RF muscles showed differences in muscle activation, while QM, AR and ES muscles showed significant differences in MVC percentage. Also, significant differences in fatigue were found in QM muscle between different STS tests. There was no statistically significant fatigue in the BF, MG and SO muscles of the leg although there appeared to be a trend of increasing fatigue. These results could be useful in describing the functional movements of the STS test used in rehabilitation programs, notwithstanding that they were measured in healthy young subjects.

Calculating hyperfine couplings in large ionic crystals containing hundreds of QM atoms: subsystem DFT is the key.

PubMed

Kevorkyants, Ruslan; Wang, Xiqiao; Close, David M; Pavanello, Michele

2013-11-14

We present an application of the linear scaling frozen density embedding (FDE) formulation of subsystem DFT to the calculation of isotropic hyperfine coupling constants (hfcc's) of atoms belonging to a guanine radical cation embedded in a guanine hydrochloride monohydrate crystal. The model systems range from an isolated guanine to a 15,000 atom QM/MM cluster where the QM region is comprised of 36 protonated guanine cations, 36 chlorine anions, and 42 water molecules. Our calculations show that the embedding effects of the surrounding crystal cannot be reproduced by small model systems nor by a pure QM/MM procedure. Instead, a large QM region is needed to fully capture the complicated nature of the embedding effects in this system. The unprecedented system size for a relativistic all-electron isotropic hfcc calculation can be approached in this work because the local nature of the electronic structure of the organic crystals considered is fully captured by the FDE approach.

[Costs and benefits of quality management].

PubMed

Schroeder-Printzen, I

2014-01-01

The establishment of quality management (QM) has been mandatory for health care providers of the national health insurance since 2004; however, certification is so far only compulsory for rehabilitation clinics. The costs have so far only been quantified in a few medical studies, while they are widely known in business administration with a basic distinction made between planning, steering, auditing, and declaration costs. Another business economics approach differentiates between prevention, appraisal, and non-conformance costs. The benefits of QM relates to customers, employees, external service providers, and health insurance providers. Also important in our consideration of the patient as a customer is that they should not be considered a customer in the usual business sense because the patient is in an emergency situation and can not freely decide. Improvements in treatment quality and in reducing the rate of adverse events make up the largest portion of the benefits of QM. Furthermore, QM can have a positive influence on motivation and employee recruitment. In addition, the cost savings that result despite costs for QM must not be forgotten.

[10 Years of Quality Management: Perception and Importance from GPs' Point of View].

PubMed

Kühlein, T; Madlo-Thiess, F; Wambach, V; Schaffer, S

2018-03-01

Quality management (QM) became mandatory for the ambulatory sector of the German health care system 10 years ago. The aim of this study was to find out how general practitioners (GPs) perceived the introduction of this measure, how they see it today and what they expect of the future concerning QM. In a qualitative study, interviews following a semi-structured guideline with GPs were conducted. Following transcription, interviews were coded in triangulation, first inductively, then deductively until saturation was reached. Main topics and code families were agreed on after discussion. There was consensus on the necessity of standardization of basic processes like hygiene. However, the application of QM to an activity that emphasizes personal relationships and communication was seen as barely possible. GPs stated that they reduced QM to a tolerable and for them reasonable minimum. GPs mostly refused certification. The next 10 years were seen with pessimism in terms of more bureaucratic guidelines. The statutory introduction of QM was an attack on medical professionalism. Instead of passive resistance and reduction of QM to a minimum, engaged independent quality work might help to regain the trust of society we seem to have lost and restore the professional autonomy we need for our work. Eigentümer und Copyright ©Georg Thieme Verlag KG 2018.

Role of a Water Network around the Mn4CaO5 Cluster in Photosynthetic Water Oxidation: A Fourier Transform Infrared Spectroscopy and Quantum Mechanics/Molecular Mechanics Calculation Study.

PubMed

Nakamura, Shin; Ota, Kai; Shibuya, Yuichi; Noguchi, Takumi

2016-01-26

Photosynthetic water oxidation takes place at the Mn4CaO5 cluster in photosystem II. Around the Mn4CaO5 cluster, a hydrogen bond network is formed by several water molecules, including four water ligands. To clarify the role of this water network in the mechanism of water oxidation, we investigated the effects of the removal of Ca(2+) and substitution with metal ions on the vibrations of water molecules coupled to the Mn4CaO5 cluster by means of Fourier transform infrared (FTIR) difference spectroscopy and quantum mechanics/molecular mechanics (QM/MM) calculations. The OH stretching vibrations of nine water molecules forming a network between D1-D61 and YZ were calculated using the QM/MM method. On the the calculated normal modes, a broad positive feature at 3200-2500 cm(-1) in an S2-minus-S1 FTIR spectrum was attributed to the vibrations of strongly hydrogen-bonded OH bonds of water involving the vibrations of water ligands to a Mn ion and the in-phase coupled vibration of a water network connected to YZ, while bands in the 3700-3500 cm(-1) region were assigned to the coupled vibrations of weakly hydrogen-bonded OH bonds of water. All the water bands were lost upon Ca(2+) depletion and Ba(2+) substitution, which inhibit the S2 → S3 transition, indicating that a solid water network was broken by these treatments. By contrast, Sr(2+) substitution slightly altered the water bands around 3600 cm(-1), reflecting minor modification in water interactions, consistent with the retention of water oxidation activity with a decreased efficiency. These results suggest that the water network around the Mn4CaO5 cluster plays an essential role in the water oxidation mechanism particularly in a concerted process of proton transfer and water insertion during the S2 → S3 transition.

A study on the interactions of amino acids with nitrogen doped graphene; docking, MD simulation, and QM/MM studies.

PubMed

Ghadari, Rahim

2016-02-14

The binding properties of twenty amino acids with nitrogen-doped graphene structures were studied using docking, MD simulation, and QM/MM methods. TDDFT studies were carried out to investigate the change in the electronic properties of the amino acids because of the presence of the solvent and nitrogen-doped graphene. The results revealed that π-π interactions between the amino acids with a benzene moiety and the surface of the graphene are the most important interactions. The observed red shifts in the TDDFT results which were related to the lower LUMO energies and higher HOMO energies are consistent with this statement.

Exploring reaction pathways for O-GlcNAc transferase catalysis. A string method study.

PubMed

Kumari, Manju; Kozmon, Stanislav; Kulhánek, Petr; Štepán, Jakub; Tvaroška, Igor; Koča, Jaroslav

2015-03-26

The inverting O-GlcNAc glycosyltransferase (OGT) is an important post-translation enzyme, which catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine (UDP-GlcNAc) to the hydroxyl group of the Ser/Thr of cytoplasmic, nuclear, and mitochondrial proteins. In the past, three different catalytic bases were proposed for the reaction: His498, α-phosphate, and Asp554. In this study, we used hybrid quantum mechanics/molecular mechanics (QM/MM) Car-Parrinello molecular dynamics to investigate reaction paths using α-phosphate and Asp554 as the catalytic bases. The string method was used to calculate the free-energy reaction profiles of the tested mechanisms. During the investigations, an additional mechanism was observed. In this mechanism, a proton is transferred to α-phosphate via a water molecule. Our calculations show that the mechanism with α-phosphate acting as the base is favorable. This reaction has a rate-limiting free-energy barrier of 23.5 kcal/mol, whereas reactions utilizing Asp554 and water-assisted α-phosphate have barriers of 41.7 and 40.9 kcal/mol, respectively. Our simulations provide a new insight into the catalysis of OGT and may thus guide rational drug design of transition-state analogue inhibitors with potential therapeutic use.

Force-field parameters of the Psi and Phi around glycosidic bonds to oxygen and sulfur atoms.

PubMed

Saito, Minoru; Okazaki, Isao

2009-12-01

The Psi and Phi torsion angles around glycosidic bonds in a glycoside chain are the most important determinants of the conformation of a glycoside chain. We determined force-field parameters for Psi and Phi torsion angles around a glycosidic bond bridged by a sulfur atom, as well as a bond bridged by an oxygen atom as a preparation for the next study, i.e., molecular dynamics free energy calculations for protein-sugar and protein-inhibitor complexes. First, we extracted the Psi or Phi torsion energy component from a quantum mechanics (QM) total energy by subtracting all the molecular mechanics (MM) force-field components except for the Psi or Phi torsion angle. The Psi and Phi energy components extracted (hereafter called "the remaining energy components") were calculated for simple sugar models and plotted as functions of the Psi and Phi angles. The remaining energy component curves of Psi and Phi were well represented by the torsion force-field functions consisting of four and three cosine functions, respectively. To confirm the reliability of the force-field parameters and to confirm its compatibility with other force-fields, we calculated adiabatic potential curves as functions of Psi and Phi for the model glycosides by adopting the Psi and Phi force-field parameters obtained and by energetically optimizing other degrees of freedom. The MM potential energy curves obtained for Psi and Phi well represented the QM adiabatic curves and also these curves' differences with regard to the glycosidic oxygen and sulfur atoms. Our Psi and Phi force-fields of glycosidic oxygen gave MM potential energy curves that more closely represented the respective QM curves than did those of the recently developed GLYCAM force-field. (c) 2009 Wiley Periodicals, Inc.

Improving the Force Field Description of Tyrosine-Choline Cation-π Interactions: QM Investigation of Phenol-N(Me)4+ Interactions.

PubMed

Khan, Hanif M; Grauffel, Cédric; Broer, Ria; MacKerell, Alexander D; Havenith, Remco W A; Reuter, Nathalie

2016-11-08

Cation-π interactions between tyrosine amino acids and compounds containing N,N,N-trimethylethanolammonium (N(CH 3 ) 3 ) are involved in the recognition of histone tails by chromodomains and in the recognition of phosphatidylcholine (PC) phospholipids by membrane-binding proteins. Yet, the lack of explicit polarization or charge transfer effects in molecular mechanics force fields raises questions about the reliability of the representation of these interactions in biomolecular simulations. Here, we investigate the nature of phenol-tetramethylammonium (TMA) interactions using quantum mechanical (QM) calculations, which we also use to evaluate the accuracy of the additive CHARMM36 and Drude polarizable force fields in modeling tyrosine-choline interactions. We show that the potential energy surface (PES) obtained using SAPT2+/aug-cc-pVDZ compares well with the large basis-set CCSD(T) PES when TMA approaches the phenol ring perpendicularly. Furthermore, the SAPT energy decomposition reveals comparable contributions from electrostatics and dispersion in phenol-TMA interactions. We then compared the SAPT2+/aug-cc-pVDZ PES obtained along various approach directions to the corresponding PES obtained with CHARMM, and we show that the force field accurately reproduces the minimum distances while the interaction energies are underestimated. The use of the Drude polarizable force field significantly improves the interaction energies but decreases the agreement on distances at energy minima. The best agreement between force field and QM PES is obtained by modifying the Lennard-Jones terms for atom pairs involved in the phenol-TMA cation-π interactions. This is further shown to improve the correlation between the occupancy of tyrosine-choline cation-π interactions obtained from molecular dynamics simulations of a bilayer-bound bacterial phospholipase and experimental affinity data of the wild-type protein and selected mutants.

Understanding product specificity of protein lysine methyltransferases from QM/MM molecular dynamics and free energy simulations: the effects of mutation on SET7/9 beyond the Tyr/Phe switch.

PubMed

Yao, Jianzhuang; Chu, Yuzhuo; An, Ran; Guo, Hong

2012-02-27

The results of hybrid quantum mechanical/molecular mechanical (QM/MM) free energy (potential of mean force) simulations for methyl-transfer processes in SET7/9 and its Y245A mutant are compared to address the question concerning the change of the product specificity as well as catalytic efficiency due to the mutation. One of the key questions is whether or not the free energy profiles of methyl transfers may be used to predict the change of the product specificity as a result of the mutations for the residues that are not located at the Tyr/Phe switch position. The simulations show that while the wild-type SET7/9 is a monomethylase, the Y245→A mutation increases the ability of the enzyme to add more methyl groups on the target lysine (i.e., acting as a trimethylase). However, the first methyl-transfer process seems to become less efficient in the mutant compared to that in wild-type. All these results are consistent with experimental observations concerning the effects of the mutation on the product specificity and catalytic efficiency. Thus, the previous suggestion that the energetics of the methyl-transfer reactions may determine the product specificity, at least in some cases, is confirmed by the present work. Moreover, the dynamic information of the reactant complexes obtained from the QM/MM molecular dynamics simulations shows that the ability of the reactant complexes to form the reactive transition-state-like configurations may be used as an important indicator for the prediction of the product specificity of PKMTs, consistent with previous computational studies.

Multiplex quantitative PCR for detection of lower respiratory tract infection and meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis

PubMed Central

2010-01-01

Background Streptococcus pneumoniae and Haemophilus influenzae cause pneumonia and as Neisseria meningitidis they are important agents of meningitis. Although several PCR methods have been described for these bacteria the specificity is an underestimated problem. Here we present a quantitative multiplex real-time PCR (qmPCR) for detection of S. pneumoniae (9802 gene fragment), H. influenzae (omp P6 gene) and N. meningitidis (ctrA gene). The method was evaluated on bronchoalveolar lavage (BAL) samples from 156 adults with lower respiratory tract infection (LRTI) and 31 controls, and on 87 cerebrospinal fluid (CSF) samples from meningitis patients. Results The analytical sensitivity was not affected by using a combined mixture of reagents and a combined DNA standard (S. pneumoniae/H. influenzae/N. meningitidis) in single tubes. By blood- and BAL-culture and S. pneumoniae urinary antigen test, S. pneumoniae and H. influenzae were aetiological agents in 21 and 31 of the LTRI patients, respectively. These pathogens were identified by qmPCR in 52 and 72 of the cases, respectively, yielding sensitivities and specificities of 95% and 75% for S. pneumoniae, and 90% and 65% for H. influenzae, respectively. When using a cut-off of 105 genome copies/mL for clinical positivity the sensitivities and specificities were 90% and 80% for S. pneumoniae, and 81% and 85% for H. influenzae, respectively. Of 44 culture negative but qmPCR positive for H. influenzae, 41 were confirmed by fucK PCR as H. influenzae. Of the 103 patients who had taken antibiotics prior to sampling, S. pneumoniae and H. influenzae were identified by culture in 6% and 20% of the cases, respectively, and by the qmPCR in 36% and 53% of the cases, respectively. In 87 CSF samples S. pneumoniae and N. meningitidis were identified by culture and/or 16 S rRNA in 14 and 10 samples and by qmPCR in 14 and 10 samples, respectively, giving a sensitivity of 100% and a specificity of 100% for both bacteria. Conclusions The PCR provides increased sensitivity and the multiplex format facilitates diagnosis of S. pneumoniae, H. influenzae and N. meningitidis and the assay enable detection after antibiotic treatment has been installed. Quantification increases the specificity of the etiology for pneumonia. PMID:21129171

Multiplex quantitative PCR for detection of lower respiratory tract infection and meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis.

PubMed

Abdeldaim, Guma M K; Strålin, Kristoffer; Korsgaard, Jens; Blomberg, Jonas; Welinder-Olsson, Christina; Herrmann, Björn

2010-12-03

Streptococcus pneumoniae and Haemophilus influenzae cause pneumonia and as Neisseria meningitidis they are important agents of meningitis. Although several PCR methods have been described for these bacteria the specificity is an underestimated problem. Here we present a quantitative multiplex real-time PCR (qmPCR) for detection of S. pneumoniae (9802 gene fragment), H. influenzae (omp P6 gene) and N. meningitidis (ctrA gene). The method was evaluated on bronchoalveolar lavage (BAL) samples from 156 adults with lower respiratory tract infection (LRTI) and 31 controls, and on 87 cerebrospinal fluid (CSF) samples from meningitis patients. The analytical sensitivity was not affected by using a combined mixture of reagents and a combined DNA standard (S. pneumoniae/H. influenzae/N. meningitidis) in single tubes. By blood- and BAL-culture and S. pneumoniae urinary antigen test, S. pneumoniae and H. influenzae were aetiological agents in 21 and 31 of the LTRI patients, respectively. These pathogens were identified by qmPCR in 52 and 72 of the cases, respectively, yielding sensitivities and specificities of 95% and 75% for S. pneumoniae, and 90% and 65% for H. influenzae, respectively. When using a cut-off of 10⁵ genome copies/mL for clinical positivity the sensitivities and specificities were 90% and 80% for S. pneumoniae, and 81% and 85% for H. influenzae, respectively. Of 44 culture negative but qmPCR positive for H. influenzae, 41 were confirmed by fucK PCR as H. influenzae. Of the 103 patients who had taken antibiotics prior to sampling, S. pneumoniae and H. influenzae were identified by culture in 6% and 20% of the cases, respectively, and by the qmPCR in 36% and 53% of the cases, respectively.In 87 CSF samples S. pneumoniae and N. meningitidis were identified by culture and/or 16 S rRNA in 14 and 10 samples and by qmPCR in 14 and 10 samples, respectively, giving a sensitivity of 100% and a specificity of 100% for both bacteria. The PCR provides increased sensitivity and the multiplex format facilitates diagnosis of S. pneumoniae, H. influenzae and N. meningitidis and the assay enable detection after antibiotic treatment has been installed. Quantification increases the specificity of the etiology for pneumonia.

Shear-wave elastography of the breast: value of a quality measure and comparison with strain elastography.

PubMed

Barr, Richard G; Zhang, Zheng

2015-04-01

To determine whether addition of quality measure (QM) of shear-wave (SW) velocity (Vs) estimation can increase SW elastography sensitivity for breast cancer. With written informed consent, this institutional review board-approved, HIPAA-compliant study included 143 women (mean age, 48.5 years ± 8.7) scheduled for breast biopsy. Mean lesion size was 16.4 mm ± 11.8; 95 (66%) lesions were benign; 48 (34%), malignant. If more than one lesion was present, lesion with highest Breast Imaging Reporting and Data System (BI-RADS) category was chosen. If there were more than one with highest BI-RADS category, a lesion was randomly selected. Conventional ultrasonography (US), strain elastography, and SW elastography were performed with QM. QM assesses SW quality to provide accurate Vs. Lesions were evaluated for Vs and QM (high or low). Lesions with Vs of less than 4.5 m/sec were classified benign; lesions with Vs of 4.5 m/sec or greater, malignant. Results were correlated with pathologic findings. Vs data with or without incorporating QM were used to determine SW elastography diagnostic performance. Binomial proportions and exact 95% confidence intervals (CIs) were calculated. In 95 benign lesions, 13 (14%) had no SW elastography signal; 77 (81%), Vs of less than 4.5 m/sec; and five (5%), Vs of 4.5 m/sec or greater. In 48 malignant lesions, eight (17%) had no SW elastography signal; 20 (42%), Vs of less than 4.5 m/sec; and 20 (42%), V of 4.5 m/sec or greater. QM was low in 17 of 20 (85%) malignant lesions with Vs of less than 4.5 m/sec. Without QM, using Vs of 4.5 m/sec or greater as test positive, SW elastography had lesion-level sensitivity of 50% (95% CI: 34%, 66%); specificity, 94% (95% CI: 86%, 98%); positive predictive value (PPV), 80% (95% CI: 59%, 93%); and negative predictive value (NPV), 79% (95% CI: 70%, 87%). Using QM where additional lesions with both low Vs and low QM were treated as test positive, SW elastography had lesion-level sensitivity of 93% (95% CI: 80%, 98%); specificity, 89% (95% CI: 80%, 95%); PPV, 80% (95% CI: 66%, 91%); and NPV, 96% (95% CI: 89%, 99%). Addition of QM can improve SW elastography sensitivity, with no significant change in specificity. © RSNA, 2014 Online supplemental material is available for this article.

Multiscale methods for computational RNA enzymology

PubMed Central

Panteva, Maria T.; Dissanayake, Thakshila; Chen, Haoyuan; Radak, Brian K.; Kuechler, Erich R.; Giambaşu, George M.; Lee, Tai-Sung; York, Darrin M.

2016-01-01

RNA catalysis is of fundamental importance to biology and yet remains ill-understood due to its complex nature. The multi-dimensional “problem space” of RNA catalysis includes both local and global conformational rearrangements, changes in the ion atmosphere around nucleic acids and metal ion binding, dependence on potentially correlated protonation states of key residues and bond breaking/forming in the chemical steps of the reaction. The goal of this article is to summarize and apply multiscale modeling methods in an effort to target the different parts of the RNA catalysis problem space while also addressing the limitations and pitfalls of these methods. Classical molecular dynamics (MD) simulations, reference interaction site model (RISM) calculations, constant pH molecular dynamics (CpHMD) simulations, Hamiltonian replica exchange molecular dynamics (HREMD) and quantum mechanical/molecular mechanical (QM/MM) simulations will be discussed in the context of the study of RNA backbone cleavage transesterification. This reaction is catalyzed by both RNA and protein enzymes, and here we examine the different mechanistic strategies taken by the hepatitis delta virus ribozyme (HDVr) and RNase A. PMID:25726472

[Quality Management in Medicine: What the Surgeon Needs to Know].

PubMed

Holtel, M; Roßmüller, T; Frommhold, K

2016-10-01

Quality management (QM) is a method used in the field of economics that was adopted late by the medical sector. The coincidence of quality management and what is referred to as economisation in medicine frequently leads to QM being - incorrectly - perceived as part of the economisation problem rather than as part of its solution. Quality assurance defines and observes key performance indicators for the achievement of quality objectives. QM is a form of active management that intends to systematically exclude the effects of chance. It is supposed to enable those in charge of an institution to deal with complex processes, to influence them and achieve quality even under unfavourable circumstances. Clearly defined written standards are an important aspect of QM and allow for 80 % of patients to be treated faster and less labour-intensively and thus to create more capacity for the individual treatment of the 20 % of patients requiring other than routine care. Standards provide a framework to rely on for department heads and other staff alike. They reduce complexity, support processes in stress situations and prevent inconsistent decisions in the course of treatment. Document management ensures transparent and up-to-date in-house standards and creates continuity. Good documents are short, easy to use, and, at the same time, comply with requirements. Specifications describe in-house standards; validation documents provide a forensically sound documentation. Quality management has a broad impact on an institution. It helps staff reflect on their daily work, and it initiates a reporting and auditing system as well as the systematic management of responses to surveys and complaints. Risk management is another aspect of QM; it provides structures to identify, analyse, assess and modify risks and subject them to risk controlling. Quality management is not necessarily associated with certification. However, if certification is intended, it serves to define requirements, increase motivation for the implementation of measures to be taken, and provide long-term continuity in newly adopted processes. Specialist certificates issued by medical associations frequently emphasise an interdisciplinary treatment approach; however, their certification processes are often of poor quality. The effectiveness and efficiency is evident for individual QM instruments in medicine. It is very likely that quality management improves effectiveness in the whole field of medicine, but this has yet to be proved. Georg Thieme Verlag KG Stuttgart · New York.

Quantum mechanical wavefunction: visualization at undergraduate level

NASA Astrophysics Data System (ADS)

Chhabra, Mahima; Das, Ritwick

2017-01-01

Quantum mechanics (QM) forms the most crucial ingredient of modern-era physical science curricula at undergraduate level. The abstract ideas involved in QM related concepts pose a challenge towards appropriate visualization as a consequence of their counter-intuitive nature and lack of experiment-assisted visualization tools. At the heart of the quantum mechanical formulation lies the concept of ‘wavefunction’, which forms the basis for understanding the behavior of physical systems. At undergraduate level, the concept of ‘wavefunction’ is introduced in an abstract framework using mathematical tools and therefore opens up an enormous scope for alternative conceptions and erroneous visualization. The present work is an attempt towards exploring the visualization models constructed by undergraduate students for appreciating the concept of ‘wavefunction’. We present a qualitative analysis of the data obtained from administering a questionnaire containing four visualization based questions on the topic of ‘wavefunction’ to a group of ten undergraduate-level students at an institute in India which excels in teaching and research of basic sciences. Based on the written responses, all ten students were interviewed in detail to unravel the exact areas of difficulty in visualization of ‘wavefunction’. The outcome of present study not only reveals the gray areas in students’ conceptualization, but also provides a plausible route to address the issues at the pedagogical level within the classroom.

How Is Acetylcholinesterase Phosphonylated by Soman? An Ab Initio QM/MM Molecular Dynamics Study

PubMed Central

2015-01-01

Acetylcholinesterase (AChE) is a crucial enzyme in the cholinergic nerve system that hydrolyzes acetylcholine (ACh) and terminates synaptic signals by reducing the effective concentration of ACh in the synaptic clefts. Organophosphate compounds irreversibly inhibit AChEs, leading to irreparable damage to nerve cells. By employing Born–Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, a state-of-the-art approach to simulate enzyme reactions, we have characterized the covalent inhibition mechanism between AChE and the nerve toxin soman and determined its free energy profile for the first time. Our results indicate that phosphonylation of the catalytic serine by soman employs an addition–elimination mechanism, which is highly associative and stepwise: in the initial addition step, which is also rate-limiting, His440 acts as a general base to facilitate the nucleophilic attack of Ser200 on the soman’s phosphorus atom to form a trigonal bipyrimidal pentacovalent intermediate; in the subsequent elimination step, Try121 of the catalytic gorge stabilizes the leaving fluorine atom prior to its dissociation from the active site. Together with our previous characterization of the aging mechanism of soman inhibited AChE, our simulations have revealed detailed molecular mechanistic insights into the damaging function of the nerve agent soman. PMID:24786171

A Molecular Dynamics-Quantum Mechanics Theoretical Study of DNA-Mediated Charge Transport in Hydrated Ionic Liquids.

PubMed

Meng, Zhenyu; Kubar, Tomas; Mu, Yuguang; Shao, Fangwei

2018-05-08

Charge transport (CT) through biomolecules is of high significance in the research fields of biology, nanotechnology, and molecular devices. Inspired by our previous work that showed the binding of ionic liquid (IL) facilitated charge transport in duplex DNA, in silico simulation is a useful means to understand the microscopic mechanism of the facilitation phenomenon. Here molecular dynamics simulations (MD) of duplex DNA in water and hydrated ionic liquids were employed to explore the helical parameters. Principal component analysis was further applied to capture the subtle conformational changes of helical DNA upon different environmental impacts. Sequentially, CT rates were calculated by a QM/MM simulation of the flickering resonance model based upon MD trajectories. Herein, MD simulation illustrated that the binding of ionic liquids can restrain dynamic conformation and lower the on-site energy of the DNA base. Confined movement among the adjacent base pairs was highly related to the increase of electronic coupling among base pairs, which may lead DNA to a CT facilitated state. Sequentially combining MD and QM/MM analysis, the rational correlations among the binding modes, the conformational changes, and CT rates illustrated the facilitation effects from hydrated IL on DNA CT and supported a conformational-gating mechanism.

Ab Initio QM/MM Study Shows a Highly Dissociated SN2 Hydrolysis Mechanism for the cGMP-Specific Phosphodiesterase-5.

PubMed

Li, Zhe; Wu, Yinuo; Feng, Ling-Jun; Wu, Ruibo; Luo, Hai-Bin

2014-12-09

Phosphodiesterases (PDEs) are the sole enzymes hydrolyzing the important second messengers cGMP and cAMP and have been identified as therapeutic targets for several diseases. The most successful examples are PDE5 inhibitors (i.e., sildenafil and tadalafil), which have been approved for the treatment of male erectile dysfunction and pulmonary hypertension. However, the side effects mostly due to nonselective inhibition toward other PDE isoforms, set back the clinical usage of PDE5 inhibitors. Until now, the exact catalytic mechanism of the substrate cGMP by PDE5 is still unclear. Herein, the first computational study on the catalytic hydrolysis mechanism of cGMP for PDE5 (catalytic domain) is performed by employing the state-of-the-art ab initio quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations. Our simulations show a SN2 type reaction procedure via a highly dissociated transition state with a reaction barrier of 8.88 kcal/mol, which is quite different from the previously suggested hydrolysis mechanism of cAMP for PDE4. Furthermore, the subsequent ligand exchange and the release of the product GMP have also been investigated by binding energy analysis and MD simulations. It is deduced that ligand exchange would be the rate-determining step of the whole reaction, which is consistent with many previous experimental results. The obtained mechanistic insights should be valuable for not only the rational design of more specific inhibitors toward PDE5 but also understanding the general hydrolysis mechanism of cGMP-specific PDEs.

Large-Scale First-Principles Molecular Dynamics Simulations with Electrostatic Embedding: Application to Acetylcholinesterase Catalysis

DOE PAGES

Fattebert, Jean-Luc; Lau, Edmond Y.; Bennion, Brian J.; ...

2015-10-22

Enzymes are complicated solvated systems that typically require many atoms to simulate their function with any degree of accuracy. We have recently developed numerical techniques for large scale First-Principles molecular dynamics simulations and applied them to study the enzymatic reaction catalyzed by acetylcholinesterase. We carried out Density functional theory calculations for a quantum mechanical (QM) sub- system consisting of 612 atoms with an O(N) complexity finite-difference approach. The QM sub-system is embedded inside an external potential field representing the electrostatic effect due to the environment. We obtained finite temperature sampling by First-Principles molecular dynamics for the acylation reaction of acetylcholinemore » catalyzed by acetylcholinesterase. Our calculations shows two energies barriers along the reaction coordinate for the enzyme catalyzed acylation of acetylcholine. In conclusion, the second barrier (8.5 kcal/mole) is rate-limiting for the acylation reaction and in good agreement with experiment.« less

Thermodynamics properties study of diatomic molecules with q-deformed modified Poschl-Teller plus Manning Rosen non-central potential in D dimensions using SUSYQM approach

NASA Astrophysics Data System (ADS)

Suparmi, A.; Cari, C.; Pratiwi, B. N.

2016-04-01

D-dimensional Dirac equation of q-deformed modified Poschl-Teller plus Manning Rosen non-central potential was solved using supersymmetric quantum mechanics (SUSY QM). The relativistic energy spectra were analyzed by using SUSY QM and shape invariant properties from radial part of D dimensional Dirac equation and the angular quantum numbers were obtained from angular part of D dimensional Dirac equation. The SUSY operators was used to generate the D dimensional relativistic wave functions both for radial and angular parts. In the non-relativistic limit, the relativistic energy equation was reduced to the non-relativistic energy. In the classical limit, the partition function of vibrational, the specific heat of vibrational, and the mean energy of vibrational of some diatomic molecules were calculated from the equation of non-relativistic energy with the help of error function and Mat-lab 2011.

Free energies of binding from large-scale first-principles quantum mechanical calculations: application to ligand hydration energies.

PubMed

Fox, Stephen J; Pittock, Chris; Tautermann, Christofer S; Fox, Thomas; Christ, Clara; Malcolm, N O J; Essex, Jonathan W; Skylaris, Chris-Kriton

2013-08-15

Schemes of increasing sophistication for obtaining free energies of binding have been developed over the years, where configurational sampling is used to include the all-important entropic contributions to the free energies. However, the quality of the results will also depend on the accuracy with which the intermolecular interactions are computed at each molecular configuration. In this context, the energy change associated with the rearrangement of electrons (electronic polarization and charge transfer) upon binding is a very important effect. Classical molecular mechanics force fields do not take this effect into account explicitly, and polarizable force fields and semiempirical quantum or hybrid quantum-classical (QM/MM) calculations are increasingly employed (at higher computational cost) to compute intermolecular interactions in free-energy schemes. In this work, we investigate the use of large-scale quantum mechanical calculations from first-principles as a way of fully taking into account electronic effects in free-energy calculations. We employ a one-step free-energy perturbation (FEP) scheme from a molecular mechanical (MM) potential to a quantum mechanical (QM) potential as a correction to thermodynamic integration calculations within the MM potential. We use this approach to calculate relative free energies of hydration of small aromatic molecules. Our quantum calculations are performed on multiple configurations from classical molecular dynamics simulations. The quantum energy of each configuration is obtained from density functional theory calculations with a near-complete psinc basis set on over 600 atoms using the ONETEP program.

ATP Hydrolysis Mechanism in a Maltose Transporter Explored by QM/MM Metadynamics Simulation.

PubMed

Hsu, Wei-Lin; Furuta, Tadaomi; Sakurai, Minoru

2016-11-03

Translocation of substrates across the cell membrane by adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporters depends on the energy provided by ATP hydrolysis within the nucleotide-binding domains (NBDs). However, the detailed mechanism remains unclear. In this study, we focused on maltose transporter NBDs (MalK 2 ) and performed a quantum mechanical/molecular mechanical (QM/MM) well-tempered metadynamics simulation to address this issue. We explored the free-energy profile along an assigned collective variable. As a result, it was determined that the activation free energy is approximately 10.5 kcal/mol, and the reaction released approximately 3.8 kcal/mol of free energy, indicating that the reaction of interest is a one-step exothermic reaction. The dissociation of the ATP γ-phosphate seems to be the rate-limiting step, which supports the so-called dissociative model. Moreover, Glu159, located in the Walker B motif, acts as a base to abstract the proton from the lytic water, but is not the catalytic base, which corresponds to an atypical general base catalysis model. We also observed two interesting proton transfers: transfer from the His192 ε-position nitrogen to the dissociated inorganic phosphate, Pi, and transfer from the Lys42 side chain to adenosine 5'-diphosphate β-phosphate. These proton transfers would stabilize the posthydrolysis state. Our study provides significant insight into the ATP hydrolysis mechanism in MalK 2 from a dynamical viewpoint, and this insight would be applicable to other ABC transporters.

Evolution from S3 to S4 States of the Oxygen-Evolving Complex in Photosystem II Monitored by Quantum Mechanics/Molecular Mechanics (QM/MM) Dynamics.

PubMed

Narzi, Daniele; Capone, Matteo; Bovi, Daniele; Guidoni, Leonardo

2018-04-16

Water oxidation in the early steps of natural photosynthesis is fulfilled by photosystem II, which is a protein complex embedded in the thylakoid membrane inside chloroplasts. The water oxidation reaction occurs in the catalytic core of photosystem II, which consists of a Mn4Ca metal cluster, at which, after the accumulation of four oxidising equivalents through five steps (S0-S4) of the Kok-Joliot cycle, two water molecules are split into electrons, protons, and molecular oxygen. In recent years, by combining experimental and theoretical approaches, new insights have been achieved into the structural and electronic properties of different steps of the catalytic cycle. Nevertheless, the exact catalytic mechanism, especially concerning the final stages of the cycle, remains elusive and greatly debated. Herein, by means of quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations, from the structural, electronic, and magnetic points of view, the S 3 state before and upon oxidation has been characterised. In contrast with the S 2 state, the oxidation of the S 3 state is not followed by a spontaneous proton-coupled electron-transfer event. Nevertheless, upon modelling the reduction of the tyrosine residue in photosystem II (Tyr Z ) and the protonation of Asp61, spontaneous proton transfer occurs, leading to the deprotonation of an oxygen atom bound to Mn1; thus making it available for O-O bond formation. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

The report of Task Group 100 of the AAPM: Application of risk analysis methods to radiation therapy quality management

PubMed Central

Huq, M. Saiful; Fraass, Benedick A.; Dunscombe, Peter B.; Gibbons, John P.; Mundt, Arno J.; Mutic, Sasa; Palta, Jatinder R.; Rath, Frank; Thomadsen, Bruce R.; Williamson, Jeffrey F.; Yorke, Ellen D.

2016-01-01

The increasing complexity of modern radiation therapy planning and delivery challenges traditional prescriptive quality management (QM) methods, such as many of those included in guidelines published by organizations such as the AAPM, ASTRO, ACR, ESTRO, and IAEA. These prescriptive guidelines have traditionally focused on monitoring all aspects of the functional performance of radiotherapy (RT) equipment by comparing parameters against tolerances set at strict but achievable values. Many errors that occur in radiation oncology are not due to failures in devices and software; rather they are failures in workflow and process. A systematic understanding of the likelihood and clinical impact of possible failures throughout a course of radiotherapy is needed to direct limit QM resources efficiently to produce maximum safety and quality of patient care. Task Group 100 of the AAPM has taken a broad view of these issues and has developed a framework for designing QM activities, based on estimates of the probability of identified failures and their clinical outcome through the RT planning and delivery process. The Task Group has chosen a specific radiotherapy process required for “intensity modulated radiation therapy (IMRT)” as a case study. The goal of this work is to apply modern risk-based analysis techniques to this complex RT process in order to demonstrate to the RT community that such techniques may help identify more effective and efficient ways to enhance the safety and quality of our treatment processes. The task group generated by consensus an example quality management program strategy for the IMRT process performed at the institution of one of the authors. This report describes the methodology and nomenclature developed, presents the process maps, FMEAs, fault trees, and QM programs developed, and makes suggestions on how this information could be used in the clinic. The development and implementation of risk-assessment techniques will make radiation therapy safer and more efficient. PMID:27370140

The report of Task Group 100 of the AAPM: Application of risk analysis methods to radiation therapy quality management

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huq, M. Saiful, E-mail: HUQS@UPMC.EDU

The increasing complexity of modern radiation therapy planning and delivery challenges traditional prescriptive quality management (QM) methods, such as many of those included in guidelines published by organizations such as the AAPM, ASTRO, ACR, ESTRO, and IAEA. These prescriptive guidelines have traditionally focused on monitoring all aspects of the functional performance of radiotherapy (RT) equipment by comparing parameters against tolerances set at strict but achievable values. Many errors that occur in radiation oncology are not due to failures in devices and software; rather they are failures in workflow and process. A systematic understanding of the likelihood and clinical impact ofmore » possible failures throughout a course of radiotherapy is needed to direct limit QM resources efficiently to produce maximum safety and quality of patient care. Task Group 100 of the AAPM has taken a broad view of these issues and has developed a framework for designing QM activities, based on estimates of the probability of identified failures and their clinical outcome through the RT planning and delivery process. The Task Group has chosen a specific radiotherapy process required for “intensity modulated radiation therapy (IMRT)” as a case study. The goal of this work is to apply modern risk-based analysis techniques to this complex RT process in order to demonstrate to the RT community that such techniques may help identify more effective and efficient ways to enhance the safety and quality of our treatment processes. The task group generated by consensus an example quality management program strategy for the IMRT process performed at the institution of one of the authors. This report describes the methodology and nomenclature developed, presents the process maps, FMEAs, fault trees, and QM programs developed, and makes suggestions on how this information could be used in the clinic. The development and implementation of risk-assessment techniques will make radiation therapy safer and more efficient.« less

The report of Task Group 100 of the AAPM: Application of risk analysis methods to radiation therapy quality management.

PubMed

Huq, M Saiful; Fraass, Benedick A; Dunscombe, Peter B; Gibbons, John P; Ibbott, Geoffrey S; Mundt, Arno J; Mutic, Sasa; Palta, Jatinder R; Rath, Frank; Thomadsen, Bruce R; Williamson, Jeffrey F; Yorke, Ellen D

2016-07-01

The increasing complexity of modern radiation therapy planning and delivery challenges traditional prescriptive quality management (QM) methods, such as many of those included in guidelines published by organizations such as the AAPM, ASTRO, ACR, ESTRO, and IAEA. These prescriptive guidelines have traditionally focused on monitoring all aspects of the functional performance of radiotherapy (RT) equipment by comparing parameters against tolerances set at strict but achievable values. Many errors that occur in radiation oncology are not due to failures in devices and software; rather they are failures in workflow and process. A systematic understanding of the likelihood and clinical impact of possible failures throughout a course of radiotherapy is needed to direct limit QM resources efficiently to produce maximum safety and quality of patient care. Task Group 100 of the AAPM has taken a broad view of these issues and has developed a framework for designing QM activities, based on estimates of the probability of identified failures and their clinical outcome through the RT planning and delivery process. The Task Group has chosen a specific radiotherapy process required for "intensity modulated radiation therapy (IMRT)" as a case study. The goal of this work is to apply modern risk-based analysis techniques to this complex RT process in order to demonstrate to the RT community that such techniques may help identify more effective and efficient ways to enhance the safety and quality of our treatment processes. The task group generated by consensus an example quality management program strategy for the IMRT process performed at the institution of one of the authors. This report describes the methodology and nomenclature developed, presents the process maps, FMEAs, fault trees, and QM programs developed, and makes suggestions on how this information could be used in the clinic. The development and implementation of risk-assessment techniques will make radiation therapy safer and more efficient.

Absolute proton hydration free energy, surface potential of water, and redox potential of the hydrogen electrode from first principles: QM/MM MD free-energy simulations of sodium and potassium hydration.

PubMed

Hofer, Thomas S; Hünenberger, Philippe H

2018-06-14

The absolute intrinsic hydration free energy G H + ,wat ◦ of the proton, the surface electric potential jump χ wat ◦ upon entering bulk water, and the absolute redox potential V H + ,wat ◦ of the reference hydrogen electrode are cornerstone quantities for formulating single-ion thermodynamics on absolute scales. They can be easily calculated from each other but remain fundamentally elusive, i.e., they cannot be determined experimentally without invoking some extra-thermodynamic assumption (ETA). The Born model provides a natural framework to formulate such an assumption (Born ETA), as it automatically factors out the contribution of crossing the water surface from the hydration free energy. However, this model describes the short-range solvation inaccurately and relies on the choice of arbitrary ion-size parameters. In the present study, both shortcomings are alleviated by performing first-principle calculations of the hydration free energies of the sodium (Na + ) and potassium (K + ) ions. The calculations rely on thermodynamic integration based on quantum-mechanical molecular-mechanical (QM/MM) molecular dynamics (MD) simulations involving the ion and 2000 water molecules. The ion and its first hydration shell are described using a correlated ab initio method, namely resolution-of-identity second-order Møller-Plesset perturbation (RIMP2). The next hydration shells are described using the extended simple point charge water model (SPC/E). The hydration free energy is first calculated at the MM level and subsequently increased by a quantization term accounting for the transformation to a QM/MM description. It is also corrected for finite-size, approximate-electrostatics, and potential-summation errors, as well as standard-state definition. These computationally intensive simulations provide accurate first-principle estimates for G H + ,wat ◦ , χ wat ◦ , and V H + ,wat ◦ , reported with statistical errors based on a confidence interval of 99%. The values obtained from the independent Na + and K + simulations are in excellent agreement. In particular, the difference between the two hydration free energies, which is not an elusive quantity, is 73.9 ± 5.4 kJ mol -1 (K + minus Na + ), to be compared with the experimental value of 71.7 ± 2.8 kJ mol -1 . The calculated values of G H + ,wat ◦ , χ wat ◦ , and V H + ,wat ◦ (-1096.7 ± 6.1 kJ mol -1 , 0.10 ± 0.10 V, and 4.32 ± 0.06 V, respectively, averaging over the two ions) are also in remarkable agreement with the values recommended by Reif and Hünenberger based on a thorough analysis of the experimental literature (-1100 ± 5 kJ mol -1 , 0.13 ± 0.10 V, and 4.28 ± 0.13 V, respectively). The QM/MM MD simulations are also shown to provide an accurate description of the hydration structure, dynamics, and energetics.

Corrosion protection properties and interfacial adhesion mechanism of an epoxy/polyamide coating applied on the steel surface decorated with cerium oxide nanofilm: Complementary experimental, molecular dynamics (MD) and first principle quantum mechanics (QM) simulation methods

NASA Astrophysics Data System (ADS)

Bahlakeh, Ghasem; Ramezanzadeh, Bahram; Saeb, Mohammad Reza; Terryn, Herman; Ghaffari, Mehdi

2017-10-01

The effect of cerium oxide treatment on the corrosion protection properties and interfacial interaction of steel/epoxy was studied by electrochemical impedance spectroscopy, (EIS) classical molecular dynamics (MD) and first principle quantum mechanics (QM) simulation methods X-ray photoelectron spectroscopy (XPS) was used to verify the chemical composition of the Ce film deposited on the steel. To probe the role of the curing agent in epoxy adsorption, computations were compared for an epoxy, aminoamide and aminoamide modified epoxy. Moreover, to study the influence of water on interfacial interactions the MD simulations were executed for poly (aminoamide)-cured epoxy resin in contact with the different crystallographic cerium dioxide (ceria, CeO2) surfaces including (100), (110), and (111) in the presence of water molecules. It was found that aminoamide-cured epoxy material was strongly adhered to all types of CeO2 substrates, so that binding to ceria surfaces followed the decreasing order CeO2 (111) > CeO2 (100) > CeO2 (110) in both dry and wet environments. Calculation of interaction energies noticed an enhanced adhesion to metal surface due to aminoamide curing of epoxy resin; where facets (100) and (111) revealed electrostatic and Lewis acid-base interactions, while an additional hydrogen bonding interaction was identified for CeO2 (110). Overall, MD simulations suggested decrement of adhesion to CeO2 in wet environment compared to dry conditions. Additionally, contact angle, pull-off test, cathodic delamination and salt spray analyses were used to confirm the simulation results. The experimental results in line with modeling results revealed that Ce layer deposited on steel enhanced substrate surface free energy, work of adhesion, and interfacial adhesion strength of the epoxy coating. Furthermore, decrement of adhesion of epoxy to CeO2 in presence of water was affirmed by experimental results. EIS results revealed remarkable enhancement of the corrosion resistance of epoxy coating applied on the steel specimens treated by cerium oxide.

Role Of Impurities On Deformation Of HCP Crystal: A Multi-Scale Approach

NASA Astrophysics Data System (ADS)

Bhatia, Mehul Anoopkumar

Commercially pure (CP) and extra low interstitial (ELI) grade Ti-alloys present excellent corrosion resistance, lightweight, and formability making them attractive materials for expanded use in transportation and medical applications. However, the strength and toughness of CP titanium are affected by relatively small variations in their impurity/solute content (IC), e.g., O, Al, and V. This increase in strength is due to the fact that the solute either increases the critical stress required for the prismatic slip systems ({10- 10}) or activates another slip system ((0001), {10-11}). In particular, solute additions such as O can effectively strengthen the alloy but with an attendant loss in ductility by changing the behavior from wavy (cross slip) to planar nature. In order to understand the underlying behavior of strengthening by solutes, it is important to understand the atomic scale mechanism. This dissertation aims to address this knowledge gap through a synergistic combination of density functional theory (DFT) and molecular dynamics. Further, due to the long-range strain fields of the dislocations and the periodicity of the DFT simulation cells, it is difficult to apply ab initio simulations to study the dislocation core structure. To alleviate this issue we developed a multiscale quantum mechanics/molecular mechanics approach (QM/MM) to study the dislocation core. We use the developed QM/MM method to study the pipe diffusion along a prismatic edge dislocation core. Complementary to the atomistic simulations, the Semi-discrete Variational Peierls-Nabarro model (SVPN) was also used to analyze the dislocation core structure and mobility. The chemical interaction between the solute/impurity and the dislocation core is captured by the so-called generalized stacking fault energy (GSFE) surface which was determined from DFT-VASP calculations. By taking the chemical interaction into consideration the SVPN model can predict the dislocation core structure and mobility in the presence and absence of the solute/impurity and thus reveal the effect of impurity/solute on the softening/hardening behavior in alpha-Ti. Finally, to study the interaction of the dislocation core with other planar defects such as grain boundaries (GB), we develop an automated method to theoretically generate GBs in HCP type materials.

Possible future changes in South East Australian frost frequency: an inter-comparison of statistical downscaling approaches

NASA Astrophysics Data System (ADS)

Crimp, Steven; Jin, Huidong; Kokic, Philip; Bakar, Shuvo; Nicholls, Neville

2018-04-01

Anthropogenic climate change has already been shown to effect the frequency, intensity, spatial extent, duration and seasonality of extreme climate events. Understanding these changes is an important step in determining exposure, vulnerability and focus for adaptation. In an attempt to support adaptation decision-making we have examined statistical modelling techniques to improve the representation of global climate model (GCM) derived projections of minimum temperature extremes (frosts) in Australia. We examine the spatial changes in minimum temperature extreme metrics (e.g. monthly and seasonal frost frequency etc.), for a region exhibiting the strongest station trends in Australia, and compare these changes with minimum temperature extreme metrics derived from 10 GCMs, from the Coupled Model Inter-comparison Project Phase 5 (CMIP 5) datasets, and via statistical downscaling. We compare the observed trends with those derived from the "raw" GCM minimum temperature data as well as examine whether quantile matching (QM) or spatio-temporal (spTimerQM) modelling with Quantile Matching can be used to improve the correlation between observed and simulated extreme minimum temperatures. We demonstrate, that the spTimerQM modelling approach provides correlations with observed daily minimum temperatures for the period August to November of 0.22. This represents an almost fourfold improvement over either the "raw" GCM or QM results. The spTimerQM modelling approach also improves correlations with observed monthly frost frequency statistics to 0.84 as opposed to 0.37 and 0.81 for the "raw" GCM and QM results respectively. We apply the spatio-temporal model to examine future extreme minimum temperature projections for the period 2016 to 2048. The spTimerQM modelling results suggest the persistence of current levels of frost risk out to 2030, with the evidence of continuing decadal variation.

Propensity, Probability, and Quantum Theory

NASA Astrophysics Data System (ADS)

Ballentine, Leslie E.

2016-08-01

Quantum mechanics and probability theory share one peculiarity. Both have well established mathematical formalisms, yet both are subject to controversy about the meaning and interpretation of their basic concepts. Since probability plays a fundamental role in QM, the conceptual problems of one theory can affect the other. We first classify the interpretations of probability into three major classes: (a) inferential probability, (b) ensemble probability, and (c) propensity. Class (a) is the basis of inductive logic; (b) deals with the frequencies of events in repeatable experiments; (c) describes a form of causality that is weaker than determinism. An important, but neglected, paper by P. Humphreys demonstrated that propensity must differ mathematically, as well as conceptually, from probability, but he did not develop a theory of propensity. Such a theory is developed in this paper. Propensity theory shares many, but not all, of the axioms of probability theory. As a consequence, propensity supports the Law of Large Numbers from probability theory, but does not support Bayes theorem. Although there are particular problems within QM to which any of the classes of probability may be applied, it is argued that the intrinsic quantum probabilities (calculated from a state vector or density matrix) are most naturally interpreted as quantum propensities. This does not alter the familiar statistical interpretation of QM. But the interpretation of quantum states as representing knowledge is untenable. Examples show that a density matrix fails to represent knowledge.

Interaction of cinnamic acid derivatives with β-cyclodextrin in water: experimental and molecular modeling studies.

PubMed

Liu, Benguo; Zeng, Jie; Chen, Chen; Liu, Yonglan; Ma, Hanjun; Mo, Haizhen; Liang, Guizhao

2016-03-01

Cyclodextrins (CDs) can be used to improve the solubility and stability of cinnamic acid derivatives (CAs). However, there was no detailed report about understanding the effects of the substituent groups in the benzene ring on the inclusion behavior between CAs and CDs in aqueous solution. Here, the interaction of β-CD with CAs, including caffeic acid, ferulic acid, and p-coumaric acid, in water was investigated by phase-solubility method, UV, fluorescence, and (1)H NMR spectroscopy, together with ONIOM (our Own N-layer Integrated Orbital molecular Mechanics)-based QM/MM (Quantum Mechanics/Molecular Mechanics) calculations. Experimental results demonstrated that CAs could form 1:1 stoichiometric inclusion complex with β-CD by non-covalent bonds, and that the maximum apparent stability constants were found in caffeic acid (176M(-1)) followed by p-coumaric acid (160M(-1)) and ferulic acid (133M(-1)). Moreover, our calculations reasonably illustrated the binding orientations of β-CD with CAs determined by experimental observations. Copyright © 2015. Published by Elsevier Ltd.

QM-8 final performance evaluation report: SEALS, volume 4

NASA Technical Reports Server (NTRS)

Nelsen, L. V.

1989-01-01

The Space Shuttle Redesigned Solid Rocket Motor (RSRM) static test of Qualification Motor-8 (QM-8) was conducted. The QM-8 test article was the fifth full-scale, full-duration test, and the third qualification motor to incorporate the redesigned case field joint and nozzle-to-case joint. This was the second static test conducted in the T-97 test facility, which is equipped with actuators for inducing external side loads to a 360 degree external tank (ET) attach ring during test motor operation, and permits heating/cooling of an entire motor. The QM-8 motor was cooled to a temperature which ensured that the maximum propellant mean bulk temperature (PMBT) of 40 F was achieved at firing. All test results are not included, but rather, the performance of the metal case, field joints, and nozzle-to-case joint is addressed. The involvement is studied of the Structural Applications and Structural Design Groups with the QM-8 test which includes: assembly procedures of the field and nozzle-to-case joints, joint leak check results, structural test results, and post-test inspection evaluations.

Hydrolysis of the quinone methide of butylated hydroxytoluene in aqueous solutions.

PubMed

Willcockson, Maren Gulsrud; Toteva, Maria M; Stella, Valentino J

2013-10-01

Butylated hydroxytoluene or BHT is an antioxidant commonly used in pharmaceutical formulations. BHT upon oxidation forms a quinone methide (QM). QM is a highly reactive electrophilic species that can undergo nucleophilic addition. Here, the kinetic reactivity of QM with water at various apparent pH values in a 50% (v/v) water-acetonitrile solution at constant ionic strength of I = 0.5 (NaCl)4 , was studied. The hydrolysis of QM in the presence of added acid, base, sodium chloride, and phosphate buffer resulted in the formation of only one product--the corresponding 3,5-di-tert-butyl-4-hydroxybenzyl alcohol (BA). The rate of BA formation was catalyzed by the addition of acid and base, but not chloride and phosphate species. Nucleophilic excipients, used in the pharmaceutical formulation, or nucleophilic groups on active pharmaceutical ingredient molecule may form adducts with QM, the immediate oxidative product of BHT degradation, thus having implications for drug product impurity profiles. Because of these considerations, BHT should be used with caution in formulations containing drugs or excipients capable of acting as nucleophiles. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Practical quantum mechanics-based fragment methods for predicting molecular crystal properties.

PubMed

Wen, Shuhao; Nanda, Kaushik; Huang, Yuanhang; Beran, Gregory J O

2012-06-07

Significant advances in fragment-based electronic structure methods have created a real alternative to force-field and density functional techniques in condensed-phase problems such as molecular crystals. This perspective article highlights some of the important challenges in modeling molecular crystals and discusses techniques for addressing them. First, we survey recent developments in fragment-based methods for molecular crystals. Second, we use examples from our own recent research on a fragment-based QM/MM method, the hybrid many-body interaction (HMBI) model, to analyze the physical requirements for a practical and effective molecular crystal model chemistry. We demonstrate that it is possible to predict molecular crystal lattice energies to within a couple kJ mol(-1) and lattice parameters to within a few percent in small-molecule crystals. Fragment methods provide a systematically improvable approach to making predictions in the condensed phase, which is critical to making robust predictions regarding the subtle energy differences found in molecular crystals.

QM/MM studies on the excited-state relaxation mechanism of a semisynthetic dTPT3 base.

PubMed

Guo, Wei-Wei; Zhang, Teng-Shuo; Fang, Wei-Hai; Cui, Ganglong

2018-02-14

Semisynthetic alphabets can potentially increase the genetic information stored in DNA through the formation of unusual base pairs. Recent experiments have shown that near-visible-light irradiation of the dTPT3 chromophore could lead to the formation of a reactive triplet state and of singlet oxygen in high quantum yields. However, the detailed excited-state relaxation paths that populate the lowest triplet state are unclear. Herein, we have for the first time employed the QM(MS-CASPT2//CASSCF)/MM method to explore the spectroscopic properties and excited-state relaxation mechanism of the aqueous dTPT3 chromophore. On the basis of the results, we have found that (1) the S 2 ( 1 ππ*) state of dTPT3 is the initially populated excited singlet state upon near-visible light irradiation; and (2) there are two efficient relaxation pathways to populate the lowest triplet state, i.e. T 1 ( 3 ππ*). In the first one, the S 2 ( 1 ππ*) system first decays to the S 1 ( 1 nπ*) state near the S 2 /S 1 conical intersection, which is followed by an efficient S 1 → T 1 intersystem crossing process at the S 1 /T 1 crossing point; in the second one, an efficient S 2 → T 2 intersystem crossing takes place first, and then, the T 2 ( 3 nπ*) system hops to the T 1 ( 3 ππ*) state through an internal conversion process at the T 2 /T 1 conical intersection. Moreover, an S 2 /S 1 /T 2 intersection region is found to play a vital role in the excited-state relaxation. These new mechanistic insights help in understanding the photophysics and photochemistry of unusual base pairs.

Understanding the reaction between muonium atoms and hydrogen molecules: zero point energy, tunnelling, and vibrational adiabaticity

NASA Astrophysics Data System (ADS)

Aldegunde, J.; Jambrina, P. G.; García, E.; Herrero, V. J.; Sáez-Rábanos, V.; Aoiz, F. J.

2013-11-01

The advent of very precise measurements of rate coefficients in reactions of muonium (Mu), the lightest hydrogen isotope, with H2 in its ground and first vibrational state and of kinetic isotope effects with respect to heavier isotopes has triggered a renewed interests in the field of muonic chemistry. The aim of the present article is to review the most recent results about the dynamics and mechanism of the reaction Mu+H2 to shed light on the importance of quantum effects such as tunnelling, the preservation of the zero point energy, and the vibrational adiabaticity. In addition to accurate quantum mechanical (QM) calculations, quasiclassical trajectories (QCT) have been run in order to check the reliability of this method for this isotopic variant. It has been found that the reaction with H2(v=0) is dominated by the high zero point energy (ZPE) of the products and that tunnelling is largely irrelevant. Accordingly, both QCT calculations that preserve the products' ZPE as well as those based on the Ring Polymer Molecular Dynamics methodology can reproduce the QM rate coefficients. However, when the hydrogen molecule is vibrationally excited, QCT calculations fail completely in the prediction of the huge vibrational enhancement of the reactivity. This failure is attributed to tunnelling, which plays a decisive role breaking the vibrational adiabaticity when v=1. By means of the analysis of the results, it can be concluded that the tunnelling takes place through the ν1=1 collinear barrier. Somehow, the tunnelling that is missing in the Mu+H2(v=0) reaction is found in Mu+H2(v=1).

Can ferric-superoxide act as a potential oxidant in P450(cam)? QM/MM investigation of hydroxylation, epoxidation, and sulfoxidation.

PubMed

Lai, Wenzhen; Shaik, Sason

2011-04-13

In view of recent reports of high reactivity of ferric-superoxide species in heme and nonheme systems (Morokuma et al. J. Am. Chem. Soc. 2010, 132, 11993-12005; Que et al. Inorg. Chem. 2010, 49, 3618-3628; Nam et al. J. Am. Chem. Soc. 2010, 132, 5958-5959; J. Am. Chem. Soc. 2010, 132, 10668-10670), we use herein combined quantum mechanics/molecular mechanics (QM/MM) methods to explore the potential reactivity of P450(cam) ferric-superoxide toward hydroxylation, epoxidation, and sulfoxidation. The calculations demonstrate that P450 ferric-superoxide is a sluggish oxidant compared with the high-valent oxoiron porphyrin cation-radical species. As such, unlike heme enzymes with a histidine axial ligand, the P450 superoxo species does not function as an oxidant in P450(cam). The origin of this different behavior of the superoxo species of P450 vis-à-vis other heme enzymes like tryptophan 2, 3-dioxygenase (TDO) is traced to the ability of the latter superoxo species to make a stronger FeOO-X (X = H,C) bond and to stabilize the corresponding bond-activation transition states by resonance with charge-transfer configurations. By contrast, the negatively charged thiolate ligand in the P450 superoxo species minimizes the mixing of charge transfer configurations in the transition state and raises the reaction barrier. However, as we demonstrate, an external electric field oriented along the Fe-O axis with a direction pointing from Fe toward O will quench Cpd I formation by slowing the reduction of ferric-superoxide and will simultaneously lower the barriers for oxidation by the latter species, thereby enabling observation of superoxo chemistry in P450. Other options for nascent superoxo reactivity in P450 are discussed. © 2011 American Chemical Society

Magnetic sensor technology for detecting mines, UXO, and other concealed security threats

NASA Astrophysics Data System (ADS)

Czipott, Peter V.; Iwanowski, Mark D.

1997-01-01

Magnetic sensors have been the sensor of choice in the detection and classification of buried mines and unexploded ordnance (UXO), both on land and underwater, Quantum Magnetics (QM), together with its research partner IBM, have developed a variety of advanced, very high sensitivity superconducting and room temperature magnetic sensors to meet military needs. This work has led to the development and utilization of a three-sensor gradiometer (TSG) patented by IBM, which cannot only detect, but also localize mines and ordnance. QM is also working with IBM and the U.S. Navy to develop an advanced superconducting gradiometer for buried underwater mine detection. The ability to both detect and classify buried non-metallic mines is virtually impossible with existing magnetic sensors. To solve this problem, Quantum Magnetics, building on work of the Naval Research Laboratory (NRL), is pioneering work in the development of quadrupole resonance (QR) methods which can be used to detect the explosive material directly. Based on recent laboratory work done at QM and previous work done in the U.S., Russia and the United Kingdom, we are confident that QR can be effectively applied to the non-metallic mine identification problem.

Reaction Mechanism of Mycobacterium Tuberculosis Glutamine Synthetase Using Quantum Mechanics/Molecular Mechanics Calculations.

PubMed

Moreira, Cátia; Ramos, Maria J; Fernandes, Pedro Alexandrino

2016-06-27

This paper is devoted to the understanding of the reaction mechanism of mycobacterium tuberculosis glutamine synthetase (mtGS) with atomic detail, using computational quantum mechanics/molecular mechanics (QM/MM) methods at the ONIOM M06-D3/6-311++G(2d,2p):ff99SB//B3LYP/6-31G(d):ff99SB level of theory. The complete reaction undergoes a three-step mechanism: the spontaneous transfer of phosphate from ATP to glutamate upon ammonium binding (ammonium quickly loses a proton to Asp54), the attack of ammonia on phosphorylated glutamate (yielding protonated glutamine), and the deprotonation of glutamine by the leaving phosphate. This exothermic reaction has an activation free energy of 21.5 kcal mol(-1) , which is consistent with that described for Escherichia coli glutamine synthetase (15-17 kcal mol(-1) ). The participating active site residues have been identified and their role and energy contributions clarified. This study provides an insightful atomic description of the biosynthetic reaction that takes place in this enzyme, opening doors for more accurate studies for developing new anti-tuberculosis therapies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Replacement of oxidizable residues predicted by QM-MM simulation of a fungal laccase generates variants with higher operational stability.

PubMed

Avelar, Mayra; Pastor, Nina; Ramirez-Ramirez, Joaquin; Ayala, Marcela

2018-01-01

In this work, we sought to obtain a more stable laccase with higher operational stability for the oxidation of phenols. During this reaction, phenoxy free radicals are produced that gradually inactivate the enzyme; the inactivation rate depends on the phenol chemical nature. In order to predict residues prone to oxidize within the active site, we simulated activated states of the catalytic region of a fungal laccase using QM-MM tools (Quantum Mechanics-Molecular Mechanics). After simulating the electron distribution in both the basal and activated state (plus or minus one electron) of several conformations of Coriolopsis gallica laccase, residues that could be susceptible to oxidation were identified, according to the values of spin density obtained from calculations. Three targets were selected (F357, F413, and F475) to be replaced by site-directed mutagenesis with less oxidizable residues such as leucine, alanine, and isoleucine. The resulting variants displayed a higher specific activity (from 1.5-to 4-fold) than the parental enzyme. Catalyst depletion during phenol oxidation was 2.5-fold lower for the variants, reflecting a higher operational stability. Copyright © 2017 Elsevier Inc. All rights reserved.

Nucleic acid reactivity: challenges for next-generation semiempirical quantum models.

PubMed

Huang, Ming; Giese, Timothy J; York, Darrin M

2015-07-05

Semiempirical quantum models are routinely used to study mechanisms of RNA catalysis and phosphoryl transfer reactions using combined quantum mechanical (QM)/molecular mechanical methods. Herein, we provide a broad assessment of the performance of existing semiempirical quantum models to describe nucleic acid structure and reactivity to quantify their limitations and guide the development of next-generation quantum models with improved accuracy. Neglect of diatomic differential overlap and self-consistent density-functional tight-binding semiempirical models are evaluated against high-level QM benchmark calculations for seven biologically important datasets. The datasets include: proton affinities, polarizabilities, nucleobase dimer interactions, dimethyl phosphate anion, nucleoside sugar and glycosidic torsion conformations, and RNA phosphoryl transfer model reactions. As an additional baseline, comparisons are made with several commonly used density-functional models, including M062X and B3LYP (in some cases with dispersion corrections). The results show that, among the semiempirical models examined, the AM1/d-PhoT model is the most robust at predicting proton affinities. AM1/d-PhoT and DFTB3-3ob/OPhyd reproduce the MP2 potential energy surfaces of 6 associative RNA phosphoryl transfer model reactions reasonably well. Further, a recently developed linear-scaling "modified divide-and-conquer" model exhibits the most accurate results for binding energies of both hydrogen bonded and stacked nucleobase dimers. The semiempirical models considered here are shown to underestimate the isotropic polarizabilities of neutral molecules by approximately 30%. The semiempirical models also fail to adequately describe torsion profiles for the dimethyl phosphate anion, the nucleoside sugar ring puckers, and the rotations about the nucleoside glycosidic bond. The modeling of pentavalent phosphorus, particularly with thio substitutions often used experimentally as mechanistic probes, was problematic for all of the models considered. Analysis of the strengths and weakness of the models suggests that the creation of robust next-generation models should emphasize the improvement of relative conformational energies and barriers, and nonbonded interactions. © 2015 Wiley Periodicals, Inc.

Combined valence bond-molecular mechanics potential-energy surface and direct dynamics study of rate constants and kinetic isotope effects for the H + C2H6 reaction.

PubMed

Chakraborty, Arindam; Zhao, Yan; Lin, Hai; Truhlar, Donald G

2006-01-28

This article presents a multifaceted study of the reaction H+C(2)H(6)-->H(2)+C(2)H(5) and three of its deuterium-substituted isotopologs. First we present high-level electronic structure calculations by the W1, G3SX, MCG3-MPWB, CBS-APNO, and MC-QCISD/3 methods that lead to a best estimate of the barrier height of 11.8+/-0.5 kcal/mol. Then we obtain a specific reaction parameter for the MPW density functional in order that it reproduces the best estimate of the barrier height; this yields the MPW54 functional. The MPW54 functional, as well as the MPW60 functional that was previously parametrized for the H+CH(4) reaction, is used with canonical variational theory with small-curvature tunneling to calculate the rate constants for all four ethane reactions from 200 to 2000 K. The final MPW54 calculations are based on curvilinear-coordinate generalized-normal-mode analysis along the reaction path, and they include scaled frequencies and an anharmonic C-C bond torsion. They agree with experiment within 31% for 467-826 K except for a 38% deviation at 748 K; the results for the isotopologs are predictions since these rate constants have never been measured. The kinetic isotope effects (KIEs) are analyzed to reveal the contributions from subsets of vibrational partition functions and from tunneling, which conspire to yield a nonmonotonic temperature dependence for one of the KIEs. The stationary points and reaction-path potential of the MPW54 potential-energy surface are then used to parametrize a new kind of analytical potential-energy surface that combines a semiempirical valence bond formalism for the reactive part of the molecule with a standard molecular mechanics force field for the rest; this may be considered to be either an extension of molecular mechanics to treat a reactive potential-energy surface or a new kind of combined quantum-mechanical/molecular mechanical (QM/MM) method in which the QM part is semiempirical valence bond theory; that is, the new potential-energy surface is a combined valence bond molecular mechanics (CVBMM) surface. Rate constants calculated with the CVBMM surface agree with the MPW54 rate constants within 12% for 534-2000 K and within 23% for 200-491 K. The full CVBMM potential-energy surface is now available for use in variety of dynamics calculations, and it provides a prototype for developing CVBMM potential-energy surfaces for other reactions.

Configurational assignments of conformationally restricted bis-monoterpene hydroquinones: utility in exploration of endangered plants.

PubMed

Oh, Joonseok; Bowling, John J; Zou, Yike; Chittiboyina, Amar G; Doerksen, Robert J; Ferreira, Daneel; Leininger, Theodor D; Hamann, Mark T

2013-08-01

Endangered plant species are an important resource for new chemistry. Lindera melissifolia is native to the Southeastern U.S. and scarcely populates the edges of lakes and ponds. Quantum mechanics (QM) used in combination with NMR/ECD is a powerful tool for the assignment of absolute configuration in lieu of X-ray crystallography. The EtOAc extract of L. melissifolia was subject to chromatographic analysis by VLC and HPLC. Spin-spin coupling constant (SSCC) were calculated using DFT at the MPW1PW91/6-31G(d,p) level for all staggered rotamers. ECD calculations employed Amber* force fields followed by PM6 semi-empirical optimizations. Hetero- and homo-nuclear coupling constants were extracted from 1D (1)H, E.COSY and HETLOC experiments. Two meroterpenoids, melissifolianes A (1) and B (2) were purified and their 2-D structures elucidated using NMR and HRESIMS. The relative configuration of 1 was established using the combination of NOE-based distance restraints and the comparisons of experimental and calculated SSCCs. The comparison of calculated and experimental ECD assigned the absolute configuration of 1. The relative configuration of a racemic mixture, melissifoliane B (2) was established utilizing J-based analysis combined with QM and NMR techniques.Conclusion Our study of the Lindera melissifolia metabolome exemplifies how new chemistry remains undiscovered among the numerous endangered plant species and demonstrates how analysis by ECD and NMR combined with various QM calculations is a sensible approach to support the stereochemical assignment of molecules with conformationally restricted conformations. QM-NMR/ECD combined approaches are of utility for unambiguous assignment of 3-D structures, especially with limited plant material and when a molecule is conformationally restricted. Conservation of an endangered plant species can be supported through identification of its new chemistry and utilization of that chemistry for commercial purposes. Copyright © 2013. Published by Elsevier B.V.

Modeling the archetype cysteine protease reaction using dispersion corrected density functional methods in ONIOM-type hybrid QM/MM calculations; the proteolytic reaction of papain.

PubMed

Fekete, Attila; Komáromi, István

2016-12-07

A proteolytic reaction of papain with a simple peptide model substrate N-methylacetamide has been studied. Our aim was twofold: (i) we proposed a plausible reaction mechanism with the aid of potential energy surface scans and second geometrical derivatives calculated at the stationary points, and (ii) we investigated the applicability of the dispersion corrected density functional methods in comparison with the popular hybrid generalized gradient approximations (GGA) method (B3LYP) without such a correction in the QM/MM calculations for this particular problem. In the resting state of papain the ion pair and neutral forms of the Cys-His catalytic dyad have approximately the same energy and they are separated by only a small barrier. Zero point vibrational energy correction shifted this equilibrium slightly to the neutral form. On the other hand, the electrostatic solvation free energy corrections, calculated using the Poisson-Boltzmann method for the structures sampled from molecular dynamics simulation trajectories, resulted in a more stable ion-pair form. All methods we applied predicted at least a two elementary step acylation process via a zwitterionic tetrahedral intermediate. Using dispersion corrected DFT methods the thioester S-C bond formation and the proton transfer from histidine occur in the same elementary step, although not synchronously. The proton transfer lags behind (or at least does not precede) the S-C bond formation. The predicted transition state corresponds mainly to the S-C bond formation while the proton is still on the histidine Nδ atom. In contrast, the B3LYP method using larger basis sets predicts a transition state in which the S-C bond is almost fully formed and the transition state can be mainly featured by the Nδ(histidine) to N(amid) proton transfer. Considerably lower activation energy was predicted (especially by the B3LYP method) for the next amide bond breaking elementary step of acyl-enzyme formation. Deacylation appeared to be a single elementary step process in all the methods we applied.

Discerning the catalytic mechanism of Staphylococcus aureus sortase A with QM/MM free energy calculations.

PubMed

Shrestha, Pooja; Wereszczynski, Jeff

2016-06-01

Sortases are key virulence factors in Gram-positive bacteria. These enzymes embed surface proteins in the cell wall through a transpeptidation reaction that involves recognizing a penta-peptide "sorting signal" in a target protein, cleaving it, and covalently attaching it to a second substrate that is later inserted into the cell wall. Although well studied, several aspects of the mechanism by which sortases perform these functions remains unclear. In particular, experiments have revealed two potential sorting signal binding motifs: a "Threonine-Out" (Thr-Out) structure in which the catalytically critical threonine residues protrudes into solution, and a "Threonine-In" (Thr-In) configuration in which this residue inserts into the binding site. To determine which of these is the biologically relevant state, we have performed a series of conventional and hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations of the Staphylococcus aureus sortase A (SrtA) enzyme bound to a sorting signal substrate. Through the use of multi-dimensional metadynamics, our simulations were able to both map the acylation mechanism of SrtA in the Thr-In and Thr-Out states, as well as determine the free energy minima and barriers along these reactions. Results indicate that in both states the catalytic mechanisms are similar, however the free energy barriers are lower in the Thr-In configuration, suggesting that Thr-In is the catalytically relevant state. This has important implications for advancing our understanding of the mechanisms of sortase enzymes, as well we for future structure based drug design efforts aimed at inhibiting sortase function in vivo. Copyright © 2016 Elsevier Inc. All rights reserved.

Inducible Alkylation of DNA by a Quinone Methide-Peptide Nucleic Acid Conjugate†

PubMed Central

Liu, Yang; Rokita, Steven E.

2012-01-01

The reversibility of alkylation by a quinone methide intermediate (QM) avoids the irreversible consumption that plagues most reagents based on covalent chemistry and allows for site specific reaction that is controlled by the thermodynamics rather than kinetics of target association. This characteristic was originally examined with an oligonucleotide QM conjugate but broad application depends on alternative derivatives that are compatible with a cellular environment. Now, a peptide nucleic acid (PNA) derivative has been constructed and shown to exhibit an equivalent ability to delivery the reactive QM in a controlled manner. This new conjugate demonstrates high selectivity for a complementary sequence of DNA even when challenged with an alternative sequence containing a single T/T mismatch. Alkylation of non-complementary sequences is only possible when a template strand is present to co-localize the conjugate and its target. For efficient alkylation in this example, a single-stranded region of the target is required adjacent to the QM conjugate. Most importantly, the intrastrand self adducts formed between the PNA and its attached QM remained active and reversible over more than eight days in aqueous solution prior to reaction with a chosen target added subsequently. PMID:22243337

QM/MM MD and Free Energy Simulation Study of Methyl Transfer Processes Catalyzed by PKMTs and PRMTs.

PubMed

Chu, Yuzhuo; Guo, Hong

2015-09-01

Methyl transfer processes catalyzed by protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs) control important biological events including transcriptional regulation and cell signaling. One important property of these enzymes is that different PKMTs and PRMTs catalyze the formation of different methylated product (product specificity). These different methylation states lead to different biological outcomes. Here, we review the results of quantum mechanics/molecular mechanics molecular dynamics and free energy simulations that have been performed to study the reaction mechanism of PKMTs and PRMTs and the mechanism underlying the product specificity of the methyl transfer processes.

Experimental Study of Mechanistic Acid Deconstruction of Lignin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sturgeon, M.; Kim, S.; Chmely, S. C.

2012-01-01

Lignin is a major component of biomass, which remains highly underutilized in selective biomass conversion strategies to renewable fuels and chemicals. Here we are interested in studying the mechanisms related to the acid deconstruction of lignin with a combined theoretical and experimental approach. Quantum mechanical calculations were employed to elucidate possible deconstruction mechanisms with transition state theory. Model dimers, imitating H, S, and G lignins, were synthesized with the most abundant {beta} - O - 4 linkage in lignin. These compounds were then depolymerized using various acids and at different operating conditions. The deconstruction products were analyzed to complement themore » QM studies and investigate proposed mechanisms.« less