Anisotropic energy flow and allosteric ligand binding in albumin.

PubMed

Li, Guifeng; Magana, Donny; Dyer, R Brian

2014-01-01

Allosteric interactions in proteins generally involve propagation of local structural changes through the protein to a remote site. Anisotropic energy transport is thought to couple the remote sites, but the nature of this process is poorly understood. Here, we report the relationship between energy flow through the structure of bovine serum albumin and allosteric interactions between remote ligand binding sites of the protein. Ultrafast infrared spectroscopy is used to probe the flow of energy through the protein backbone following excitation of a heater dye, a metalloporphyrin or malachite green, bound to different binding sites in the protein. We observe ballistic and anisotropic energy flow through the protein structure following input of thermal energy into the flexible ligand binding sites, without local heating of the rigid helix bundles that connect these sites. This efficient energy transport mechanism enables the allosteric propagation of binding energy through the connecting helix structures.

Anisotropic energy flow and allosteric ligand binding in albumin

PubMed Central

Li, Guifeng; Magana, Donny; Dyer, R. Brian

2014-01-01

Allosteric interactions in proteins generally involve propagation of local structural changes through the protein to a remote site. Anisotropic energy transport is thought to couple the remote sites, but the nature of this process is poorly understood. Here, we report the relationship between energy flow through the structure of bovine serum albumin and allosteric interactions between remote ligand binding sites of the protein. Ultrafast infrared spectroscopy is used to probe the flow of energy through the protein backbone following excitation of a heater dye, a metalloporphyrin or malachite green, bound to different binding sites in the protein. We observe ballistic and anisotropic energy flow through the protein structure following input of thermal energy into the flexible ligand binding sites, without local heating of the rigid helix bundles that connect these sites. This efficient energy transport mechanism enables the allosteric propagation of binding energy through the connecting helix structures. PMID:24445265

Binding Energy and Enzymatic Catalysis.

ERIC Educational Resources Information Center

Hansen, David E.; Raines, Ronald T.

1990-01-01

Discussed is the fundamental role that the favorable free energy of binding of the rate-determining transition state plays in catalysis. The principle that all of the catalytic factors discussed are realized by the use of this binding energy is reviewed. (CW)

Determination of the absolute binding free energies of HIV-1 protease inhibitors using non-equilibrium molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Ngo, Son Tung; Nguyen, Minh Tung; Nguyen, Minh Tho

2017-05-01

The absolute binding free energy of an inhibitor to HIV-1 Protease (PR) was determined throughout evaluation of the non-bonded interaction energy difference between the two bound and unbound states of the inhibitor and surrounding molecules by the fast pulling of ligand (FPL) process using non-equilibrium molecular dynamics (NEMD) simulations. The calculated free energy difference terms help clarifying the nature of the binding. Theoretical binding affinities are in good correlation with experimental data, with R = 0.89. The paradigm used is able to rank two inhibitors having the maximum difference of ∼1.5 kcal/mol in absolute binding free energies.

Simultaneous effects of pressure and temperature on donor binding energy in Pöschl-Teller quantum well

NASA Astrophysics Data System (ADS)

Hakimyfard, Alireza; Barseghyan, M. G.; Duque, C. A.; Kirakosyan, A. A.

2009-12-01

In the frame of the variational method and the effective-mass approximation, the effects of hydrostatic pressure and temperature on the binding energy for donor impurities in the Pöschl-Teller quantum well are studied. The binding energy dependencies on the width of the quantum well, the hydrostatic pressure, the impurity position, the temperature, and the parameters of the confining potential are reported. The results show that the binding energy increases (decreases) with the increasing of the hydrostatic pressure (temperature). It is also found that, associated with the symmetry breaking in the Pöschl-Teller quantum well, and depending on the impurity position, the binding energy can increase or decrease.

Implicit ligand theory for relative binding free energies

NASA Astrophysics Data System (ADS)

Nguyen, Trung Hai; Minh, David D. L.

2018-03-01

Implicit ligand theory enables noncovalent binding free energies to be calculated based on an exponential average of the binding potential of mean force (BPMF)—the binding free energy between a flexible ligand and rigid receptor—over a precomputed ensemble of receptor configurations. In the original formalism, receptor configurations were drawn from or reweighted to the apo ensemble. Here we show that BPMFs averaged over a holo ensemble yield binding free energies relative to the reference ligand that specifies the ensemble. When using receptor snapshots from an alchemical simulation with a single ligand, the new statistical estimator outperforms the original.

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

Parkes, Marie V.; Sava Gallis, Dorina F.; Greathouse, Jeffery A.

Computational screening of metal-organic framework (MOF) materials for selective oxygen adsorption from air could lead to new sorbents for the oxyfuel combustion process feedstock streams. A comprehensive study on the effect of MOF metal chemistry on gas binding energies in two common but structurally disparate metal-organic frameworks has been undertaken. Dispersion-corrected density functional theory methods were used to calculate the oxygen and nitrogen binding energies with each of fourteen metals, respectively, substituted into two MOF series, M 2(dobdc) and M 3(btc) 2. The accuracy of DFT methods was validated by comparing trends in binding energy with experimental gas sorption measurements.more » A periodic trend in oxygen binding energies was found, with greater oxygen binding energies for early transition-metal-substituted MOFs compared to late transition metal MOFs; this was independent of MOF structural type. The larger binding energies were associated with oxygen binding in a side-on configuration to the metal, with concomitant lengthening of the O-O bond. In contrast, nitrogen binding energies were similar across the transition metal series, regardless of both MOF structural type and metal identity. Altogether, these findings suggest that early transition metal MOFs are best suited to separating oxygen from nitrogen, and that the MOF structural type is less important than the metal identity.« less

An investigation on the effect of impurity position on the binding energy of quantum box under electric field with pressure and temperature

NASA Astrophysics Data System (ADS)

Yilmaz, S.; Kirak, M.

2018-05-01

In the present study, we have studied theoretically the influences of donor impurity position on the binding energy of a GaAs cubic quantum box structure. The binding energy is calculated as functions of the position of impurity, electric field, temperature and hydrostatic pressure. The variational method is employed to obtain the energy eigenvalues of the structure in the framework of the effective mass approximation. It has been found that the impurity positions with electric field, pressure and temperature have an important effect on the binding energy of structure considered. The results can be used to manufacture semiconductor device application by manipulating the binding energy with the impurity positions, electric field, pressure and temperature.

Pairwise additivity of energy components in protein-ligand binding: The HIV II protease-Indinavir case

NASA Astrophysics Data System (ADS)

Ucisik, Melek N.; Dashti, Danial S.; Faver, John C.; Merz, Kenneth M.

2011-08-01

An energy expansion (binding energy decomposition into n-body interaction terms for n ≥ 2) to express the receptor-ligand binding energy for the fragmented HIV II protease-Indinavir system is described to address the role of cooperativity in ligand binding. The outcome of this energy expansion is compared to the total receptor-ligand binding energy at the Hartree-Fock, density functional theory, and semiempirical levels of theory. We find that the sum of the pairwise interaction energies approximates the total binding energy to ˜82% for HF and to >95% for both the M06-L density functional and PM6-DH2 semiempirical method. The contribution of the three-body interactions amounts to 18.7%, 3.8%, and 1.4% for HF, M06-L, and PM6-DH2, respectively. We find that the expansion can be safely truncated after n = 3. That is, the contribution of the interactions involving more than three parties to the total binding energy of Indinavir to the HIV II protease receptor is negligible. Overall, we find that the two-body terms represent a good approximation to the total binding energy of the system, which points to pairwise additivity in the present case. This basic principle of pairwise additivity is utilized in fragment-based drug design approaches and our results support its continued use. The present results can also aid in the validation of non-bonded terms contained within common force fields and in the correction of systematic errors in physics-based score functions.

Electronic and optical properties of exciton, trions and biexciton in II-VI parabolic quantum dot

NASA Astrophysics Data System (ADS)

Sujanah, P.; John Peter, A.; Woo Lee, Chang

2015-08-01

Binding energies of exciton, trions and biexciton and their interband optical transition energies are studied in a CdTe/ZnTe quantum dot nanostructure taking into consideration the geometrical confinement effect. The radial spread of the wavefunctions, binding energies, optical transition energies, oscillator strength, radiative life time and the absorption coefficients of exciton, positively and negatively charged excitons and biexciton are carried out. It is found that the ratio of the radiative life time of exciton with the trions and biexciton enhances with the reduction of geometrical confinement. The results show that (i) the binding energies of exciton, positive and negative trions and the biexciton have strong influence on the reduction of geometrical confinement effect, (ii) the binding energy is found to decrease from the binding energies of exciton to positive trion through biexciton and negative trion binding energies, (iii) the oscillator strength of trions is found to be lesser than exciton and the biexciton and (iv) the electronic and optical properties of exciton, trions and the biexciton are considerably dependent on the spatial confinement, incident photon energy and the radiative life time. The obtained results are in good agreement with the other existing literature.

Calculation of Host-Guest Binding Affinities Using a Quantum-Mechanical Energy Model.

PubMed

Muddana, Hari S; Gilson, Michael K

2012-06-12

The prediction of protein-ligand binding affinities is of central interest in computer-aided drug discovery, but it is still difficult to achieve a high degree of accuracy. Recent studies suggesting that available force fields may be a key source of error motivate the present study, which reports the first mining minima (M2) binding affinity calculations based on a quantum mechanical energy model, rather than an empirical force field. We apply a semi-empirical quantum-mechanical energy function, PM6-DH+, coupled with the COSMO solvation model, to 29 host-guest systems with a wide range of measured binding affinities. After correction for a systematic error, which appears to derive from the treatment of polar solvation, the computed absolute binding affinities agree well with experimental measurements, with a mean error 1.6 kcal/mol and a correlation coefficient of 0.91. These calculations also delineate the contributions of various energy components, including solute energy, configurational entropy, and solvation free energy, to the binding free energies of these host-guest complexes. Comparison with our previous calculations, which used empirical force fields, point to significant differences in both the energetic and entropic components of the binding free energy. The present study demonstrates successful combination of a quantum mechanical Hamiltonian with the M2 affinity method.

Estimation of the Binding Free Energy of AC1NX476 to HIV-1 Protease Wild Type and Mutations Using Free Energy Perturbation Method.

PubMed

Ngo, Son Tung; Mai, Binh Khanh; Hiep, Dinh Minh; Li, Mai Suan

2015-10-01

The binding mechanism of AC1NX476 to HIV-1 protease wild type and mutations was studied by the docking and molecular dynamics simulations. The binding free energy was calculated using the double-annihilation binding free energy method. It is shown that the binding affinity of AC1NX476 to wild type is higher than not only ritonavir but also darunavir, making AC1NX476 become attractive candidate for HIV treatment. Our theoretical results are in excellent agreement with the experimental data as the correlation coefficient between calculated and experimentally measured binding free energies R = 0.993. Residues Asp25-A, Asp29-A, Asp30-A, Ile47-A, Gly48-A, and Val50-A from chain A, and Asp25-B from chain B play a crucial role in the ligand binding. The mutations were found to reduce the receptor-ligand interaction by widening the binding cavity, and the binding propensity is mainly driven by the van der Waals interaction. Our finding may be useful for designing potential drugs to combat with HIV. © 2015 John Wiley & Sons A/S.

Large scale affinity calculations of cyclodextrin host-guest complexes: Understanding the role of reorganization in the molecular recognition process

PubMed Central

Wickstrom, Lauren; He, Peng; Gallicchio, Emilio; Levy, Ronald M.

2013-01-01

Host-guest inclusion complexes are useful models for understanding the structural and energetic aspects of molecular recognition. Due to their small size relative to much larger protein-ligand complexes, converged results can be obtained rapidly for these systems thus offering the opportunity to more reliably study fundamental aspects of the thermodynamics of binding. In this work, we have performed a large scale binding affinity survey of 57 β-cyclodextrin (CD) host guest systems using the binding energy distribution analysis method (BEDAM) with implicit solvation (OPLS-AA/AGBNP2). Converged estimates of the standard binding free energies are obtained for these systems by employing techniques such as parallel Hamitionian replica exchange molecular dynamics, conformational reservoirs and multistate free energy estimators. Good agreement with experimental measurements is obtained in terms of both numerical accuracy and affinity rankings. Overall, average effective binding energies reproduce affinity rank ordering better than the calculated binding affinities, even though calculated binding free energies, which account for effects such as conformational strain and entropy loss upon binding, provide lower root mean square errors when compared to measurements. Interestingly, we find that binding free energies are superior rank order predictors for a large subset containing the most flexible guests. The results indicate that, while challenging, accurate modeling of reorganization effects can lead to ligand design models of superior predictive power for rank ordering relative to models based only on ligand-receptor interaction energies. PMID:25147485

Free energy decomposition of protein-protein interactions.

PubMed

Noskov, S Y; Lim, C

2001-08-01

A free energy decomposition scheme has been developed and tested on antibody-antigen and protease-inhibitor binding for which accurate experimental structures were available for both free and bound proteins. Using the x-ray coordinates of the free and bound proteins, the absolute binding free energy was computed assuming additivity of three well-defined, physical processes: desolvation of the x-ray structures, isomerization of the x-ray conformation to a nearby local minimum in the gas-phase, and subsequent noncovalent complex formation in the gas phase. This free energy scheme, together with the Generalized Born model for computing the electrostatic solvation free energy, yielded binding free energies in remarkable agreement with experimental data. Two assumptions commonly used in theoretical treatments; viz., the rigid-binding approximation (which assumes no conformational change upon complexation) and the neglect of vdW interactions, were found to yield large errors in the binding free energy. Protein-protein vdW and electrostatic interactions between complementary surfaces over a relatively large area (1400--1700 A(2)) were found to drive antibody-antigen and protease-inhibitor binding.

Effect of metal in M 3(btc) 2 and M 2(dobdc) MOFs for O 2/N 2 separations: A combined density functional theory and experimental study

DOE PAGES

Parkes, Marie V.; Sava Gallis, Dorina F.; Greathouse, Jeffery A.; ...

2015-03-02

Computational screening of metal-organic framework (MOF) materials for selective oxygen adsorption from air could lead to new sorbents for the oxyfuel combustion process feedstock streams. A comprehensive study on the effect of MOF metal chemistry on gas binding energies in two common but structurally disparate metal-organic frameworks has been undertaken. Dispersion-corrected density functional theory methods were used to calculate the oxygen and nitrogen binding energies with each of fourteen metals, respectively, substituted into two MOF series, M 2(dobdc) and M 3(btc) 2. The accuracy of DFT methods was validated by comparing trends in binding energy with experimental gas sorption measurements.more » A periodic trend in oxygen binding energies was found, with greater oxygen binding energies for early transition-metal-substituted MOFs compared to late transition metal MOFs; this was independent of MOF structural type. The larger binding energies were associated with oxygen binding in a side-on configuration to the metal, with concomitant lengthening of the O-O bond. In contrast, nitrogen binding energies were similar across the transition metal series, regardless of both MOF structural type and metal identity. Altogether, these findings suggest that early transition metal MOFs are best suited to separating oxygen from nitrogen, and that the MOF structural type is less important than the metal identity.« less

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.

Reexamine structures and relative stability of medium-sized silicon clusters: Low-lying endohedral fullerene-like clusters Si 30-Si 38

NASA Astrophysics Data System (ADS)

Yoo, Soohaeng; Shao, Nan; Zeng, X. C.

2009-10-01

We report improved results of lowest-lying silicon clusters Si 30-Si 38. A large population of low-energy clusters are collected from previous searches by several research groups and the binding energies of these clusters are computed using density-functional theory (DFT) methods. Best candidates (isomers with high binding energies) are identified from the screening calculations. Additional constrained search is then performed for the best candidates using the basin-hopping method combined with DFT geometry optimization. The obtained low-lying clusters are classified according to binding energies computed using either the Perdew-Burke-Ernzerhof (PBE) functional or the Becke exchange and Lee-Yang-Parr correlation (BLYP) functional. We propose to rank low-lying clusters according to the mean PBE/BLYP binding energies in view that the PBE functional tends to give greater binding energies for more compact clusters whereas the BLYP functional tends to give greater binding energies for less compact clusters or clusters composed of small-sized magic-number clusters. Except for Si 30, the new search confirms again that medium-size silicon clusters Si 31-Si 38 constructed with proper fullerene cage motifs are most promising to be the lowest-energy structures.

Free Energy-Based Virtual Screening and Optimization of RNase H Inhibitors of HIV-1 Reverse Transcriptase.

PubMed

Zhang, Baofeng; D'Erasmo, Michael P; Murelli, Ryan P; Gallicchio, Emilio

2016-09-30

We report the results of a binding free energy-based virtual screening campaign of a library of 77 α-hydroxytropolone derivatives against the challenging RNase H active site of the reverse transcriptase (RT) enzyme of human immunodeficiency virus-1. Multiple protonation states, rotamer states, and binding modalities of each compound were individually evaluated. The work involved more than 300 individual absolute alchemical binding free energy parallel molecular dynamics calculations and over 1 million CPU hours on national computing clusters and a local campus computational grid. The thermodynamic and structural measures obtained in this work rationalize a series of characteristics of this system useful for guiding future synthetic and biochemical efforts. The free energy model identified key ligand-dependent entropic and conformational reorganization processes difficult to capture using standard docking and scoring approaches. Binding free energy-based optimization of the lead compounds emerging from the virtual screen has yielded four compounds with very favorable binding properties, which will be the subject of further experimental investigations. This work is one of the few reported applications of advanced-binding free energy models to large-scale virtual screening and optimization projects. It further demonstrates that, with suitable algorithms and automation, advanced-binding free energy models can have a useful role in early-stage drug-discovery programs.

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.

Binding free energy analysis of protein-protein docking model structures by evERdock.

PubMed

Takemura, Kazuhiro; Matubayasi, Nobuyuki; Kitao, Akio

2018-03-14

To aid the evaluation of protein-protein complex model structures generated by protein docking prediction (decoys), we previously developed a method to calculate the binding free energies for complexes. The method combines a short (2 ns) all-atom molecular dynamics simulation with explicit solvent and solution theory in the energy representation (ER). We showed that this method successfully selected structures similar to the native complex structure (near-native decoys) as the lowest binding free energy structures. In our current work, we applied this method (evERdock) to 100 or 300 model structures of four protein-protein complexes. The crystal structures and the near-native decoys showed the lowest binding free energy of all the examined structures, indicating that evERdock can successfully evaluate decoys. Several decoys that show low interface root-mean-square distance but relatively high binding free energy were also identified. Analysis of the fraction of native contacts, hydrogen bonds, and salt bridges at the protein-protein interface indicated that these decoys were insufficiently optimized at the interface. After optimizing the interactions around the interface by including interfacial water molecules, the binding free energies of these decoys were improved. We also investigated the effect of solute entropy on binding free energy and found that consideration of the entropy term does not necessarily improve the evaluations of decoys using the normal model analysis for entropy calculation.

Binding free energy analysis of protein-protein docking model structures by evERdock

NASA Astrophysics Data System (ADS)

Takemura, Kazuhiro; Matubayasi, Nobuyuki; Kitao, Akio

2018-03-01

To aid the evaluation of protein-protein complex model structures generated by protein docking prediction (decoys), we previously developed a method to calculate the binding free energies for complexes. The method combines a short (2 ns) all-atom molecular dynamics simulation with explicit solvent and solution theory in the energy representation (ER). We showed that this method successfully selected structures similar to the native complex structure (near-native decoys) as the lowest binding free energy structures. In our current work, we applied this method (evERdock) to 100 or 300 model structures of four protein-protein complexes. The crystal structures and the near-native decoys showed the lowest binding free energy of all the examined structures, indicating that evERdock can successfully evaluate decoys. Several decoys that show low interface root-mean-square distance but relatively high binding free energy were also identified. Analysis of the fraction of native contacts, hydrogen bonds, and salt bridges at the protein-protein interface indicated that these decoys were insufficiently optimized at the interface. After optimizing the interactions around the interface by including interfacial water molecules, the binding free energies of these decoys were improved. We also investigated the effect of solute entropy on binding free energy and found that consideration of the entropy term does not necessarily improve the evaluations of decoys using the normal model analysis for entropy calculation.

A Comprehensive Docking and MM/GBSA Rescoring Study of Ligand Recognition upon Binding Antithrombin

DOE PAGES

Zhang, Xiaohua; Perez-Sanchez, Horacio; C. Lightstone, Felice

2017-04-06

A high-throughput virtual screening pipeline has been extended from single energetically minimized structure Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) rescoring to ensemble-average MM/GBSA rescoring. The correlation coefficient (R2) of calculated and experimental binding free energies for a series of antithrombin ligands has been improved from 0.36 to 0.69 when switching from the single-structure MM/GBSA rescoring to ensemble-average one. The electrostatic interactions in both solute and solvent are identified to play an important role in determining the binding free energy after the decomposition of the calculated binding free energy. Furthermore, the increasing negative charge of the compounds provides a more favorablemore » electrostatic energy change but creates a higher penalty for the solvation free energy. Such a penalty is compensated by the electrostatic energy change, which results in a better binding affinity. A highly hydrophobic ligand is determined by the docking program to be a non-specific binder. Finally, these results have demonstrated that it is very important to keep a few top poses for rescoring, if the binding is non-specific or the binding mode is not well determined by the docking calculation.« less

A Comprehensive Docking and MM/GBSA Rescoring Study of Ligand Recognition upon Binding Antithrombin

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

Zhang, Xiaohua; Perez-Sanchez, Horacio; C. Lightstone, Felice

A high-throughput virtual screening pipeline has been extended from single energetically minimized structure Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) rescoring to ensemble-average MM/GBSA rescoring. The correlation coefficient (R2) of calculated and experimental binding free energies for a series of antithrombin ligands has been improved from 0.36 to 0.69 when switching from the single-structure MM/GBSA rescoring to ensemble-average one. The electrostatic interactions in both solute and solvent are identified to play an important role in determining the binding free energy after the decomposition of the calculated binding free energy. Furthermore, the increasing negative charge of the compounds provides a more favorablemore » electrostatic energy change but creates a higher penalty for the solvation free energy. Such a penalty is compensated by the electrostatic energy change, which results in a better binding affinity. A highly hydrophobic ligand is determined by the docking program to be a non-specific binder. Finally, these results have demonstrated that it is very important to keep a few top poses for rescoring, if the binding is non-specific or the binding mode is not well determined by the docking calculation.« less

On binding energy of trions in bulk materials

NASA Astrophysics Data System (ADS)

Filikhin, Igor; Kezerashvili, Roman Ya.; Vlahovic, Branislav

2018-03-01

We study the negatively T- and positively T+ charged trions in bulk materials in the effective mass approximation within the framework of a potential model. The binding energies of trions in various semiconductors are calculated by employing Faddeev equation in configuration space. Results of calculations of the binding energies for T- are consistent with previous computational studies and are in reasonable agreement with experimental measurements, while the T+ is unbound for all considered cases. The mechanism of formation of the binding energy of trions is analyzed by comparing contributions of a mass-polarization term related to kinetic energy operators and a term related to the Coulomb repulsion of identical particles.

Absolute binding free energies between T4 lysozyme and 141 small molecules: calculations based on multiple rigid receptor configurations

PubMed Central

Xie, Bing; Nguyen, Trung Hai; Minh, David D. L.

2017-01-01

We demonstrate the feasibility of estimating protein-ligand binding free energies using multiple rigid receptor configurations. Based on T4 lysozyme snapshots extracted from six alchemical binding free energy calculations with a flexible receptor, binding free energies were estimated for a total of 141 ligands. For 24 ligands, the calculations reproduced flexible-receptor estimates with a correlation coefficient of 0.90 and a root mean square error of 1.59 kcal/mol. The accuracy of calculations based on Poisson-Boltzmann/Surface Area implicit solvent was comparable to previously reported free energy calculations. PMID:28430432

Exploring the free-energy landscape of carbohydrate-protein complexes: development and validation of scoring functions considering the binding-site topology

NASA Astrophysics Data System (ADS)

Eid, Sameh; Saleh, Noureldin; Zalewski, Adam; Vedani, Angelo

2014-12-01

Carbohydrates play a key role in a variety of physiological and pathological processes and, hence, represent a rich source for the development of novel therapeutic agents. Being able to predict binding mode and binding affinity is an essential, yet lacking, aspect of the structure-based design of carbohydrate-based ligands. We assembled a diverse data set comprising 273 carbohydrate-protein crystal structures with known binding affinity and evaluated the prediction accuracy of a large collection of well-established scoring and free-energy functions, as well as combinations thereof. Unfortunately, the tested functions were not capable of reproducing binding affinities in the studied complexes. To simplify the complex free-energy surface of carbohydrate-protein systems, we classified the studied proteins according to the topology and solvent exposure of the carbohydrate-binding site into five distinct categories. A free-energy model based on the proposed classification scheme reproduced binding affinities in the carbohydrate data set with an r 2 of 0.71 and root-mean-squared-error of 1.25 kcal/mol ( N = 236). The improvement in model performance underlines the significance of the differences in the local micro-environments of carbohydrate-binding sites and demonstrates the usefulness of calibrating free-energy functions individually according to binding-site topology and solvent exposure.

Allosteric Ligand Binding and Anisotropic Energy Flow in Albumin

NASA Astrophysics Data System (ADS)

Dyer, Brian

2014-03-01

Protein allostery usually involves propagation of local structural changes through the protein to a remote site. Coupling of structural changes at remote sites is thought to occur through anisotropic energy transport, but the nature of this process is poorly understood. We have studied the relationship between allosteric interactions of remote ligand binding sites of the protein and energy flow through the structure of bovine serum albumin (BSA). We applied ultrafast infrared spectroscopy to probe the flow of energy through the protein backbone following excitation of a heater dye, a metalloporphyrin or malachite green, bound to different binding sites in the protein. We observe ballistic flow through the protein structure following input of thermal energy into the flexible ligand binding sites. We also observe anisotropic heat flow through the structure, without local heating of the rigid helix bundles that connect these sites. We will discuss the implications of this efficient energy transport mechanism with regard to the allosteric propagation of binding energy through the connecting helix structures.

Funnel metadynamics as accurate binding free-energy method

PubMed Central

Limongelli, Vittorio; Bonomi, Massimiliano; Parrinello, Michele

2013-01-01

A detailed description of the events ruling ligand/protein interaction and an accurate estimation of the drug affinity to its target is of great help in speeding drug discovery strategies. We have developed a metadynamics-based approach, named funnel metadynamics, that allows the ligand to enhance the sampling of the target binding sites and its solvated states. This method leads to an efficient characterization of the binding free-energy surface and an accurate calculation of the absolute protein–ligand binding free energy. We illustrate our protocol in two systems, benzamidine/trypsin and SC-558/cyclooxygenase 2. In both cases, the X-ray conformation has been found as the lowest free-energy pose, and the computed protein–ligand binding free energy in good agreement with experiments. Furthermore, funnel metadynamics unveils important information about the binding process, such as the presence of alternative binding modes and the role of waters. The results achieved at an affordable computational cost make funnel metadynamics a valuable method for drug discovery and for dealing with a variety of problems in chemistry, physics, and material science. PMID:23553839

Enzyme activation through the utilization of intrinsic dianion binding energy.

PubMed

Amyes, T L; Malabanan, M M; Zhai, X; Reyes, A C; Richard, J P

2017-03-01

We consider 'the proposition that the intrinsic binding energy that results from the noncovalent interaction of a specific substrate with the active site of the enzyme is considerably larger than is generally believed. An important part of this binding energy may be utilized to provide the driving force for catalysis, so that the observed binding energy represents only what is left over after this utilization' [Jencks,W.P. (1975) Adv. Enzymol. Relat. Areas. Mol. Biol. , , 219-410]. The large ~12 kcal/mol intrinsic substrate phosphodianion binding energy for reactions catalyzed by triosephosphate isomerase (TIM), orotidine 5'-monophosphate decarboxylase and glycerol-3-phosphate dehydrogenase is divided into 4-6 kcal/mol binding energy that is expressed on the formation of the Michaelis complex in anchoring substrates to the respective enzyme, and 6-8 kcal/mol binding energy that is specifically expressed at the transition state in activating the respective enzymes for catalysis. A structure-based mechanism is described where the dianion binding energy drives a conformational change that activates these enzymes for catalysis. Phosphite dianion plays the active role of holding TIM in a high-energy closed active form, but acts as passive spectator in showing no effect on transition-state structure. The result of studies on mutant enzymes is presented, which support the proposal that the dianion-driven enzyme conformational change plays a role in enhancing the basicity of side chain of E167, the catalytic base, by clamping the base between a pair of hydrophobic side chains. The insight these results provide into the architecture of enzyme active sites and the development of strategies for the de novo design of protein catalysts is discussed. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Role of Ligand Reorganization and Conformational Restraints on the Binding Free Energies of DAPY Non-Nucleoside Inhibitors to HIV Reverse Transcriptase

PubMed Central

Gallicchio, Emilio

2012-01-01

The results of computer simulations of the binding of etravirine (TMC125) and rilpivirine (TMC278) to HIV reverse transcriptase are reported. It is confirmed that consistent binding free energy estimates are obtained with or without the application of torsional restraints when the free energies of imposing the restraints are taken into account. The restraints have a smaller influence on the thermodynamics and apparent kinetics of binding of TMC125 compared to the more flexible TMC278 inhibitor. The concept of the reorganization free energy of binding is useful to understand and categorize these effects. Contrary to expectations, the use of conformational restraints did not consistently enhance convergence of binding free energy estimates due to suppression of binding/unbinding pathways and due to the influence of rotational degrees of freedom not directly controlled by the restraints. Physical insights concerning the thermodynamic driving forces for binding and the role of “jiggling” and “wiggling” motion of the ligands are discussed. Based on these insights we conclude that an ideal inhibitor, if chemically realizable, would possess the electrostatic charge distribution of TMC125, so as to form strong interactions with the receptor, and the larger and more flexible substituents of TMC278, so as to minimize reorganization free energy penalties and the effects of resistance mutations, suitably modified, as in TMC125, so as to disfavor the formation of non-binding competent extended conformations when free in solution. PMID:22708073

Integrating water exclusion theory into βcontacts to predict binding free energy changes and binding hot spots

PubMed Central

2014-01-01

Background Binding free energy and binding hot spots at protein-protein interfaces are two important research areas for understanding protein interactions. Computational methods have been developed previously for accurate prediction of binding free energy change upon mutation for interfacial residues. However, a large number of interrupted and unimportant atomic contacts are used in the training phase which caused accuracy loss. Results This work proposes a new method, βACV ASA , to predict the change of binding free energy after alanine mutations. βACV ASA integrates accessible surface area (ASA) and our newly defined β contacts together into an atomic contact vector (ACV). A β contact between two atoms is a direct contact without being interrupted by any other atom between them. A β contact’s potential contribution to protein binding is also supposed to be inversely proportional to its ASA to follow the water exclusion hypothesis of binding hot spots. Tested on a dataset of 396 alanine mutations, our method is found to be superior in classification performance to many other methods, including Robetta, FoldX, HotPOINT, an ACV method of β contacts without ASA integration, and ACV ASA methods (similar to βACV ASA but based on distance-cutoff contacts). Based on our data analysis and results, we can draw conclusions that: (i) our method is powerful in the prediction of binding free energy change after alanine mutation; (ii) β contacts are better than distance-cutoff contacts for modeling the well-organized protein-binding interfaces; (iii) β contacts usually are only a small fraction number of the distance-based contacts; and (iv) water exclusion is a necessary condition for a residue to become a binding hot spot. Conclusions βACV ASA is designed using the advantages of both β contacts and water exclusion. It is an excellent tool to predict binding free energy changes and binding hot spots after alanine mutation. PMID:24568581

Large scale free energy calculations for blind predictions of protein-ligand binding: the D3R Grand Challenge 2015.

PubMed

Deng, Nanjie; Flynn, William F; Xia, Junchao; Vijayan, R S K; Zhang, Baofeng; He, Peng; Mentes, Ahmet; Gallicchio, Emilio; Levy, Ronald M

2016-09-01

We describe binding free energy calculations in the D3R Grand Challenge 2015 for blind prediction of the binding affinities of 180 ligands to Hsp90. The present D3R challenge was built around experimental datasets involving Heat shock protein (Hsp) 90, an ATP-dependent molecular chaperone which is an important anticancer drug target. The Hsp90 ATP binding site is known to be a challenging target for accurate calculations of ligand binding affinities because of the ligand-dependent conformational changes in the binding site, the presence of ordered waters and the broad chemical diversity of ligands that can bind at this site. Our primary focus here is to distinguish binders from nonbinders. Large scale absolute binding free energy calculations that cover over 3000 protein-ligand complexes were performed using the BEDAM method starting from docked structures generated by Glide docking. Although the ligand dataset in this study resembles an intermediate to late stage lead optimization project while the BEDAM method is mainly developed for early stage virtual screening of hit molecules, the BEDAM binding free energy scoring has resulted in a moderate enrichment of ligand screening against this challenging drug target. Results show that, using a statistical mechanics based free energy method like BEDAM starting from docked poses offers better enrichment than classical docking scoring functions and rescoring methods like Prime MM-GBSA for the Hsp90 data set in this blind challenge. Importantly, among the three methods tested here, only the mean value of the BEDAM binding free energy scores is able to separate the large group of binders from the small group of nonbinders with a gap of 2.4 kcal/mol. None of the three methods that we have tested provided accurate ranking of the affinities of the 147 active compounds. We discuss the possible sources of errors in the binding free energy calculations. The study suggests that BEDAM can be used strategically to discriminate binders from nonbinders in virtual screening and to more accurately predict the ligand binding modes prior to the more computationally expensive FEP calculations of binding affinity.

Large scale free energy calculations for blind predictions of protein-ligand binding: the D3R Grand Challenge 2015

NASA Astrophysics Data System (ADS)

Deng, Nanjie; Flynn, William F.; Xia, Junchao; Vijayan, R. S. K.; Zhang, Baofeng; He, Peng; Mentes, Ahmet; Gallicchio, Emilio; Levy, Ronald M.

2016-09-01

We describe binding free energy calculations in the D3R Grand Challenge 2015 for blind prediction of the binding affinities of 180 ligands to Hsp90. The present D3R challenge was built around experimental datasets involving Heat shock protein (Hsp) 90, an ATP-dependent molecular chaperone which is an important anticancer drug target. The Hsp90 ATP binding site is known to be a challenging target for accurate calculations of ligand binding affinities because of the ligand-dependent conformational changes in the binding site, the presence of ordered waters and the broad chemical diversity of ligands that can bind at this site. Our primary focus here is to distinguish binders from nonbinders. Large scale absolute binding free energy calculations that cover over 3000 protein-ligand complexes were performed using the BEDAM method starting from docked structures generated by Glide docking. Although the ligand dataset in this study resembles an intermediate to late stage lead optimization project while the BEDAM method is mainly developed for early stage virtual screening of hit molecules, the BEDAM binding free energy scoring has resulted in a moderate enrichment of ligand screening against this challenging drug target. Results show that, using a statistical mechanics based free energy method like BEDAM starting from docked poses offers better enrichment than classical docking scoring functions and rescoring methods like Prime MM-GBSA for the Hsp90 data set in this blind challenge. Importantly, among the three methods tested here, only the mean value of the BEDAM binding free energy scores is able to separate the large group of binders from the small group of nonbinders with a gap of 2.4 kcal/mol. None of the three methods that we have tested provided accurate ranking of the affinities of the 147 active compounds. We discuss the possible sources of errors in the binding free energy calculations. The study suggests that BEDAM can be used strategically to discriminate binders from nonbinders in virtual screening and to more accurately predict the ligand binding modes prior to the more computationally expensive FEP calculations of binding affinity.

Effects of the Hydroxyl Group on Phenyl Based Ligand/ERRγ Protein Binding

PubMed Central

2015-01-01

Bisphenol-A (4,4′-dihydroxy-2,2-diphenylpropane, BPA, or BPA-A) and its derivatives, when exposed to humans, may affect functions of multiple organs by specific binding to the human estrogen-related receptor γ (ERRγ). We carried out atomistic molecular dynamics (MD) simulations of three ligand compounds including BPA-A, 4-α-cumylphenol (BPA-C), and 2,2-diphenylpropane (BPA-D) binding to the ligand binding domain (LBD) of a human ERRγ to study the structures and energies associated with the binding. We used the implicit Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) method to estimate the free energies of binding for the phenyl based compound/ERRγ systems. The addition of hydroxyl groups to the aromatic ring had only a minor effect on binding structures and a significant effect on ligand/protein binding energy in an aqueous solution. Free binding energies of BPA-D to the ERRγ were found to be considerably less than those of BPA-A and BPA-C to the ERRγ. These results are well correlated with those from experiments where no binding affinities were determined in the BPA-D/ERRγ complex. No conformational change was observed for the helix 12 (H-12) of ERRγ upon binding of these compounds preserving an active transcriptional conformation state. PMID:25098505

Fragmentation cross sections and binding energies of neutron-rich nuclei

NASA Astrophysics Data System (ADS)

Tsang, M. B.; Lynch, W. G.; Friedman, W. A.; Mocko, M.; Sun, Z. Y.; Aoi, N.; Cook, J. M.; Delaunay, F.; Famiano, M. A.; Hui, H.; Imai, N.; Iwasaki, H.; Motobayashi, T.; Niikura, M.; Onishi, T.; Rogers, A. M.; Sakurai, H.; Suzuki, H.; Takeshita, E.; Takeuchi, S.; Wallace, M. S.

2007-10-01

An exponential dependence of the fragmentation cross section on the average binding energy is observed and reproduced with a statistical model. The observed functional dependence is robust and allows the extraction of binding energies from measured cross sections. From the systematics of Cu isotope cross sections, the binding energies of Cu76,77,78,79 have been extracted. They are 636.94±0.4,647.1±0.4,651.6±0.4, and 657.8±0.5 MeV, respectively. Specifically, the uncertainty of the binding energy of Cu75 is reduced from 980 keV, as listed in the 2003 mass table of Audi, Wapstra, and Thibault to 400 keV. The predicted cross sections of two near drip-line nuclei, Na39 and Mg40 from the fragmentation of Ca48 are discussed.

Interactions of solute (3p, 4p, 5p and 6p) with solute, vacancy and divacancy in bcc Fe

NASA Astrophysics Data System (ADS)

You, Yu-Wei; Kong, Xiang-Shan; Wu, Xue-Bang; Liu, Wei; Liu, C. S.; Fang, Q. F.; Chen, J. L.; Luo, G.-N.; Wang, Zhiguang

2014-12-01

Solute-vacancy binding energy is a key quantity in understanding solute diffusion kinetics and phase segregation, and may help choice of alloy compositions for future material design. However, the binding energy of solute with vacancy is notoriously difficult to measure and largely unknown in bcc Fe. With first-principles method, we systemically calculate the binding energies of solute (3p, 4p, 5p and 6p alloying solutes are included) with vacancy, divacancy and solute in bcc Fe. The binding energy of Si with vacancy in the present work is in good consistent with experimental value available. All the solutes considered are able to form stable solute-vacancy, solute-divacancy complexes, and the binding strength of solute-divacancy is about two times larger than that of solute-vacancy. Most solutes could not form stable solute-solute complexes except S, Se, In and Tl. The factors controlling the binding energies are analyzed at last.

Exciton binding energy in GaAsBiN spherical quantum dot heterostructures

NASA Astrophysics Data System (ADS)

Das, Subhasis; Dhar, S.

2017-03-01

The ground state exciton binding energies (EBE) of heavy hole excitons in GaAs1-x-yBixNy - GaAs spherical quantum dots (QD) are calculated using a variational approach under 1s hydrogenic wavefunctions within the framework of effective mass approximation. Both the nitrogen and the bismuth content in the material are found to affect the binding energy, in particular for larger nitrogen content and lower dot radii. Calculations also show that the ground state exciton binding energies of heavy holes increase more at smaller dot sizes as compared to that for the light hole excitons.

Energetics of Glutamate Binding to an Ionotropic Glutamate Receptor.

PubMed

Yu, Alvin; Lau, Albert Y

2017-11-22

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are responsible for the majority of excitatory transmission at the synaptic cleft. Mechanically speaking, agonist binding to the ligand binding domain (LBD) activates the receptor by triggering a conformational change that is transmitted to the transmembrane region, opening the ion channel pore. We use fully atomistic molecular dynamics simulations to investigate the binding process in the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, an iGluR subtype. The string method with swarms of trajectories was applied to calculate the possible pathways glutamate traverses during ligand binding. Residues peripheral to the binding cleft are found to metastably bind the ligand prior to ligand entry into the binding pocket. Umbrella sampling simulations were performed to compute the free energy barriers along the binding pathways. The calculated free energy profiles demonstrate that metastable interactions contribute substantially to the energetics of ligand binding and form local minima in the overall free energy landscape. Protein-ligand interactions at sites outside of the orthosteric agonist-binding site may serve to lower the transition barriers of the binding process.

On the contribution of vibrational anharmonicity to the binding energies of water clusters.

PubMed

Diri, Kadir; Myshakin, Evgeniy M; Jordan, Kenneth D

2005-05-05

The second-order vibrational perturbation theory method has been used together with the B3LYP and MP2 electronic structure methods to investigate the effects of anharmonicity on the vibrational zero-point energy (ZPE) contributions to the binding energies of (H2O)n, n = 2-6, clusters. For the low-lying isomers of (H2O)6, the anharmonicity correction to the binding energy is calculated to range from -248 to -355 cm(-1). It is also demonstrated that although high-order electron correlation effects are important for the individual vibrational frequencies, they are relatively unimportant for the net ZPE contributions to the binding energies of water clusters.

The positive binding energy envelopes of low-mass helium stars

NASA Astrophysics Data System (ADS)

Hall, Philip D.; Jeffery, C. Simon

2018-04-01

It has been hypothesized that stellar envelopes with positive binding energy may be ejected if the release of recombination energy can be triggered and the calculation of binding energy includes this contribution. The implications of this hypothesis for the evolution of normal hydrogen-rich stars have been investigated, but the implications for helium stars - which may represent mass-transfer or merger remnants in binary star systems - have not. Making a set of model helium stars, we find that those with masses between 0.9 and 2.4 M⊙ evolve to configurations with positive binding energy envelopes. We discuss consequences of the ejection hypothesis for such stars, and possible observational tests of these predictions.

The volume- and surface-binding energies of ice systems containing CO, CO2, and H2O

NASA Technical Reports Server (NTRS)

Sandford, Scott A.; Allamandola, Louis J.

1990-01-01

Laboratory-measured, temperature-dependent sticking efficiencies are presently used to derive the surface-binding energies of CO and CO2 on H2O-rich ices, with a view to determining the condensation and vaporization properties of these systems as well as to the measured energies' implications for both cometary behavior and the evolution of interstellar ices. The molecular volume and the surface binding energies are not found to be necessarily related on the basis of simple nearest-neighbor scaling in surface and bulk sites; this may be due to the physical constraints associated with matrix structure-associated physical constraints, which sometimes dominate the volume-binding energies.

SAAMBE: Webserver to Predict the Charge of Binding Free Energy Caused by Amino Acids Mutations.

PubMed

Petukh, Marharyta; Dai, Luogeng; Alexov, Emil

2016-04-12

Predicting the effect of amino acid substitutions on protein-protein affinity (typically evaluated via the change of protein binding free energy) is important for both understanding the disease-causing mechanism of missense mutations and guiding protein engineering. In addition, researchers are also interested in understanding which energy components are mostly affected by the mutation and how the mutation affects the overall structure of the corresponding protein. Here we report a webserver, the Single Amino Acid Mutation based change in Binding free Energy (SAAMBE) webserver, which addresses the demand for tools for predicting the change of protein binding free energy. SAAMBE is an easy to use webserver, which only requires that a coordinate file be inputted and the user is provided with various, but easy to navigate, options. The user specifies the mutation position, wild type residue and type of mutation to be made. The server predicts the binding free energy change, the changes of the corresponding energy components and provides the energy minimized 3D structure of the wild type and mutant proteins for download. The SAAMBE protocol performance was tested by benchmarking the predictions against over 1300 experimentally determined changes of binding free energy and a Pearson correlation coefficient of 0.62 was obtained. How the predictions can be used for discriminating disease-causing from harmless mutations is discussed. The webserver can be accessed via http://compbio.clemson.edu/saambe_webserver/.

Prediction of Ras-effector interactions using position energy matrices.

PubMed

Kiel, Christina; Serrano, Luis

2007-09-01

One of the more challenging problems in biology is to determine the cellular protein interaction network. Progress has been made to predict protein-protein interactions based on structural information, assuming that structural similar proteins interact in a similar way. In a previous publication, we have determined a genome-wide Ras-effector interaction network based on homology models, with a high accuracy of predicting binding and non-binding domains. However, for a prediction on a genome-wide scale, homology modelling is a time-consuming process. Therefore, we here successfully developed a faster method using position energy matrices, where based on different Ras-effector X-ray template structures, all amino acids in the effector binding domain are sequentially mutated to all other amino acid residues and the effect on binding energy is calculated. Those pre-calculated matrices can then be used to score for binding any Ras or effector sequences. Based on position energy matrices, the sequences of putative Ras-binding domains can be scanned quickly to calculate an energy sum value. By calibrating energy sum values using quantitative experimental binding data, thresholds can be defined and thus non-binding domains can be excluded quickly. Sequences which have energy sum values above this threshold are considered to be potential binding domains, and could be further analysed using homology modelling. This prediction method could be applied to other protein families sharing conserved interaction types, in order to determine in a fast way large scale cellular protein interaction networks. Thus, it could have an important impact on future in silico structural genomics approaches, in particular with regard to increasing structural proteomics efforts, aiming to determine all possible domain folds and interaction types. All matrices are deposited in the ADAN database (http://adan-embl.ibmc.umh.es/). Supplementary data are available at Bioinformatics online.

Free Energy Simulations of Ligand Binding to the Aspartate Transporter GltPh

PubMed Central

Heinzelmann, Germano; Baştuğ, Turgut; Kuyucak, Serdar

2011-01-01

Glutamate/Aspartate transporters cotransport three Na+ and one H+ ions with the substrate and countertransport one K+ ion. The binding sites for the substrate and two Na+ ions have been observed in the crystal structure of the archeal homolog GltPh, while the binding site for the third Na+ ion has been proposed from computational studies and confirmed by experiments. Here we perform detailed free energy simulations of GltPh, giving a comprehensive characterization of the substrate and ion binding sites, and calculating their binding free energies in various configurations. Our results show unequivocally that the substrate binds after the binding of two Na+ ions. They also shed light into Asp/Glu selectivity of GltPh, which is not observed in eukaryotic glutamate transporters. PMID:22098736

Influences of Mutations on the Electrostatic Binding Free Energies of Chloride Ions in Escherichia Coli ClC

PubMed Central

Yu, Tao; Wang, Xiao-Qing; Sang, Jian-Ping; Pan, Chun-Xu; Zou, Xian-Wu; Chen, Tsung-Yu; Zou, Xiaoqin

2012-01-01

Mutations in ClC channel proteins may cause serious functional changes and even diseases. The function of ClC proteins mainly manifests as Cl− transport, which is related to the binding free energies of chloride ions. Therefore, the influence of a mutation on ClC function can be studied by investigating the mutational effect on the binding free energies of chloride ions. The present study provides quantitative and systematic investigations on the influences of residue mutations on the electrostatic binding free energies in Escherichia coli ClC (EcClC) proteins, using all-atom molecular dynamics simulations. It was found that the change of the electrostatic binding free energy decreases linearly with the increase of the residue-chloride ion distance for a mutation. This work reveals how changes in the charge of a mutated residue and in the distance between the mutated residue and the binding site govern the variations in the electrostatic binding free energies, and therefore influence the transport of chloride ions and conduction in EcClC. This work would facilitate our understanding of the mutational effects on transport of chloride ions and functions of ClC proteins, and provide a guideline to estimate which residue mutations will have great influences on ClC functions. PMID:22612693

Free energy landscape for the binding process of Huperzine A to acetylcholinesterase

PubMed Central

Bai, Fang; Xu, Yechun; Chen, Jing; Liu, Qiufeng; Gu, Junfeng; Wang, Xicheng; Ma, Jianpeng; Li, Honglin; Onuchic, José N.; Jiang, Hualiang

2013-01-01

Drug-target residence time (t = 1/koff, where koff is the dissociation rate constant) has become an important index in discovering better- or best-in-class drugs. However, little effort has been dedicated to developing computational methods that can accurately predict this kinetic parameter or related parameters, koff and activation free energy of dissociation (). In this paper, energy landscape theory that has been developed to understand protein folding and function is extended to develop a generally applicable computational framework that is able to construct a complete ligand-target binding free energy landscape. This enables both the binding affinity and the binding kinetics to be accurately estimated. We applied this method to simulate the binding event of the anti-Alzheimer’s disease drug (−)−Huperzine A to its target acetylcholinesterase (AChE). The computational results are in excellent agreement with our concurrent experimental measurements. All of the predicted values of binding free energy and activation free energies of association and dissociation deviate from the experimental data only by less than 1 kcal/mol. The method also provides atomic resolution information for the (−)−Huperzine A binding pathway, which may be useful in designing more potent AChE inhibitors. We expect this methodology to be widely applicable to drug discovery and development. PMID:23440190

Free energy landscape for the binding process of Huperzine A to acetylcholinesterase.

PubMed

Bai, Fang; Xu, Yechun; Chen, Jing; Liu, Qiufeng; Gu, Junfeng; Wang, Xicheng; Ma, Jianpeng; Li, Honglin; Onuchic, José N; Jiang, Hualiang

2013-03-12

Drug-target residence time (t = 1/k(off), where k(off) is the dissociation rate constant) has become an important index in discovering better- or best-in-class drugs. However, little effort has been dedicated to developing computational methods that can accurately predict this kinetic parameter or related parameters, k(off) and activation free energy of dissociation (ΔG(off)≠). In this paper, energy landscape theory that has been developed to understand protein folding and function is extended to develop a generally applicable computational framework that is able to construct a complete ligand-target binding free energy landscape. This enables both the binding affinity and the binding kinetics to be accurately estimated. We applied this method to simulate the binding event of the anti-Alzheimer's disease drug (-)-Huperzine A to its target acetylcholinesterase (AChE). The computational results are in excellent agreement with our concurrent experimental measurements. All of the predicted values of binding free energy and activation free energies of association and dissociation deviate from the experimental data only by less than 1 kcal/mol. The method also provides atomic resolution information for the (-)-Huperzine A binding pathway, which may be useful in designing more potent AChE inhibitors. We expect this methodology to be widely applicable to drug discovery and development.

Approximations to complete basis set-extrapolated, highly correlated non-covalent interaction energies.

PubMed

Mackie, Iain D; DiLabio, Gino A

2011-10-07

The first-principles calculation of non-covalent (particularly dispersion) interactions between molecules is a considerable challenge. In this work we studied the binding energies for ten small non-covalently bonded dimers with several combinations of correlation methods (MP2, coupled-cluster single double, coupled-cluster single double (triple) (CCSD(T))), correlation-consistent basis sets (aug-cc-pVXZ, X = D, T, Q), two-point complete basis set energy extrapolations, and counterpoise corrections. For this work, complete basis set results were estimated from averaged counterpoise and non-counterpoise-corrected CCSD(T) binding energies obtained from extrapolations with aug-cc-pVQZ and aug-cc-pVTZ basis sets. It is demonstrated that, in almost all cases, binding energies converge more rapidly to the basis set limit by averaging the counterpoise and non-counterpoise corrected values than by using either counterpoise or non-counterpoise methods alone. Examination of the effect of basis set size and electron correlation shows that the triples contribution to the CCSD(T) binding energies is fairly constant with the basis set size, with a slight underestimation with CCSD(T)∕aug-cc-pVDZ compared to the value at the (estimated) complete basis set limit, and that contributions to the binding energies obtained by MP2 generally overestimate the analogous CCSD(T) contributions. Taking these factors together, we conclude that the binding energies for non-covalently bonded systems can be accurately determined using a composite method that combines CCSD(T)∕aug-cc-pVDZ with energy corrections obtained using basis set extrapolated MP2 (utilizing aug-cc-pVQZ and aug-cc-pVTZ basis sets), if all of the components are obtained by averaging the counterpoise and non-counterpoise energies. With such an approach, binding energies for the set of ten dimers are predicted with a mean absolute deviation of 0.02 kcal/mol, a maximum absolute deviation of 0.05 kcal/mol, and a mean percent absolute deviation of only 1.7%, relative to the (estimated) complete basis set CCSD(T) results. Use of this composite approach to an additional set of eight dimers gave binding energies to within 1% of previously published high-level data. It is also shown that binding within parallel and parallel-crossed conformations of naphthalene dimer is predicted by the composite approach to be 9% greater than that previously reported in the literature. The ability of some recently developed dispersion-corrected density-functional theory methods to predict the binding energies of the set of ten small dimers was also examined. © 2011 American Institute of Physics

A structure-based design of new C2- and C13-substituted taxanes: tubulin binding affinities and extended quantitative structure-activity relationships using comparative binding energy (COMBINE) analysis.

PubMed

Coderch, Claire; Tang, Yong; Klett, Javier; Zhang, Shu-En; Ma, Yun-Tao; Shaorong, Wang; Matesanz, Ruth; Pera, Benet; Canales, Angeles; Jiménez-Barbero, Jesús; Morreale, Antonio; Díaz, J Fernando; Fang, Wei-Shuo; Gago, Federico

2013-05-14

Ten novel taxanes bearing modifications at the C2 and C13 positions of the baccatin core have been synthesized and their binding affinities for mammalian tubulin have been experimentally measured. The design strategy was guided by (i) calculation of interaction energy maps with carbon, nitrogen and oxygen probes within the taxane-binding site of β-tubulin, and (ii) the prospective use of a structure-based QSAR (COMBINE) model derived from an earlier series comprising 47 congeneric taxanes. The tubulin-binding affinity displayed by one of the new compounds (CTX63) proved to be higher than that of docetaxel, and an updated COMBINE model provided a good correlation between the experimental binding free energies and a set of weighted residue-based ligand-receptor interaction energies for 54 out of the 57 compounds studied. The remaining three outliers from the original training series have in common a large unfavourable entropic contribution to the binding free energy that we attribute to taxane preorganization in aqueous solution in a conformation different from that compatible with tubulin binding. Support for this proposal was obtained from solution NMR experiments and molecular dynamics simulations in explicit water. Our results shed additional light on the determinants of tubulin-binding affinity for this important class of antitumour agents and pave the way for further rational structural modifications.

Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies

NASA Astrophysics Data System (ADS)

Pang, Yuan-Ping; Kozikowski, Alan P.

1994-12-01

We have performed docking studies with the SYSDOC program on acetylcholinesterase (AChE) to predict the binding sites in AChE of huperzine A (HA), which is a potent and selective, reversible inhibitor of AChE. The unique aspects of our docking studies include the following: (i) Molecular flexibility of the guest and the host is taken into account, which permits both to change their conformations upon binding. (ii) The binding energy is evaluated by a sum of energies of steric, electrostatic and hydrogen bonding interactions. In the energy calculation no grid approximation is used, and all hydrogen atoms of the system are treated explicitly. (iii) The energy of cation-π interactions between the guest and the host, which is important in the binding of AChE, is included in the calculated binding energy. (iv) Docking is performed in all regions of the host's binding cavity. Based on our docking studies and the pharmacological results reported for HA and its analogs, we predict that HA binds to the bottom of the binding cavity of AChE (the gorge) with its ammonium group interacting with Trp84, Phe330, Glu199 and Asp72 (catalytic site). At the the opening of the gorge with its ammonium group partially interacting with Trp279 (peripheral site). At the catalytic site, three partially overlapping subsites of HA were identified which might provide a dynamic view of binding of HA to the catalytic site.

Role of Desolvation in Thermodynamics and Kinetics of Ligand Binding to a Kinase

PubMed Central

2015-01-01

Computer simulations are used to determine the free energy landscape for the binding of the anticancer drug Dasatinib to its src kinase receptor and show that before settling into a free energy basin the ligand must surmount a free energy barrier. An analysis based on using both the ligand-pocket separation and the pocket-water occupancy as reaction coordinates shows that the free energy barrier is a result of the free energy cost for almost complete desolvation of the binding pocket. The simulations further show that the barrier is not a result of the reorganization free energy of the binding pocket. Although a continuum solvent model gives the location of free energy minima, it is not able to reproduce the intermediate free energy barrier. Finally, it is shown that a kinetic model for the on rate constant in which the ligand diffuses up to a doorway state and then surmounts the desolvation free energy barrier is consistent with published microsecond time-scale simulations of the ligand binding kinetics for this system [Shaw, D. E. et al. J. Am. Chem. Soc.2011, 133, 9181−918321545110]. PMID:25516727

Noncovalent Interactions of Tiopronin-Protected Gold Nanoparticles with DNA: Two Methods to Quantify Free Energy of Binding

PubMed Central

Prado-Gotor, R.; Grueso, E.

2014-01-01

The binding of gold nanoparticles capped with N-(2-mercaptopropionyl)glycine (Au@tiopronin) with double-stranded DNA has been investigated and quantified in terms of free energies by using two different approaches. The first approach follows the DNA conformational changes induced by gold nanoparticles using the CD technique. The second methodology consists in the use of pyrene-1-carboxaldehyde as a fluorescent probe. This second procedure implies the determination of the “true” free energy of binding of the probe with DNA, after corrections through solubility measurements. Working at different salt concentrations, the nonelectrostatic and electrostatic components of the binding free energy have been separated. The results obtained revealed that the binding is of nonelectrostatic character, fundamentally. The procedure used in this work could be extended to quantify the binding affinity of other AuNPs/DNA systems. PMID:24587710

Deconvoluting AMP-activated protein kinase (AMPK) adenine nucleotide binding and sensing

PubMed Central

Gu, Xin; Yan, Yan; Novick, Scott J.; Kovach, Amanda; Goswami, Devrishi; Ke, Jiyuan; Tan, M. H. Eileen; Wang, Lili; Li, Xiaodan; de Waal, Parker W.; Webb, Martin R.; Griffin, Patrick R.; Xu, H. Eric

2017-01-01

AMP-activated protein kinase (AMPK) is a central cellular energy sensor that adapts metabolism and growth to the energy state of the cell. AMPK senses the ratio of adenine nucleotides (adenylate energy charge) by competitive binding of AMP, ADP, and ATP to three sites (CBS1, CBS3, and CBS4) in its γ-subunit. Because these three binding sites are functionally interconnected, it remains unclear how nucleotides bind to individual sites, which nucleotides occupy each site under physiological conditions, and how binding to one site affects binding to the other sites. Here, we comprehensively analyze nucleotide binding to wild-type and mutant AMPK protein complexes by quantitative competition assays and by hydrogen-deuterium exchange MS. We also demonstrate that NADPH, in addition to the known AMPK ligand NADH, directly and competitively binds AMPK at the AMP-sensing CBS3 site. Our findings reveal how AMP binding to one site affects the conformation and adenine nucleotide binding at the other two sites and establish CBS3, and not CBS1, as the high affinity exchangeable AMP/ADP/ATP-binding site. We further show that AMP binding at CBS4 increases AMP binding at CBS3 by 2 orders of magnitude and reverses the AMP/ATP preference of CBS3. Together, these results illustrate how the three CBS sites collaborate to enable highly sensitive detection of cellular energy states to maintain the tight ATP homeostastis required for cellular metabolism. PMID:28615457

Fragmentation cross sections and binding energies of neutron-rich nuclei

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

Tsang, M. B.; Lynch, W. G.; Mocko, M.

An exponential dependence of the fragmentation cross section on the average binding energy is observed and reproduced with a statistical model. The observed functional dependence is robust and allows the extraction of binding energies from measured cross sections. From the systematics of Cu isotope cross sections, the binding energies of {sup 76,77,78,79}Cu have been extracted. They are 636.94{+-}0.4,647.1{+-}0.4,651.6{+-}0.4, and 657.8{+-}0.5 MeV, respectively. Specifically, the uncertainty of the binding energy of {sup 75}Cu is reduced from 980 keV, as listed in the 2003 mass table of Audi, Wapstra, and Thibault to 400 keV. The predicted cross sections of two near drip-linemore » nuclei, {sup 39}Na and {sup 40}Mg from the fragmentation of {sup 48}Ca are discussed.« less

Using the fast fourier transform in binding free energy calculations.

PubMed

Nguyen, Trung Hai; Zhou, Huan-Xiang; Minh, David D L

2018-04-30

According to implicit ligand theory, the standard binding free energy is an exponential average of the binding potential of mean force (BPMF), an exponential average of the interaction energy between the unbound ligand ensemble and a rigid receptor. Here, we use the fast Fourier transform (FFT) to efficiently evaluate BPMFs by calculating interaction energies when rigid ligand configurations from the unbound ensemble are discretely translated across rigid receptor conformations. Results for standard binding free energies between T4 lysozyme and 141 small organic molecules are in good agreement with previous alchemical calculations based on (1) a flexible complex ( R≈0.9 for 24 systems) and (2) flexible ligand with multiple rigid receptor configurations ( R≈0.8 for 141 systems). While the FFT is routinely used for molecular docking, to our knowledge this is the first time that the algorithm has been used for rigorous binding free energy calculations. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Universal binding energy relations in metallic adhesion

NASA Technical Reports Server (NTRS)

Ferrante, J.; Smith, J. R.; Rose, J. J.

1984-01-01

Rose, Smith, and Ferrante have discovered scaling relations which map the adhesive binding energy calculated by Ferrante and Smith onto a single universal binding energy curve. These binding energies are calculated for all combinations of Al(111), Zn(0001), Mg(0001), and Na(110) in contact. The scaling involves normalizing the energy by the maximum binding energy and normalizing distances by a suitable combination of Thomas-Fermi screening lengths. Rose et al. have also found that the calculated cohesive energies of K, Ba, Cu, Mo, and Sm scale by similar simple relations, suggesting the universal relation may be more general than for the simple free electron metals for which it was derived. In addition, the scaling length was defined more generally in order to relate it to measurable physical properties. Further this universality can be extended to chemisorption. A simple and yet quite accurate prediction of a zero temperature equation of state (volume as a function of pressure for metals and alloys) is presented. Thermal expansion coefficients and melting temperatures are predicted by simple, analytic expressions, and results compare favorably with experiment for a broad range of metals.

Exciton size and binding energy limitations in one-dimensional organic materials.

PubMed

Kraner, S; Scholz, R; Plasser, F; Koerner, C; Leo, K

2015-12-28

In current organic photovoltaic devices, the loss in energy caused by the charge transfer step necessary for exciton dissociation leads to a low open circuit voltage, being one of the main reasons for rather low power conversion efficiencies. A possible approach to avoid these losses is to tune the exciton binding energy to a value of the order of thermal energy, which would lead to free charges upon absorption of a photon, and therefore increase the power conversion efficiency towards the Shockley-Queisser limit. We determine the size of the excitons for different organic molecules and polymers by time dependent density functional theory calculations. For optically relevant transitions, the exciton size saturates around 0.7 nm for one-dimensional molecules with a size longer than about 4 nm. For the ladder-type polymer poly(benzimidazobenzophenanthroline), we obtain an exciton binding energy of about 0.3 eV, serving as a lower limit of the exciton binding energy for the organic materials investigated. Furthermore, we show that charge transfer transitions increase the exciton size and thus identify possible routes towards a further decrease of the exciton binding energy.

Donor impurity binding energies of coaxial GaAs / Alx Ga1 - x As cylindrical quantum wires in a parallel applied magnetic field

NASA Astrophysics Data System (ADS)

Tshipa, M.; Winkoun, D. P.; Nijegorodov, N.; Masale, M.

2018-04-01

Theoretical investigations are carried out of binding energies of a donor charge assumed to be located exactly at the center of symmetry of two concentric cylindrical quantum wires. The intrinsic confinement potential in the region of the inner cylinder is modeled in any one of the three profiles: simple parabolic, shifted parabolic or the polynomial potential. The potential inside the shell is taken to be a potential step or potential barrier of a finite height. Additional confinement of the charge carriers is due to the vector potential of the axial applied magnetic field. It is found that the binding energies attain maxima in their variations with the radius of the inner cylinder irrespective of the particular intrinsic confinement of the inner cylinder. As the radius of the inner cylinder is increased further, the binding energies corresponding to either the parabolic or the polynomial potentials attain minima at some critical core-radius. Finally, as anticipated, the binding energies increase with the increase of the parallel applied magnetic field. This behaviour of the binding energies is irrespective of the particular electric potential of the nanostructure or its specific dimensions.

BFEE: A User-Friendly Graphical Interface Facilitating Absolute Binding Free-Energy Calculations.

PubMed

Fu, Haohao; Gumbart, James C; Chen, Haochuan; Shao, Xueguang; Cai, Wensheng; Chipot, Christophe

2018-03-26

Quantifying protein-ligand binding has attracted the attention of both theorists and experimentalists for decades. Many methods for estimating binding free energies in silico have been reported in recent years. Proper use of the proposed strategies requires, however, adequate knowledge of the protein-ligand complex, the mathematical background for deriving the underlying theory, and time for setting up the simulations, bookkeeping, and postprocessing. Here, to minimize human intervention, we propose a toolkit aimed at facilitating the accurate estimation of standard binding free energies using a geometrical route, coined the binding free-energy estimator (BFEE), and introduced it as a plug-in of the popular visualization program VMD. Benefitting from recent developments in new collective variables, BFEE can be used to generate the simulation input files, based solely on the structure of the complex. Once the simulations are completed, BFEE can also be utilized to perform the post-treatment of the free-energy calculations, allowing the absolute binding free energy to be estimated directly from the one-dimensional potentials of mean force in simulation outputs. The minimal amount of human intervention required during the whole process combined with the ergonomic graphical interface makes BFEE a very effective and practical tool for the end-user.

First-principles study of the binding energy between nanostructures and its scaling with system size

NASA Astrophysics Data System (ADS)

Tao, Jianmin; Jiao, Yang; Mo, Yuxiang; Yang, Zeng-Hui; Zhu, Jian-Xin; Hyldgaard, Per; Perdew, John P.

2018-04-01

The equilibrium van der Waals binding energy is an important factor in the design of materials and devices. However, it presents great computational challenges for materials built up from nanostructures. Here we investigate the binding-energy scaling behavior from first-principles calculations. We show that the equilibrium binding energy per atom between identical nanostructures can scale up or down with nanostructure size, but can be parametrized for large N with an analytical formula (in meV/atom), Eb/N =a +b /N +c /N2+d /N3 , where N is the number of atoms in a nanostructure and a , b , c , and d are fitting parameters, depending on the properties of a nanostructure. The formula is consistent with a finite large-size limit of binding energy per atom. We find that there are two competing factors in the determination of the binding energy: Nonadditivities of van der Waals coefficients and center-to-center distance between nanostructures. To decode the detail, the nonadditivity of the static multipole polarizability is investigated from an accurate spherical-shell model. We find that the higher-order multipole polarizability displays ultrastrong intrinsic nonadditivity, no matter if the dipole polarizability is additive or not.

Toward an Experimental Quantum Chemistry: Exploring a New Energy Partitioning.

PubMed

Rahm, Martin; Hoffmann, Roald

2015-08-19

Following the work of L. C. Allen, this work begins by relating the central chemical concept of electronegativity with the average binding energy of electrons in a system. The average electron binding energy, χ̅, is in principle accessible from experiment, through photoelectron and X-ray spectroscopy. It can also be estimated theoretically. χ̅ has a rigorous and understandable connection to the total energy. That connection defines a new kind of energy decomposition scheme. The changing total energy in a reaction has three primary contributions to it: the average electron binding energy, the nuclear-nuclear repulsion, and multielectron interactions. This partitioning allows one to gain insight into the predominant factors behind a particular energetic preference. We can conclude whether an energy change in a transformation is favored or resisted by collective changes to the binding energy of electrons, the movement of nuclei, or multielectron interactions. For example, in the classical formation of H2 from atoms, orbital interactions dominate nearly canceling nuclear-nuclear repulsion and two-electron interactions. While in electron attachment to an H atom, the multielectron interactions drive the reaction. Looking at the balance of average electron binding energy, multielectron, and nuclear-nuclear contributions one can judge when more traditional electronegativity arguments can be justifiably invoked in the rationalization of a particular chemical event.

Atomic Mass and Nuclear Binding Energy for I-131 (Iodine)

NASA Astrophysics Data System (ADS)

Sukhoruchkin, S. I.; Soroko, Z. N.

This document is part of the Supplement containing the complete sets of data of Subvolume A `Nuclei with Z = 1 - 54' of Volume 22 `Nuclear Binding Energies and Atomic Masses' of Landolt-Börnstein - Group I `Elementary Particles, Nuclei and Atoms'. It provides atomic mass, mass excess, nuclear binding energy, nucleon separation energies, Q-values, and nucleon residual interaction parameters for atomic nuclei of the isotope I-131 (Iodine, atomic number Z = 53, mass number A = 131).

Atomic Mass and Nuclear Binding Energy for F-22 (Fluorine)

NASA Astrophysics Data System (ADS)

Sukhoruchkin, S. I.; Soroko, Z. N.

This document is part of the Supplement containing the complete sets of data of Subvolume A `Nuclei with Z = 1 - 54' of Volume 22 `Nuclear Binding Energies and Atomic Masses' of Landolt-Börnstein - Group I `Elementary Particles, Nuclei and Atoms'. It provides atomic mass, mass excess, nuclear binding energy, nucleon separation energies, Q-values, and nucleon residual interaction parameters for atomic nuclei of the isotope F-22 (Fluorine, atomic number Z = 9, mass number A = 22).

Predicting relative binding affinities of non-peptide HIV protease inhibitors with free energy perturbation calculations

NASA Astrophysics Data System (ADS)

McCarrick, Margaret A.; Kollman, Peter A.

1999-03-01

The relative binding free energies in HIV protease of haloperidol thioketal (THK) and three of its derivatives were examined with free energy calculations. THK is a weak inhibitor (IC50 = 15 μM) for which two cocrystal structures with HIV type 1 proteases have been solved [Rutenber, E. et al., J. Biol. Chem., 268 (1993) 15343]. A THK derivative with a phenyl group on C2 of the piperidine ring was expected to be a poor inhibitor based on experiments with haloperidol ketal and its 2- phenyl derivative (Caldera, P., personal communication). Our calculations predict that a 5-phenyl THK derivative, suggested based on examination of the crystal structure, will bind significantly better than THK. Although there are large error bars as estimated from hysteresis, the calculations predict that the 5-phenyl substituent is clearly favored over the 2-phenyl derivative as well as the parent compound. The unfavorable free energies of solvation of both phenyl THK derivatives relative to the parent compound contributed to their predicted binding free energies. In a third simulation, the change in binding free energy for 5-benzyl THK relative to THK was calculated. Although this derivative has a lower free energy in the protein, its decreased free energy of solvation increases the predicted ΔΔG(bind) to the same range as that of the 2-phenyl derivative.

Accurate determination of the binding energy of the formic acid dimer: The importance of geometry relaxation

NASA Astrophysics Data System (ADS)

Kalescky, Robert; Kraka, Elfi; Cremer, Dieter

2014-02-01

The formic acid dimer in its C2h-symmetrical cyclic form is stabilized by two equivalent H-bonds. The currently accepted interaction energy is 18.75 kcal/mol whereas the experimental binding energy D0 value is only 14.22 ±0.12 kcal/mol [F. Kollipost, R. W. Larsen, A. V. Domanskaya, M. Nörenberg, and M. A. Suhm, J. Chem. Phys. 136, 151101 (2012)]. Calculation of the binding energies De and D0 at the CCSD(T) (Coupled Cluster with Single and Double excitations and perturbative Triple excitations)/CBS (Complete Basis Set) level of theory, utilizing CCSD(T)/CBS geometries and the frequencies of the dimer and monomer, reveals that there is a 3.2 kcal/mol difference between interaction energy and binding energy De, which results from (i) not relaxing the geometry of the monomers upon dissociation of the dimer and (ii) approximating CCSD(T) correlation effects with MP2. The most accurate CCSD(T)/CBS values obtained in this work are De = 15.55 and D0 = 14.32 kcal/mol where the latter binding energy differs from the experimental value by 0.1 kcal/mol. The necessity of employing augmented VQZ and VPZ calculations and relaxing monomer geometries of H-bonded complexes upon dissociation to obtain reliable binding energies is emphasized.

Virtual screening of integrase inhibitors by large scale binding free energy calculations: the SAMPL4 challenge

PubMed Central

Gallicchio, Emilio; Deng, Nanjie; He, Peng; Wickstrom, Lauren; Perryman, Alexander L.; Santiago, Daniel N.; Forli, Stefano; Olson, Arthur J.; Levy, Ronald M.

2014-01-01

As part of the SAMPL4 blind challenge, filtered AutoDock Vina ligand docking predictions and large scale binding energy distribution analysis method binding free energy calculations have been applied to the virtual screening of a focused library of candidate binders to the LEDGF site of the HIV integrase protein. The computational protocol leveraged docking and high level atomistic models to improve enrichment. The enrichment factor of our blind predictions ranked best among all of the computational submissions, and second best overall. This work represents to our knowledge the first example of the application of an all-atom physics-based binding free energy model to large scale virtual screening. A total of 285 parallel Hamiltonian replica exchange molecular dynamics absolute protein-ligand binding free energy simulations were conducted starting from docked poses. The setup of the simulations was fully automated, calculations were distributed on multiple computing resources and were completed in a 6-weeks period. The accuracy of the docked poses and the inclusion of intramolecular strain and entropic losses in the binding free energy estimates were the major factors behind the success of the method. Lack of sufficient time and computing resources to investigate additional protonation states of the ligands was a major cause of mispredictions. The experiment demonstrated the applicability of binding free energy modeling to improve hit rates in challenging virtual screening of focused ligand libraries during lead optimization. PMID:24504704

The Universal Statistical Distributions of the Affinity, Equilibrium Constants, Kinetics and Specificity in Biomolecular Recognition

PubMed Central

Zheng, Xiliang; Wang, Jin

2015-01-01

We uncovered the universal statistical laws for the biomolecular recognition/binding process. We quantified the statistical energy landscapes for binding, from which we can characterize the distributions of the binding free energy (affinity), the equilibrium constants, the kinetics and the specificity by exploring the different ligands binding with a particular receptor. The results of the analytical studies are confirmed by the microscopic flexible docking simulations. The distribution of binding affinity is Gaussian around the mean and becomes exponential near the tail. The equilibrium constants of the binding follow a log-normal distribution around the mean and a power law distribution in the tail. The intrinsic specificity for biomolecular recognition measures the degree of discrimination of native versus non-native binding and the optimization of which becomes the maximization of the ratio of the free energy gap between the native state and the average of non-native states versus the roughness measured by the variance of the free energy landscape around its mean. The intrinsic specificity obeys a Gaussian distribution near the mean and an exponential distribution near the tail. Furthermore, the kinetics of binding follows a log-normal distribution near the mean and a power law distribution at the tail. Our study provides new insights into the statistical nature of thermodynamics, kinetics and function from different ligands binding with a specific receptor or equivalently specific ligand binding with different receptors. The elucidation of distributions of the kinetics and free energy has guiding roles in studying biomolecular recognition and function through small-molecule evolution and chemical genetics. PMID:25885453

Accurate Binding Free Energy Predictions in Fragment Optimization.

PubMed

Steinbrecher, Thomas B; Dahlgren, Markus; Cappel, Daniel; Lin, Teng; Wang, Lingle; Krilov, Goran; Abel, Robert; Friesner, Richard; Sherman, Woody

2015-11-23

Predicting protein-ligand binding free energies is a central aim of computational structure-based drug design (SBDD)--improved accuracy in binding free energy predictions could significantly reduce costs and accelerate project timelines in lead discovery and optimization. The recent development and validation of advanced free energy calculation methods represents a major step toward this goal. Accurately predicting the relative binding free energy changes of modifications to ligands is especially valuable in the field of fragment-based drug design, since fragment screens tend to deliver initial hits of low binding affinity that require multiple rounds of synthesis to gain the requisite potency for a project. In this study, we show that a free energy perturbation protocol, FEP+, which was previously validated on drug-like lead compounds, is suitable for the calculation of relative binding strengths of fragment-sized compounds as well. We study several pharmaceutically relevant targets with a total of more than 90 fragments and find that the FEP+ methodology, which uses explicit solvent molecular dynamics and physics-based scoring with no parameters adjusted, can accurately predict relative fragment binding affinities. The calculations afford R(2)-values on average greater than 0.5 compared to experimental data and RMS errors of ca. 1.1 kcal/mol overall, demonstrating significant improvements over the docking and MM-GBSA methods tested in this work and indicating that FEP+ has the requisite predictive power to impact fragment-based affinity optimization projects.

Exploring the Origin of Differential Binding Affinities of Human Tubulin Isotypes αβII, αβIII and αβIV for DAMA-Colchicine Using Homology Modelling, Molecular Docking and Molecular Dynamics Simulations

PubMed Central

Panda, Dulal; Kunwar, Ambarish

2016-01-01

Tubulin isotypes are found to play an important role in regulating microtubule dynamics. The isotype composition is also thought to contribute in the development of drug resistance as tubulin isotypes show differential binding affinities for various anti-cancer agents. Tubulin isotypes αβII, αβIII and αβIV show differential binding affinity for colchicine. However, the origin of differential binding affinity is not well understood at the molecular level. Here, we investigate the origin of differential binding affinity of a colchicine analogue N-deacetyl-N-(2-mercaptoacetyl)-colchicine (DAMA-colchicine) for human αβII, αβIII and αβIV isotypes, employing sequence analysis, homology modeling, molecular docking, molecular dynamics simulation and MM-GBSA binding free energy calculations. The sequence analysis study shows that the residue compositions are different in the colchicine binding pocket of αβII and αβIII, whereas no such difference is present in αβIV tubulin isotypes. Further, the molecular docking and molecular dynamics simulations results show that residue differences present at the colchicine binding pocket weaken the bonding interactions and the correct binding of DAMA-colchicine at the interface of αβII and αβIII tubulin isotypes. Post molecular dynamics simulation analysis suggests that these residue variations affect the structure and dynamics of αβII and αβIII tubulin isotypes, which in turn affect the binding of DAMA-colchicine. Further, the binding free-energy calculation shows that αβIV tubulin isotype has the highest binding free-energy and αβIII has the lowest binding free-energy for DAMA-colchicine. The order of binding free-energy for DAMA-colchicine is αβIV ≃ αβII >> αβIII. Thus, our computational approaches provide an insight into the effect of residue variations on differential binding of αβII, αβIII and αβIV tubulin isotypes with DAMA-colchicine and may help to design new analogues with higher binding affinities for tubulin isotypes. PMID:27227832

Exciton Binding Energy of Monolayer WS2

PubMed Central

Zhu, Bairen; Chen, Xi; Cui, Xiaodong

2015-01-01

The optical properties of monolayer transition metal dichalcogenides (TMDC) feature prominent excitonic natures. Here we report an experimental approach to measuring the exciton binding energy of monolayer WS2 with linear differential transmission spectroscopy and two-photon photoluminescence excitation spectroscopy (TP-PLE). TP-PLE measurements show the exciton binding energy of 0.71 ± 0.01 eV around K valley in the Brillouin zone. PMID:25783023

A computational analysis of the binding model of MDM2 with inhibitors

NASA Astrophysics Data System (ADS)

Hu, Guodong; Wang, Dunyou; Liu, Xinguo; Zhang, Qinggang

2010-08-01

It is a new and promising strategy for anticancer drug design to block the MDM2-p53 interaction using a non-peptide small-molecule inhibitor. We carry out molecular dynamics simulations to study the binding of a set of six non-peptide small-molecule inhibitors with the MDM2. The relative binding free energies calculated using molecular mechanics Poisson-Boltzmann surface area method produce a good correlation with experimentally determined results. The study shows that the van der Waals energies are the largest component of the binding free energy for each complex, which indicates that the affinities of these inhibitors for MDM2 are dominated by shape complementarity. The A-ligands and the B-ligands are the same except for the conformation of 2,2-dimethylbutane group. The quantum mechanics and the binding free energies calculation also show the B-ligands are the more possible conformation of ligands. Detailed binding free energies between inhibitors and individual protein residues are calculated to provide insights into the inhibitor-protein binding model through interpretation of the structural and energetic results from the simulations. The study shows that G1, G2 and G3 group mimic the Phe19, Trp23 and Leu26 residues in p53 and their interactions with MDM2, but the binding model of G4 group differs from the original design strategy to mimic Leu22 residue in p53.

Resolving the problem of trapped water in binding cavities: prediction of host-guest binding free energies in the SAMPL5 challenge by funnel metadynamics

NASA Astrophysics Data System (ADS)

Bhakat, Soumendranath; Söderhjelm, Pär

2017-01-01

The funnel metadynamics method enables rigorous calculation of the potential of mean force along an arbitrary binding path and thereby evaluation of the absolute binding free energy. A problem of such physical paths is that the mechanism characterizing the binding process is not always obvious. In particular, it might involve reorganization of the solvent in the binding site, which is not easily captured with a few geometrically defined collective variables that can be used for biasing. In this paper, we propose and test a simple method to resolve this trapped-water problem by dividing the process into an artificial host-desolvation step and an actual binding step. We show that, under certain circumstances, the contribution from the desolvation step can be calculated without introducing further statistical errors. We apply the method to the problem of predicting host-guest binding free energies in the SAMPL5 blind challenge, using two octa-acid hosts and six guest molecules. For one of the hosts, well-converged results are obtained and the prediction of relative binding free energies is the best among all the SAMPL5 submissions. For the other host, which has a narrower binding pocket, the statistical uncertainties are slightly higher; longer simulations would therefore be needed to obtain conclusive results.

Energy Fluctuations Shape Free Energy of Nonspecific Biomolecular Interactions

NASA Astrophysics Data System (ADS)

Elkin, Michael; Andre, Ingemar; Lukatsky, David B.

2012-01-01

Understanding design principles of biomolecular recognition is a key question of molecular biology. Yet the enormous complexity and diversity of biological molecules hamper the efforts to gain a predictive ability for the free energy of protein-protein, protein-DNA, and protein-RNA binding. Here, using a variant of the Derrida model, we predict that for a large class of biomolecular interactions, it is possible to accurately estimate the relative free energy of binding based on the fluctuation properties of their energy spectra, even if a finite number of the energy levels is known. We show that the free energy of the system possessing a wider binding energy spectrum is almost surely lower compared with the system possessing a narrower energy spectrum. Our predictions imply that low-affinity binding scores, usually wasted in protein-protein and protein-DNA docking algorithms, can be efficiently utilized to compute the free energy. Using the results of Rosetta docking simulations of protein-protein interactions from Andre et al. (Proc. Natl. Acad. Sci. USA 105:16148, 2008), we demonstrate the power of our predictions.

Independent-Trajectory Thermodynamic Integration: a practical guide to protein-drug binding free energy calculations using distributed computing.

PubMed

Lawrenz, Morgan; Baron, Riccardo; Wang, Yi; McCammon, J Andrew

2012-01-01

The Independent-Trajectory Thermodynamic Integration (IT-TI) approach for free energy calculation with distributed computing is described. IT-TI utilizes diverse conformational sampling obtained from multiple, independent simulations to obtain more reliable free energy estimates compared to single TI predictions. The latter may significantly under- or over-estimate the binding free energy due to finite sampling. We exemplify the advantages of the IT-TI approach using two distinct cases of protein-ligand binding. In both cases, IT-TI yields distributions of absolute binding free energy estimates that are remarkably centered on the target experimental values. Alternative protocols for the practical and general application of IT-TI calculations are investigated. We highlight a protocol that maximizes predictive power and computational efficiency.

Binding free energy prediction in strongly hydrophobic biomolecular systems.

PubMed

Charlier, Landry; Nespoulous, Claude; Fiorucci, Sébastien; Antonczak, Serge; Golebiowski, Jérome

2007-11-21

We present a comparison of various computational approaches aiming at predicting the binding free energy in ligand-protein systems where the ligand is located within a highly hydrophobic cavity. The relative binding free energy between similar ligands is obtained by means of the thermodynamic integration (TI) method and compared to experimental data obtained through isothermal titration calorimetry measurements. The absolute free energy of binding prediction was obtained on a similar system (a pyrazine derivative bound to a lipocalin) by TI, potential of mean force (PMF) and also by means of the MMPBSA protocols. Although the TI protocol performs poorly either with an explicit or an implicit solvation scheme, the PMF calculation using an implicit solvation scheme leads to encouraging results, with a prediction of the binding affinity being 2 kcal mol(-1) lower than the experimental value. The use of an implicit solvation scheme appears to be well suited for the study of such hydrophobic systems, due to the lack of water molecules within the binding site.

Using docking and alchemical free energy approach to determine the binding mechanism of eEF2K inhibitors and prioritizing the compound synthesis.

PubMed

Wang, Qiantao; Edupuganti, Ramakrishna; Tavares, Clint D J; Dalby, Kevin N; Ren, Pengyu

2015-01-01

A-484954 is a known eEF2K inhibitor with submicromolar IC50 potency. However, the binding mechanism and the crystal structure of the kinase remains unknown. Here, we employ a homology eEF2K model, docking and alchemical free energy simulations to probe the binding mechanism of eEF2K, and in turn, guide the optimization of potential lead compounds. The inhibitor was docked into the ATP-binding site of a homology model first. Three different binding poses, hypothesis 1, 2, and 3, were obtained and subsequently applied to molecular dynamics (MD) based alchemical free energy simulations. The calculated relative binding free energy of the analogs of A-484954 using the binding pose of hypothesis 1 show a good correlation with the experimental IC50 values, yielding an r (2) coefficient of 0.96 after removing an outlier (compound 5). Calculations using another two poses show little correlation with experimental data, (r (2) of less than 0.5 with or without removing any outliers). Based on hypothesis 1, the calculated relative free energy suggests that bigger cyclic groups, at R1 e.g., cyclobutyl and cyclopentyl promote more favorable binding than smaller groups, such as cyclopropyl and hydrogen. Moreover, this study also demonstrates the ability of the alchemical free energy approach in combination with docking and homology modeling to prioritize compound synthesis. This can be an effective means of facilitating structure-based drug design when crystal structures are not available.

The feasibility of an efficient drug design method with high-performance computers.

PubMed

Yamashita, Takefumi; Ueda, Akihiko; Mitsui, Takashi; Tomonaga, Atsushi; Matsumoto, Shunji; Kodama, Tatsuhiko; Fujitani, Hideaki

2015-01-01

In this study, we propose a supercomputer-assisted drug design approach involving all-atom molecular dynamics (MD)-based binding free energy prediction after the traditional design/selection step. Because this prediction is more accurate than the empirical binding affinity scoring of the traditional approach, the compounds selected by the MD-based prediction should be better drug candidates. In this study, we discuss the applicability of the new approach using two examples. Although the MD-based binding free energy prediction has a huge computational cost, it is feasible with the latest 10 petaflop-scale computer. The supercomputer-assisted drug design approach also involves two important feedback procedures: The first feedback is generated from the MD-based binding free energy prediction step to the drug design step. While the experimental feedback usually provides binding affinities of tens of compounds at one time, the supercomputer allows us to simultaneously obtain the binding free energies of hundreds of compounds. Because the number of calculated binding free energies is sufficiently large, the compounds can be classified into different categories whose properties will aid in the design of the next generation of drug candidates. The second feedback, which occurs from the experiments to the MD simulations, is important to validate the simulation parameters. To demonstrate this, we compare the binding free energies calculated with various force fields to the experimental ones. The results indicate that the prediction will not be very successful, if we use an inaccurate force field. By improving/validating such simulation parameters, the next prediction can be made more accurate.

Accurate ab initio binding energies of the benzene dimer.

PubMed

Park, Young Choon; Lee, Jae Shin

2006-04-20

Accurate binding energies of the benzene dimer at the T and parallel displaced (PD) configurations were determined using the single- and double-coupled cluster method with perturbative triple correction (CCSD(T)) with correlation-consistent basis sets and an effective basis set extrapolation scheme recently devised. The difference between the estimated CCSD(T) basis set limit electronic binding energies for the T and PD shapes appears to amount to more than 0.3 kcal/mol, indicating the PD shape is a more stable configuration than the T shape for this dimer in the gas phase. This conclusion is further strengthened when a vibrational zero-point correction to the electronic binding energies of this dimer is made, which increases the difference between the two configurations to 0.4-0.5 kcal/mol. The binding energies of 2.4 and 2.8 kcal/mol for the T and PD configurations are in good accord with the previous experimental result from ionization potential measurement.

Binding energy of the donor impurities in GaAs-Ga 1- x Al x As quantum well wires with Morse potential in the presence of electric and magnetic fields

NASA Astrophysics Data System (ADS)

Aciksoz, Esra; Bayrak, Orhan; Soylu, Asim

2016-10-01

The behavior of a donor in the GaAs-Ga1-x Al x As quantum well wire represented by the Morse potential is examined within the framework of the effective-mass approximation. The donor binding energies are numerically calculated for with and without the electric and magnetic fields in order to show their influence on the binding energies. Moreover, how the donor binding energies change for the constant potential parameters (D e, r e, and a) as well as with the different values of the electric and magnetic field strengths is determined. It is found that the donor binding energy is highly dependent on the external electric and magnetic fields as well as parameters of the Morse potential. Project supported by the Turkish Science Research Council (TÜBİTAK) and the Financial Supports from Akdeniz and Nigde Universities.

Exciton size and binding energy limitations in one-dimensional organic materials

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

Kraner, S., E-mail: stefan.kraner@iapp.de; Koerner, C.; Leo, K.

2015-12-28

In current organic photovoltaic devices, the loss in energy caused by the charge transfer step necessary for exciton dissociation leads to a low open circuit voltage, being one of the main reasons for rather low power conversion efficiencies. A possible approach to avoid these losses is to tune the exciton binding energy to a value of the order of thermal energy, which would lead to free charges upon absorption of a photon, and therefore increase the power conversion efficiency towards the Shockley-Queisser limit. We determine the size of the excitons for different organic molecules and polymers by time dependent densitymore » functional theory calculations. For optically relevant transitions, the exciton size saturates around 0.7 nm for one-dimensional molecules with a size longer than about 4 nm. For the ladder-type polymer poly(benzimidazobenzophenanthroline), we obtain an exciton binding energy of about 0.3 eV, serving as a lower limit of the exciton binding energy for the organic materials investigated. Furthermore, we show that charge transfer transitions increase the exciton size and thus identify possible routes towards a further decrease of the exciton binding energy.« less

Computational design of enzyme-ligand binding using a combined energy function and deterministic sequence optimization algorithm.

PubMed

Tian, Ye; Huang, Xiaoqiang; Zhu, Yushan

2015-08-01

Enzyme amino-acid sequences at ligand-binding interfaces are evolutionarily optimized for reactions, and the natural conformation of an enzyme-ligand complex must have a low free energy relative to alternative conformations in native-like or non-native sequences. Based on this assumption, a combined energy function was developed for enzyme design and then evaluated by recapitulating native enzyme sequences at ligand-binding interfaces for 10 enzyme-ligand complexes. In this energy function, the electrostatic interaction between polar or charged atoms at buried interfaces is described by an explicitly orientation-dependent hydrogen-bonding potential and a pairwise-decomposable generalized Born model based on the general side chain in the protein design framework. The energy function is augmented with a pairwise surface-area based hydrophobic contribution for nonpolar atom burial. Using this function, on average, 78% of the amino acids at ligand-binding sites were predicted correctly in the minimum-energy sequences, whereas 84% were predicted correctly in the most-similar sequences, which were selected from the top 20 sequences for each enzyme-ligand complex. Hydrogen bonds at the enzyme-ligand binding interfaces in the 10 complexes were usually recovered with the correct geometries. The binding energies calculated using the combined energy function helped to discriminate the active sequences from a pool of alternative sequences that were generated by repeatedly solving a series of mixed-integer linear programming problems for sequence selection with increasing integer cuts.

Computational scheme for pH-dependent binding free energy calculation with explicit solvent.

PubMed

Lee, Juyong; Miller, Benjamin T; Brooks, Bernard R

2016-01-01

We present a computational scheme to compute the pH-dependence of binding free energy with explicit solvent. Despite the importance of pH, the effect of pH has been generally neglected in binding free energy calculations because of a lack of accurate methods to model it. To address this limitation, we use a constant-pH methodology to obtain a true ensemble of multiple protonation states of a titratable system at a given pH and analyze the ensemble using the Bennett acceptance ratio (BAR) method. The constant pH method is based on the combination of enveloping distribution sampling (EDS) with the Hamiltonian replica exchange method (HREM), which yields an accurate semi-grand canonical ensemble of a titratable system. By considering the free energy change of constraining multiple protonation states to a single state or releasing a single protonation state to multiple states, the pH dependent binding free energy profile can be obtained. We perform benchmark simulations of a host-guest system: cucurbit[7]uril (CB[7]) and benzimidazole (BZ). BZ experiences a large pKa shift upon complex formation. The pH-dependent binding free energy profiles of the benchmark system are obtained with three different long-range interaction calculation schemes: a cutoff, the particle mesh Ewald (PME), and the isotropic periodic sum (IPS) method. Our scheme captures the pH-dependent behavior of binding free energy successfully. Absolute binding free energy values obtained with the PME and IPS methods are consistent, while cutoff method results are off by 2 kcal mol(-1) . We also discuss the characteristics of three long-range interaction calculation methods for constant-pH simulations. © 2015 The Protein Society.

Investigation of naphthofuran moiety as potential dual inhibitor against BACE-1 and GSK-3β: molecular dynamics simulations, binding energy, and network analysis to identify first-in-class dual inhibitors against Alzheimer's disease.

PubMed

Kumar, Akhil; Srivastava, Gaurava; Srivastava, Swati; Verma, Seema; Negi, Arvind S; Sharma, Ashok

2017-08-01

BACE-1 and GSK-3β are potential therapeutic drug targets for Alzheimer's disease. Recently, both the targets received attention for designing dual inhibitors for Alzheimer's disease. Until now, only two-scaffold triazinone and curcumin have been reported as BACE-1 and GSK-3β dual inhibitors. Docking, molecular dynamics, clustering, binding energy, and network analysis of triazinone derivatives with BACE-1 and GSK-3β was performed to get molecular insight into the first reported dual inhibitor. Further, we designed and evaluated a naphthofuran series for its ability to inhibit BACE-1 and GSK-3β with the computational approaches. Docking study of naphthofuran series showed a good binding affinity towards both the targets. Molecular dynamics, binding energy, and network analysis were performed to compare their binding with the targets and amino acids responsible for binding. Naphthofuran series derivatives showed good interaction within the active site residues of both of the targets. Hydrogen bond occupancy and binding energy suggested strong binding with the targets. Dual-inhibitor binding was mostly governed by the hydrophobic interactions for both of the targets. Per residue energy decomposition and network analysis identified the key residues involved in the binding and inhibiting BACE-1 and GSK-3β. The results indicated that naphthofuran series derivative 11 may be a promising first-in-class dual inhibitor against BACE-1 and GSK-3β. This naphthofuran series may be further explored to design better dual inhibitors. Graphical abstract Naphthofuran derivative as a dual inhibitor for BACE-1 and GSK-3β.

Identification of new 2,5-diketopiperazine derivatives as simultaneous effective inhibitors of αβ-tubulin and BCRP proteins: Molecular docking, Structure-Activity Relationships and virtual consensus docking studies

NASA Astrophysics Data System (ADS)

Fani, Najmeh; Sattarinezhad, Elham; Bordbar, Abdol-Khalegh

2017-06-01

In the first part of this paper, docking method was employed in order to study the binding mechanism of breast cancer resistance protein (BCRP) with a group of previously synthesized TPS-A derivatives which known as potent inhibitors of this protein to get insight into drug binding site of BCRP and to explore structure-activity relationship of these compounds. Molecular docking results showed that most of these compounds bind in the binding site of BCRP at the interface between the membrane and outer environment. In the second part, a group of designed TPS-A derivatives which showed good binding energies in the binding site of αβ-tubulin in the previous study were chosen to study their binding energies in the binding site of BCRP to investigate their simultaneous inhibitory effect on both αβ-tubulin and BCRP. The results showed that all of these compounds bind to the binding site of BCRP with relatively suitable binding energies and therefore could be potential inhibitors of both αβ-tubulin and BCRP proteins. Finally, virtual consensus docking method was utilized with the aim of design of new 2,5-diketopiperazine derivatives with significant inhibitory effect on both αβ-tubulin and BCRP proteins. For this purpose binding energies of a library of 2,5-diketopiperazine derivatives in the binding sites of αβ-tubulin and BCRP was investigated by using AutoDock and AutoDock vina tools. Molecular docking results revealed that a group of 36 compounds among them exhibit strong anti-tubulin and anti-BCRP activity.

Specificity and Affinity Quantification of Flexible Recognition from Underlying Energy Landscape Topography

PubMed Central

Chu, Xiakun; Wang, Jin

2014-01-01

Flexibility in biomolecular recognition is essential and critical for many cellular activities. Flexible recognition often leads to moderate affinity but high specificity, in contradiction with the conventional wisdom that high affinity and high specificity are coupled. Furthermore, quantitative understanding of the role of flexibility in biomolecular recognition is still challenging. Here, we meet the challenge by quantifying the intrinsic biomolecular recognition energy landscapes with and without flexibility through the underlying density of states. We quantified the thermodynamic intrinsic specificity by the topography of the intrinsic binding energy landscape and the kinetic specificity by association rate. We found that the thermodynamic and kinetic specificity are strongly correlated. Furthermore, we found that flexibility decreases binding affinity on one hand, but increases binding specificity on the other hand, and the decreasing or increasing proportion of affinity and specificity are strongly correlated with the degree of flexibility. This shows more (less) flexibility leads to weaker (stronger) coupling between affinity and specificity. Our work provides a theoretical foundation and quantitative explanation of the previous qualitative studies on the relationship among flexibility, affinity and specificity. In addition, we found that the folding energy landscapes are more funneled with binding, indicating that binding helps folding during the recognition. Finally, we demonstrated that the whole binding-folding energy landscapes can be integrated by the rigid binding and isolated folding energy landscapes under weak flexibility. Our results provide a novel way to quantify the affinity and specificity in flexible biomolecular recognition. PMID:25144525

Specificity and affinity quantification of flexible recognition from underlying energy landscape topography.

PubMed

Chu, Xiakun; Wang, Jin

2014-08-01

Flexibility in biomolecular recognition is essential and critical for many cellular activities. Flexible recognition often leads to moderate affinity but high specificity, in contradiction with the conventional wisdom that high affinity and high specificity are coupled. Furthermore, quantitative understanding of the role of flexibility in biomolecular recognition is still challenging. Here, we meet the challenge by quantifying the intrinsic biomolecular recognition energy landscapes with and without flexibility through the underlying density of states. We quantified the thermodynamic intrinsic specificity by the topography of the intrinsic binding energy landscape and the kinetic specificity by association rate. We found that the thermodynamic and kinetic specificity are strongly correlated. Furthermore, we found that flexibility decreases binding affinity on one hand, but increases binding specificity on the other hand, and the decreasing or increasing proportion of affinity and specificity are strongly correlated with the degree of flexibility. This shows more (less) flexibility leads to weaker (stronger) coupling between affinity and specificity. Our work provides a theoretical foundation and quantitative explanation of the previous qualitative studies on the relationship among flexibility, affinity and specificity. In addition, we found that the folding energy landscapes are more funneled with binding, indicating that binding helps folding during the recognition. Finally, we demonstrated that the whole binding-folding energy landscapes can be integrated by the rigid binding and isolated folding energy landscapes under weak flexibility. Our results provide a novel way to quantify the affinity and specificity in flexible biomolecular recognition.

Free energy simulations and MM-PBSA analyses on the affinity and specificity of steroid binding to antiestradiol antibody.

PubMed

Laitinen, Tuomo; Kankare, Jussi A; Peräkylä, Mikael

2004-04-01

Antiestradiol antibody 57-2 binds 17beta-estradiol (E2) with moderately high affinity (K(a) = 5 x 10(8) M(-1)). The structurally related natural estrogens estrone and estriol as well synthetic 17-deoxy-estradiol and 17alpha-estradiol are bound to the antibody with 3.7-4.9 kcal mol(-1) lower binding free energies than E2. Free energy perturbation (FEP) simulations and the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method were applied to investigate the factors responsible for the relatively low cross-reactivity of the antibody with these four steroids, differing from E2 by the substituents of the steroid D-ring. In addition, computational alanine scanning of the binding site residues was carried out with the MM-PBSA method. Both the FEP and MM-PBSA methods reproduced the experimental relative affinities of the five steroids in good agreement with experiment. On the basis of FEP simulations, the number of hydrogen bonds formed between the antibody and steroids, which varied from 0 to 3 in the steroids studied, determined directly the magnitude of the steroid-antibody interaction free energies. One hydrogen bond was calculated to contribute about 3 kcal mol(-1) to the interaction energy. Because the relative binding free energies of estrone (two antibody-steroid hydrogen bonds), estriol (three hydrogen bonds), 17-deoxy-estradiol (no hydrogen bonds), and 17alpha-estradiol (two hydrogen bonds) are close to each other and clearly lower than that of E2 (three hydrogen bonds), the water-steroid interactions lost upon binding to the antibody make an important contribution to the binding free energies. The MM-PBSA calculations showed that the binding of steroids to the antiestradiol antibody is driven by van der Waals interactions, whereas specificity is solely due to electrostatic interactions. In addition, binding of steroids to the antiestradiol antibody 57-2 was compared to the binding to the antiprogesterone antibody DB3 and antitestosterone antibody 3-C4F5, studied earlier with the MM-PBSA method. Copyright 2004 Wiley-Liss, Inc.

Hydrogenic impurity bound polaron in an anisotropic quantum dot

NASA Astrophysics Data System (ADS)

Chen, Shi-Hua

2018-01-01

The effect of the electron-phonon interaction on an electron bound to a hydrogenic impurity in a three-dimensional (3D) anisotropic quantum dot (QD) is studied theoretically. We use the Landau-Pekar variational approach to calculate the binding energy of ground state (GS) and first-excited state (ES) with considering electron-phonon interaction. The expressions of the GS and ES energies under investigation depict a rich variety of dependent relationship with the variational parameters in three different limiting cases. Numerical calculations were performed for ZnSe QDs with different confinement lengths in the xy-plane and the z-direction, respectively. It is illustrated that binding energies of impurity polarons corresponding to each level are larger in small QDs. Furthermore, the contribution to binding energy from phonon is about 15% of the total binding energy.

Atomic Mass and Nuclear Binding Energy for U-287 (Uranium)

NASA Astrophysics Data System (ADS)

Sukhoruchkin, S. I.; Soroko, Z. N.

This document is part of the Supplement containing the complete sets of data of Subvolume B `Nuclei with Z = 55 - 100' of Volume 22 `Nuclear Binding Energies and Atomic Masses' of Landolt-Börnstein - Group I `Elementary Particles, Nuclei and Atoms', and additionally including data for nuclei with Z = 101 - 130. It provides atomic mass, mass excess, nuclear binding energy, nucleon separation energies, Q-values, and nucleon residual interaction parameters for atomic nuclei of the isotope U-287 (Uranium, atomic number Z = 92, mass number A = 287).

Atomic Mass and Nuclear Binding Energy for Ac-212 (Actinium)

NASA Astrophysics Data System (ADS)

Sukhoruchkin, S. I.; Soroko, Z. N.

This document is part of the Supplement containing the complete sets of data of Subvolume B `Nuclei with Z = 55 - 100' of Volume 22 `Nuclear Binding Energies and Atomic Masses' of Landolt-Börnstein - Group I `Elementary Particles, Nuclei and Atoms', and additionally including data for nuclei with Z = 101 - 130. It provides atomic mass, mass excess, nuclear binding energy, nucleon separation energies, Q-values, and nucleon residual interaction parameters for atomic nuclei of the isotope Ac-212 (Actinium, atomic number Z = 89, mass number A = 212).

Interaction Entropy: A New Paradigm for Highly Efficient and Reliable Computation of Protein-Ligand Binding Free Energy.

PubMed

Duan, Lili; Liu, Xiao; Zhang, John Z H

2016-05-04

Efficient and reliable calculation of protein-ligand binding free energy is a grand challenge in computational biology and is of critical importance in drug design and many other molecular recognition problems. The main challenge lies in the calculation of entropic contribution to protein-ligand binding or interaction systems. In this report, we present a new interaction entropy method which is theoretically rigorous, computationally efficient, and numerically reliable for calculating entropic contribution to free energy in protein-ligand binding and other interaction processes. Drastically different from the widely employed but extremely expensive normal mode method for calculating entropy change in protein-ligand binding, the new method calculates the entropic component (interaction entropy or -TΔS) of the binding free energy directly from molecular dynamics simulation without any extra computational cost. Extensive study of over a dozen randomly selected protein-ligand binding systems demonstrated that this interaction entropy method is both computationally efficient and numerically reliable and is vastly superior to the standard normal mode approach. This interaction entropy paradigm introduces a novel and intuitive conceptual understanding of the entropic effect in protein-ligand binding and other general interaction systems as well as a practical method for highly efficient calculation of this effect.

On the atomic-number similarity of the binding energies of electrons in filled shells of elements of the periodic table

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

Karpov, V. Ya.; Shpatakovskaya, G. V., E-mail: shpagalya@yandex.ru

An expression for the binding energies of electrons in the ground state of an atom is derived on the basis of the Bohr–Sommerfeld quantization rule within the Thomas–Fermi model. The validity of this relation for all elements from neon to uranium is tested within a more perfect quantum-mechanical model with and without the inclusion of relativistic effects, as well as with experimental binding energies. As a result, the ordering of electronic levels in filled atomic shells is established, manifested in an approximate atomic-number similarity. It is proposed to use this scaling property to analytically estimate the binding energies of electronsmore » in an arbitrary atom.« less

Ligand deconstruction: Why some fragment binding positions are conserved and others are not.

PubMed

Kozakov, Dima; Hall, David R; Jehle, Stefan; Jehle, Sefan; Luo, Lingqi; Ochiana, Stefan O; Jones, Elizabeth V; Pollastri, Michael; Allen, Karen N; Whitty, Adrian; Vajda, Sandor

2015-05-19

Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots--regions of the protein where interactions with a ligand contribute substantial binding free energy--the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even when other parts of the ligand are removed. This hypothesis is supported by eight case studies. The condition helps identify whether a protein is suitable for FBDD, predicts the size of fragments required for screening, and determines whether a fragment hit can be extended into a higher affinity ligand. Our results show that ligand binding sites can usefully be thought of in terms of an anchor site, which is the top-ranked hot spot and dominates the free energy of binding, surrounded by a number of weaker satellite sites that confer improved affinity and selectivity for a particular ligand and that it is the intrinsic binding potential of the protein surface that determines whether it can serve as a robust binding site for a suitably optimized ligand.

Computational Calorimetry: High-Precision Calculation of Host–Guest Binding Thermodynamics

PubMed Central

2015-01-01

We present a strategy for carrying out high-precision calculations of binding free energy and binding enthalpy values from molecular dynamics simulations with explicit solvent. The approach is used to calculate the thermodynamic profiles for binding of nine small molecule guests to either the cucurbit[7]uril (CB7) or β-cyclodextrin (βCD) host. For these systems, calculations using commodity hardware can yield binding free energy and binding enthalpy values with a precision of ∼0.5 kcal/mol (95% CI) in a matter of days. Crucially, the self-consistency of the approach is established by calculating the binding enthalpy directly, via end point potential energy calculations, and indirectly, via the temperature dependence of the binding free energy, i.e., by the van’t Hoff equation. Excellent agreement between the direct and van’t Hoff methods is demonstrated for both host–guest systems and an ion-pair model system for which particularly well-converged results are attainable. Additionally, we find that hydrogen mass repartitioning allows marked acceleration of the calculations with no discernible cost in precision or accuracy. Finally, we provide guidance for accurately assessing numerical uncertainty of the results in settings where complex correlations in the time series can pose challenges to statistical analysis. The routine nature and high precision of these binding calculations opens the possibility of including measured binding thermodynamics as target data in force field optimization so that simulations may be used to reliably interpret experimental data and guide molecular design. PMID:26523125

The electronic and optical properties of quantum nano-structures

NASA Astrophysics Data System (ADS)

Ham, Heon

In semiconducting quantum nano-structures, the excitonic effects play an important role when we fabricate opto-electronic devices, such as lasers, diodes, detectors, etc. To gain a better understanding of the excitonic effects in quantum nano-structures, we investigated the exciton binding energy, oscillator strength, and linewidth in quantum nano-structures using both the infinite and finite well models. We investigated also the hydrogenic impurity binding energy and the photoionization cross section of the hydrogenic impurity in a spherical quantum dot. In our work, the variational approach is used in all calculations, because the Hamiltonian of the system is not separable, due to the different symmetries of the Coulomb and confining potentials. In the infinite well model of the semiconducting quantum nanostructures, the binding energy of the exciton increases with decreasing width of the potential barriers due to the increase in the effective strength of the Coulomb interaction between the electron and hole. In the finite well model, the exciton binding energy reaches a peak value, and the binding energy decreases with further decrease in the width of the potential barriers. The exciton linewidth in the infinite well model increases with decreasing wire radius, because the scattering rate of the exciton increases with decreasing wire radius. In the finite well model, the exciton linewidth in a cylindrical quantum wire reaches a peak value and the exciton linewidth decreases with further decrease in the wire radius, because the exciton is not well confined at very smaller wire radii. The binding energy of the hydrogenic impurity in a spherical quantum dot has also calculated using both the infinite and the finite well models. The binding energy of the hydrogenic impurity was calculated for on center and off center impurities in the spherical quantum dots. With decreasing radii of the dots, the binding energy of the hydrogenic impurity increases in the infinite well model. The binding energy of the hydrogenic impurity in the finite well model reaches a peak value and decreases with further decrease in the dot radii for both on center and off center impurities. We have calculated the photoionization cross section as a function of the radius and the frequency using both the infinite and finite well models. The photoionizaton cross section has a peak value at a frequency where the photon energy equals the difference between the final and initial state energies of the impurity. The behavior of the cross section with dot radius depends upon the location of the impurity and the polarization of the electromagnetic field.

Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations.

PubMed

Hou, Tingjun; Wang, Junmei; Li, Youyong; Wang, Wei

2011-01-24

The Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) and the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) methods calculate binding free energies for macromolecules by combining molecular mechanics calculations and continuum solvation models. To systematically evaluate the performance of these methods, we report here an extensive study of 59 ligands interacting with six different proteins. First, we explored the effects of the length of the molecular dynamics (MD) simulation, ranging from 400 to 4800 ps, and the solute dielectric constant (1, 2, or 4) on the binding free energies predicted by MM/PBSA. The following three important conclusions could be observed: (1) MD simulation length has an obvious impact on the predictions, and longer MD simulation is not always necessary to achieve better predictions. (2) The predictions are quite sensitive to the solute dielectric constant, and this parameter should be carefully determined according to the characteristics of the protein/ligand binding interface. (3) Conformational entropy often show large fluctuations in MD trajectories, and a large number of snapshots are necessary to achieve stable predictions. Next, we evaluated the accuracy of the binding free energies calculated by three Generalized Born (GB) models. We found that the GB model developed by Onufriev and Case was the most successful model in ranking the binding affinities of the studied inhibitors. Finally, we evaluated the performance of MM/GBSA and MM/PBSA in predicting binding free energies. Our results showed that MM/PBSA performed better in calculating absolute, but not necessarily relative, binding free energies than MM/GBSA. Considering its computational efficiency, MM/GBSA can serve as a powerful tool in drug design, where correct ranking of inhibitors is often emphasized.

Nonbonded interactions in membrane active cyclic biopolymers. IV - Cation dependence

NASA Technical Reports Server (NTRS)

Radhakrishnan, R.; Srinivasan, S.; Prasad, C. V.; Brinda, S. R.; Macelroy, R. D.; Sundaram, K.

1980-01-01

Interactions of valinomycin and form of its analogs in several conformations with the central ions Li(+), Na(+), K(+), Rb(+) and Cs(+) are investigated as part of a study of the specific preference of valinomycin for potassium and the mechanisms of carrier-mediated ion transport across membranes. Ion binding energies and conformational potential energies are calculated taking into account polarization energy formulas and repulsive energy between the central ion and the ligand atoms for conformations representing various stages in ion capture and release for each of the two ring chiralities of valinomycin and its analogs. Results allow the prediction of the chirality and conformation most likely to be observed for a given analog, and may be used to synthesize analogs with a desired rigidity or flexibility. The binding energies with the alkali metal cations are found to decrease with increasing ion size, and to be smaller than the corresponding ion hydration energies. It is pointed out that the observed potassium preference may be explainable in terms of differences between binding and hydration energies. Binding energies are also noted to depend on ligand conformation.

Glycine Hinges with Opposing Actions at the Acetylcholine Receptor-Channel Transmitter Binding SiteS⃞

PubMed Central

Purohit, Prasad

2011-01-01

The extent to which agonists activate synaptic receptor-channels depends on both the intrinsic tendency of the unliganded receptor to open and the amount of agonist binding energy realized in the channel-opening process. We examined mutations of the nicotinic acetylcholine receptor transmitter binding site (α subunit loop B) with regard to both of these parameters. αGly147 is an “activation” hinge where backbone flexibility maintains high values for intrinsic gating, the affinity of the resting conformation for agonists and net ligand binding energy. αGly153 is a “deactivation” hinge that maintains low values for these parameters. αTrp149 (between these two glycines) serves mainly to provide ligand binding energy for gating. We propose that a concerted motion of the two glycine hinges (plus other structural elements at the binding site) positions αTrp149 so that it provides physiologically optimal binding and gating function at the nerve-muscle synapse. PMID:21115636

Atomic and molecular adsorption on Au(111)

DOE PAGES

Santiago-Rodriguez, Yohaselly; Herron, Jeffrey A.; Curet-Arana, Maria C.; ...

2014-05-02

Periodic self-consistent density functional theory (DFT-GGA) calculations were used to study the adsorption of several atomic species, molecular species and molecular fragments on the Au(111) surface with a coverage of 1/4 monolayer (ML). Binding geometries, binding energies, and diffusion barriers were calculated for 27 species. Furthermore, we calculated the surface deformation energy associated with the binding events. The binding strength for all the analyzed species can be ordered as follows: NH 3 < NO < CO < CH 3 < HCO < NH 2 < COOH < OH < HCOO < CNH 2 < H < N < NH

Predicting Binding Free Energy Change Caused by Point Mutations with Knowledge-Modified MM/PBSA Method.

PubMed

Petukh, Marharyta; Li, Minghui; Alexov, Emil

2015-07-01

A new methodology termed Single Amino Acid Mutation based change in Binding free Energy (SAAMBE) was developed to predict the changes of the binding free energy caused by mutations. The method utilizes 3D structures of the corresponding protein-protein complexes and takes advantage of both approaches: sequence- and structure-based methods. The method has two components: a MM/PBSA-based component, and an additional set of statistical terms delivered from statistical investigation of physico-chemical properties of protein complexes. While the approach is rigid body approach and does not explicitly consider plausible conformational changes caused by the binding, the effect of conformational changes, including changes away from binding interface, on electrostatics are mimicked with amino acid specific dielectric constants. This provides significant improvement of SAAMBE predictions as indicated by better match against experimentally determined binding free energy changes over 1300 mutations in 43 proteins. The final benchmarking resulted in a very good agreement with experimental data (correlation coefficient 0.624) while the algorithm being fast enough to allow for large-scale calculations (the average time is less than a minute per mutation).

C60 fullerene binding to DNA

NASA Astrophysics Data System (ADS)

Alshehri, Mansoor H.; Cox, Barry J.; Hill, James M.

2014-09-01

Fullerenes have attracted considerable attention in various areas of science and technology. Owing to their exceptional physical, chemical, and biological properties, they have many applications, particularly in cosmetic and medical products. Using the Lennard-Jones 6-12 potential function and the continuum approximation, which assumes that intermolecular interactions can be approximated by average atomic surface densities, we determine the binding energies of a C60 fullerene with respect to both single-strand and double-strand DNA molecules. We assume that all configurations are in a vacuum and that the C60 fullerene is initially at rest. Double integrals are performed to determine the interaction energy of the system. We find that the C60 fullerene binds to the double-strand DNA molecule, at either the major or minor grooves, with binding energies of -4.7 eV or -2.3 eV, respectively, and that the C60 molecule binds to the single-strand DNA molecule with a binding energy of -1.6 eV. Our results suggest that the C60 molecule is most likely to be linked to the major groove of the dsDNA molecule.

The HSP90 binding mode of a radicicol-like E-oxime from docking, binding free energy estimations, and NMR 15N chemical shifts

PubMed Central

Spichty, Martin; Taly, Antoine; Hagn, Franz; Kessler, Horst; Barluenga, Sofia; Winssinger, Nicolas; Karplus, Martin

2009-01-01

We determine the binding mode of a macrocyclic radicicol-like oxime to yeast HSP90 by combining computer simulations and experimental measurements. We sample the macrocyclic scaffold of the unbound ligand by parallel tempering simulations and dock the most populated conformations to yeast HSP90. Docking poses are then evaluated by the use of binding free energy estimations with the linear interaction energy method. Comparison of QM/MM-calculated NMR chemical shifts with experimental shift data for a selective subset of back-bone 15N provides an additional evaluation criteria. As a last test we check the binding modes against available structure-activity-relationships. We find that the most likely binding mode of the oxime to yeast HSP90 is very similar to the known structure of the radicicol-HSP90 complex. PMID:19482409

Free energy changes and components implicit in the MWC allosteric model for the cooperative oxygen binding of hemoglobin.#

PubMed Central

Bucci, Enrico

2013-01-01

Hill’s plots of oxygen binding isotherms reveal the presence of a transition between two different oxygen affinities at the beginning and end of the isotherm. They correspond to the two conformations anticipated by the MWC model, namely the T and R conformations at the beginning and end of oxygen binding, when the lower affinity of the T form develops into the higher affinity of the R form. The difference between the binding Gibbs free energies changes of the two affinities (ΔGL) is the free energy of binding cooperativity. Notably ΔGL is positive in favor of the T form, that moves to a higher energy level upon oxygen release. Osmotic stress reveals a higher volume/surface ratio of deoxyHb, with a positive ΔGW also in favor of the T form . Increasing protein concentration shifts the isotherms to the right indicating the formation of intermediate polymeric forms. Enthalpy of the intermediates show a strong absorption of heat at the third oxygenation step due to polymers formation with quinary, and above, structures. The disassembly of intermediate polymers releases energy with a negative ΔG that compensates and allow the positivity of ΔGL. High energy polymers are the barrier preventing the relaxation of the T and R conformations into one another. The MWC allosteric model is the best justification of oxygen binding cooperativity . PMID:23710673

Factors driving stable growth of He clusters in W: first-principles study

NASA Astrophysics Data System (ADS)

Feng, Y. J.; Xin, T. Y.; Xu, Q.; Wang, Y. X.

2018-07-01

The evolution of helium (He) bubbles is responsible for the surface morphology variation and subsequent degradation of the properties of plasma-facing materials (PFMs) in nuclear fusion reactors. These severe problems unquestionably trace back to the behavior of He in PFMs, which is closely associated with the interaction between He and the matrix. In this paper, we decomposed the binding energy of the He cluster into three parts, those from W–W, W–He, and He–He interactions, using density functional theory. As a result, we clearly identified the main factors that determine a steplike decrease in the binding energy with increasing number of He atoms, which explains the process of self-trapping and athermal vacancy generation during He cluster growth in the PFM tungsten. The three interactions were found to synergetically shape the features of the steplike decrease in the binding energy. Fairly strong He–He repulsive forces at a short distance, which stem from antibonding states between He atoms, need to be released when additional He atoms are continuously bonded to the He cluster. This causes the steplike feature in the binding energy. The bonding states between W and He atoms in principle facilitate the decreasing trend of the binding energy. The decrease in binding energy with increasing number of He atoms implies that He clusters can grow stably.

Tinker-OpenMM: Absolute and relative alchemical free energies using AMOEBA on GPUs.

PubMed

Harger, Matthew; Li, Daniel; Wang, Zhi; Dalby, Kevin; Lagardère, Louis; Piquemal, Jean-Philip; Ponder, Jay; Ren, Pengyu

2017-09-05

The capabilities of the polarizable force fields for alchemical free energy calculations have been limited by the high computational cost and complexity of the underlying potential energy functions. In this work, we present a GPU-based general alchemical free energy simulation platform for polarizable potential AMOEBA. Tinker-OpenMM, the OpenMM implementation of the AMOEBA simulation engine has been modified to enable both absolute and relative alchemical simulations on GPUs, which leads to a ∼200-fold improvement in simulation speed over a single CPU core. We show that free energy values calculated using this platform agree with the results of Tinker simulations for the hydration of organic compounds and binding of host-guest systems within the statistical errors. In addition to absolute binding, we designed a relative alchemical approach for computing relative binding affinities of ligands to the same host, where a special path was applied to avoid numerical instability due to polarization between the different ligands that bind to the same site. This scheme is general and does not require ligands to have similar scaffolds. We show that relative hydration and binding free energy calculated using this approach match those computed from the absolute free energy approach. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Neutral-atom electron binding energies from relaxed-orbital relativistic Hartree-Fock-Slater calculations for Z between 2 and 106

NASA Technical Reports Server (NTRS)

Huang, K.-N.; Aoyagi, M.; Mark, H.; Chen, M. H.; Crasemann, B.

1976-01-01

Electron binding energies in neutral atoms have been calculated relativistically, with the requirement of complete relaxation. Hartree-Fock-Slater wave functions served as zeroth-order eigenfunctions to compute the expectation of the total Hamiltonian. A first-order correction to the local approximation was thus included. Quantum-electrodynamic corrections were made. For all elements with atomic numbers ranging from 2 to 106, the following quantities are listed: total energies, electron kinetic energies, electron-nucleus potential energies, electron-electron potential energies consisting of electrostatic and Breit interaction (magnetic and retardation) terms, and vacuum polarization energies. Binding energies including relaxation are listed for all electrons in all atoms over the indicated range of atomic numbers. A self-energy correction is included for the 1s, 2s, and 2p(1/2) levels. Results for selected atoms are compared with energies calculated by other methods and with experimental values.

Spatial Analysis and Quantification of the Thermodynamic Driving Forces in Protein-Ligand Binding: Binding Site Variability

PubMed Central

Raman, E. Prabhu; MacKerell, Alexander D.

2015-01-01

The thermodynamic driving forces behind small molecule-protein binding are still not well understood, including the variability of those forces associated with different types of ligands in different binding pockets. To better understand these phenomena we calculate spatially resolved thermodynamic contributions of the different molecular degrees of freedom for the binding of propane and methanol to multiple pockets on the proteins Factor Xa and p38 MAP kinase. Binding thermodynamics are computed using a statistical thermodynamics based end-point method applied on a canonical ensemble comprising the protein-ligand complexes and the corresponding free states in an explicit solvent environment. Energetic and entropic contributions of water and ligand degrees of freedom computed from the configurational ensemble provides an unprecedented level of detail into the mechanisms of binding. Direct protein-ligand interaction energies play a significant role in both non-polar and polar binding, which is comparable to water reorganization energy. Loss of interactions with water upon binding strongly compensates these contributions leading to relatively small binding enthalpies. For both solutes, the entropy of water reorganization is found to favor binding in agreement with the classical view of the “hydrophobic effect”. Depending on the specifics of the binding pocket, both energy-entropy compensation and reinforcement mechanisms are observed. Notable is the ability to visualize the spatial distribution of the thermodynamic contributions to binding at atomic resolution showing significant differences in the thermodynamic contributions of water to the binding of propane versus methanol. PMID:25625202

Relativistic excited state binding energies and RMS radii of Λ-hypernuclei

NASA Astrophysics Data System (ADS)

Nejad, S. Mohammad Moosavi; Armat, A.

2018-02-01

Using an analytical solution for the relativistic equation of single Λ-hypernuclei in the presence of Woods-Saxon (WS) potential we present, for the first time, an analytical form for the excited state binding energies of 1p, 1d, 1f and 1g shells of a number of hypernuclei. Based on phenomenological analysis of the Λ binding energies in a set of Λ-hypernuclei, the WS potential parameters are obtained phenomenologically for the set of Λ-hypernuclei. Systematic study of the energy levels of single Λ-hypernuclei enables us to extract more detailed information about the Λ-nucleon interaction. We also study the root mean square (RMS) radii of the Λ orbits in the hypernuclear ground states. Our results are presented for several hypernuclei and it is shown that our results for the binding energies are in good agreement with experimental data.

Relation between heat of vaporization, ion transport, molar volume, and cation-anion binding energy for ionic liquids.

PubMed

Borodin, Oleg

2009-09-10

A number of correlations between heat of vaporization (H(vap)), cation-anion binding energy (E(+/-)), molar volume (V(m)), self-diffusion coefficient (D), and ionic conductivity for 29 ionic liquids have been investigated using molecular dynamics (MD) simulations that employed accurate and validated many-body polarizable force fields. A significant correlation between D and H(vap) has been found, while the best correlation was found for -log(DV(m)) vs H(vap) + 0.28E(+/-). A combination of enthalpy of vaporization and a fraction of the cation-anion binding energy was suggested as a measure of the effective cohesive energy for ionic liquids. A deviation of some ILs from the reported master curve is explained based upon ion packing and proposed diffusion pathways. No general correlations were found between the ion diffusion coefficient and molecular volume or the diffusion coefficient and cation/anion binding energy.

Theoretical study of the BeLi, BeNa, MgLi, MgNa, and AlBe molecules and their negative ions

NASA Technical Reports Server (NTRS)

Bauschlicher, Charles W., Jr.; Langhoff, Stephen R.; Partridge, Harry

1992-01-01

The alkaline earth-alkali diatomics are found to have weak bonds, because the diffuse alkali valence s orbitals cannot form a bond of sufficient strength to pay the promotion energy of the alkaline-earth atoms. This leads to van der Waals bonding in the neutrals as well as the negative ions. In fact, the negative ions have larger binding energies than the neutrals as a result of the much larger polarizability of the negative ion. The binding energy of AlBe is significantly larger than the Be-alkali molecules, due to a covalent contribution to the bonding. The binding energy in AlBe(-) is considerably larger than AlBe; the binding energy of the X 3Sigma(-) state of AlBe(-) is computed to be 1.36 eV, as compared with 0.57 eV for the X 2Pi state of AlBe.

Binding energies and modelling of nuclei in semiclassical simulations

NASA Astrophysics Data System (ADS)

Pérez-García, M. Ángeles; Tsushima, K.; Valcarce, A.

2008-03-01

We study the binding energies of spin isospin saturated nuclei with nucleon number 8⩽A⩽100 in semiclassical Monte Carlo many-body simulations. The model Hamiltonian consists of (i) nucleon kinetic energy, (ii) a nucleon nucleon interaction potential, and (iii) an effective Pauli potential which depends on density. The basic ingredients of the nucleon nucleon potential are a short-range repulsion, and a medium-range attraction. Our results demonstrate that one can always expect to obtain the empirical binding energies for a set of nuclei by introducing a proper density dependent Pauli potential in terms of a single variable, the nucleon number, A. The present work shows that in the suggested procedure there is a delicate counterbalance of kinetic and potential energetic contributions allowing a good reproduction of the experimental nuclear binding energies. This type of calculations may be of interest in further reproduction of other properties of nuclei such as radii and also exotic nuclei.

Importance of ligand reorganization free energy in protein-ligand binding-affinity prediction.

PubMed

Yang, Chao-Yie; Sun, Haiying; Chen, Jianyong; Nikolovska-Coleska, Zaneta; Wang, Shaomeng

2009-09-30

Accurate prediction of the binding affinities of small-molecule ligands to their biological targets is fundamental for structure-based drug design but remains a very challenging task. In this paper, we have performed computational studies to predict the binding models of 31 small-molecule Smac (the second mitochondria-derived activator of caspase) mimetics to their target, the XIAP (X-linked inhibitor of apoptosis) protein, and their binding affinities. Our results showed that computational docking was able to reliably predict the binding models, as confirmed by experimentally determined crystal structures of some Smac mimetics complexed with XIAP. However, all the computational methods we have tested, including an empirical scoring function, two knowledge-based scoring functions, and MM-GBSA (molecular mechanics and generalized Born surface area), yield poor to modest prediction for binding affinities. The linear correlation coefficient (r(2)) value between the predicted affinities and the experimentally determined affinities was found to be between 0.21 and 0.36. Inclusion of ensemble protein-ligand conformations obtained from molecular dynamic simulations did not significantly improve the prediction. However, major improvement was achieved when the free-energy change for ligands between their free- and bound-states, or "ligand-reorganization free energy", was included in the MM-GBSA calculation, and the r(2) value increased from 0.36 to 0.66. The prediction was validated using 10 additional Smac mimetics designed and evaluated by an independent group. This study demonstrates that ligand reorganization free energy plays an important role in the overall binding free energy between Smac mimetics and XIAP. This term should be evaluated for other ligand-protein systems and included in the development of new scoring functions. To our best knowledge, this is the first computational study to demonstrate the importance of ligand reorganization free energy for the prediction of protein-ligand binding free energy.

Seeking potential anticonvulsant agents that target GABAA receptors using experimental and theoretical procedures

NASA Astrophysics Data System (ADS)

Saavedra-Vélez, Margarita Virginia; Correa-Basurto, José; Matus, Myrna H.; Gasca-Pérez, Eloy; Bello, Martiniano; Cuevas-Hernández, Roberto; García-Rodríguez, Rosa Virginia; Trujillo-Ferrara, José; Ramos-Morales, Fernando Rafael

2014-12-01

The aim of this study was to identify compounds that possess anticonvulsant activity by using a pentylenetetrazol (PTZ)-induced seizure model. Theoretical studies of a set of ligands, explored the binding affinities of the ligands for the GABAA receptor (GABAAR), including some benzodiazepines. The ligands satisfy the Lipinski rules and contain a pharmacophore core that has been previously reported to be a GABAAR activator. To select the ligands with the best physicochemical properties, all of the compounds were analyzed by quantum mechanics and the energies of the highest occupied molecular orbital and lowest unoccupied molecular orbital were determined. Docking calculations between the ligands and the GABAAR were used to identify the complexes with the highest Gibbs binding energies. The identified compound D1 (dibenzo( b,f)(1,4)diazocine-6,11(5H,12H)-dione) was synthesized, experimentally tested, and the GABAAR-D1 complex was submitted to 12-ns-long molecular dynamics (MD) simulations to corroborate the binding conformation obtained by docking techniques. MD simulations were also used to analyze the decomposition of the Gibbs binding energy of the residues involved in the stabilization of the complex. To validate our theoretical results, molecular docking and MD simulations were also performed for three reference compounds that are currently in commercial use: clonazepam (CLZ), zolpidem and eszopiclone. The theoretical results show that the GABAAR-D1, and GABAAR-CLZ complexes bind to the benzodiazepine binding site, share a similar map of binding residues, and have similar Gibbs binding energies and entropic components. Experimental studies using a PTZ-induced seizure model showed that D1 possesses similar activity to CLZ, which corroborates the predicted binding free energy identified by theoretical calculations.

Protein surface roughness accounts for binding free energy of Plasmepsin II-ligand complexes.

PubMed

Valdés-Tresanco, Mario E; Valdés-Tresanco, Mario S; Valiente, Pedro A; Cocho, Germinal; Mansilla, Ricardo; Nieto-Villar, J M

2018-01-01

The calculation of absolute binding affinities for protein-inhibitor complexes remains as one of the main challenges in computational structure-based ligand design. The present work explored the calculations of surface fractal dimension (as a measure of surface roughness) and the relationship with experimental binding free energies of Plasmepsin II complexes. Plasmepsin II is an attractive target for novel therapeutic compounds to treat malaria. However, the structural flexibility of this enzyme is a drawback when searching for specific inhibitors. Concerning that, we performed separate explicitly solvated molecular dynamics simulations using the available high-resolution crystal structures of different Plasmepsin II complexes. Molecular dynamics simulations allowed a better approximation to systems dynamics and, therefore, a more reliable estimation of surface roughness. This constitutes a novel approximation in order to obtain more realistic values of fractal dimension, because previous works considered only x-ray structures. Binding site fractal dimension was calculated considering the ensemble of structures generated at different simulation times. A linear relationship between binding site fractal dimension and experimental binding free energies of the complexes was observed within 20 ns. Previous studies of the subject did not uncover this relationship. Regression model, coined FD model, was built to estimate binding free energies from binding site fractal dimension values. Leave-one-out cross-validation showed that our model reproduced accurately the absolute binding free energies for our training set (R 2  = 0.76; <|error|> =0.55 kcal/mol; SD error  = 0.19 kcal/mol). The fact that such a simple model may be applied raises some questions that are addressed in the article. Copyright © 2017 John Wiley & Sons, Ltd.

Calculating binding free energies for protein-carbohydrate complexes.

PubMed

Hadden, Jodi A; Tessier, Matthew B; Fadda, Elisa; Woods, Robert J

2015-01-01

A variety of computational techniques may be applied to compute theoretical binding free energies for protein-carbohydrate complexes. Elucidation of the intermolecular interactions, as well as the thermodynamic effects, that contribute to the relative strength of receptor binding can shed light on biomolecular recognition, and the resulting initiation or inhibition of a biological process. Three types of free energy methods are discussed here, including MM-PB/GBSA, thermodynamic integration, and a non-equilibrium alternative utilizing SMD. Throughout this chapter, the well-known concanavalin A lectin is employed as a model system to demonstrate the application of these methods to the special case of carbohydrate binding.

Protein-ligand binding free energy estimation using molecular mechanics and continuum electrostatics. Application to HIV-1 protease inhibitors

NASA Astrophysics Data System (ADS)

Zoete, V.; Michielin, O.; Karplus, M.

2003-12-01

A method is proposed for the estimation of absolute binding free energy of interaction between proteins and ligands. Conformational sampling of the protein-ligand complex is performed by molecular dynamics (MD) in vacuo and the solvent effect is calculated a posteriori by solving the Poisson or the Poisson-Boltzmann equation for selected frames of the trajectory. The binding free energy is written as a linear combination of the buried surface upon complexation, SAS bur, the electrostatic interaction energy between the ligand and the protein, Eelec, and the difference of the solvation free energies of the complex and the isolated ligand and protein, ΔGsolv. The method uses the buried surface upon complexation to account for the non-polar contribution to the binding free energy because it is less sensitive to the details of the structure than the van der Waals interaction energy. The parameters of the method are developed for a training set of 16 HIV-1 protease-inhibitor complexes of known 3D structure. A correlation coefficient of 0.91 was obtained with an unsigned mean error of 0.8 kcal/mol. When applied to a set of 25 HIV-1 protease-inhibitor complexes of unknown 3D structures, the method provides a satisfactory correlation between the calculated binding free energy and the experimental pIC 50 without reparametrization.

Effect of binding in cyclic phosphorylation-dephosphorylation process and in energy transformation.

PubMed

Sarkar, A; Beard, D A; Franza, B R

2006-07-01

The effects of binding on the phosphorylation-dephosphorylation cycle (PDPC) - one of the key components of the signal transduction processes - is analyzed based on a mathematical model. The model shows that binding of proteins, forming a complex, diminishes the ultrasensitivity of the PDPC to the differences in activity between kinase and phosphatase in the cycle. It is also found that signal amplification depends upon the strength of the binding affinity of the protein (phosphorylated or dephosphorylated) to other proteins . It is also observed that the amplification of signal is not only dependent on phosphorylation potential but also on binding properties and resulting adjustments in binding energies.

Virtual screening using molecular simulations.

PubMed

Yang, Tianyi; Wu, Johnny C; Yan, Chunli; Wang, Yuanfeng; Luo, Ray; Gonzales, Michael B; Dalby, Kevin N; Ren, Pengyu

2011-06-01

Effective virtual screening relies on our ability to make accurate prediction of protein-ligand binding, which remains a great challenge. In this work, utilizing the molecular-mechanics Poisson-Boltzmann (or Generalized Born) surface area approach, we have evaluated the binding affinity of a set of 156 ligands to seven families of proteins, trypsin β, thrombin α, cyclin-dependent kinase (CDK), cAMP-dependent kinase (PKA), urokinase-type plasminogen activator, β-glucosidase A, and coagulation factor Xa. The effect of protein dielectric constant in the implicit-solvent model on the binding free energy calculation is shown to be important. The statistical correlations between the binding energy calculated from the implicit-solvent approach and experimental free energy are in the range of 0.56-0.79 across all the families. This performance is better than that of typical docking programs especially given that the latter is directly trained using known binding data whereas the molecular mechanics is based on general physical parameters. Estimation of entropic contribution remains the barrier to accurate free energy calculation. We show that the traditional rigid rotor harmonic oscillator approximation is unable to improve the binding free energy prediction. Inclusion of conformational restriction seems to be promising but requires further investigation. On the other hand, our preliminary study suggests that implicit-solvent based alchemical perturbation, which offers explicit sampling of configuration entropy, can be a viable approach to significantly improve the prediction of binding free energy. Overall, the molecular mechanics approach has the potential for medium to high-throughput computational drug discovery. Copyright © 2011 Wiley-Liss, Inc.

Computation of pH-Dependent Binding Free Energies

PubMed Central

Kim, M. Olivia; McCammon, J. Andrew

2015-01-01

Protein-ligand binding accompanies changes in the surrounding electrostatic environments of the two binding partners and may lead to changes in protonation upon binding. In cases where the complex formation results in a net transfer of protons, the binding process is pH-dependent. However, conventional free energy computations or molecular docking protocols typically employ fixed protonation states for the titratable groups in both binding partners set a priori, which are identical for the free and bound states. In this review, we draw attention to these important yet largely ignored binding-induced protonation changes in protein-ligand association by outlining physical origins and prevalence of the protonation changes upon binding. Following a summary of various theoretical methods for pKa prediction, we discuss the theoretical framework to examine the pH dependence of protein-ligand binding processes. PMID:26202905

Computational screening of functional groups for capture of toxic industrial chemicals in porous materials.

PubMed

Kim, Ki Chul; Fairen-Jimenez, David; Snurr, Randall Q

2017-12-06

A thermodynamic analysis using quantum chemical methods was carried out to identify optimal functional group candidates that can be included in metal-organic frameworks and activated carbons for the selective capture of toxic industrial chemicals (TICs) in humid air. We calculated the binding energies of 14 critical TICs plus water with a series of 10 functional groups attached to a naphthalene ring model. Using vibrational calculations, the free energies of adsorption were calculated in addition to the binding energies. Our results show that, in these systems, the binding energies and free energies follow similar trends. We identified copper(i) carboxylate as the optimal functional group (among those studied) for the selective binding of the majority of the TICs in humid air, and this functional group exhibits especially strong binding for sulfuric acid. Further thermodynamic analysis shows that the presence of water weakens the binding strength of sulfuric acid with the copper carboxylate group. Our calculations predict that functionalization of aromatic rings would be detrimental to selective capture of COCl 2 , CO 2 , and Cl 2 under humid conditions. Finally, we found that forming an ionic complex, H 3 O + HSO 4 - , between H 2 SO 4 and H 2 O via proton transfer is not favorable on copper carboxylate.

New measurements of the sticking coefficient and binding energy of molecules on non-porous amorphous solid water in the submonolayer regime

NASA Astrophysics Data System (ADS)

He, Jiao; Acharyya, Kinsuk; Emtiaz, S. M.; Vidali, Gianfranco

2016-06-01

Sticking and adsorption of molecules on dust grains are two important processes in gas-grain interactions. We accurately measured both the sticking coefficient and the binding energy of several key molecules on the surface of amorphous solid water as a function of coverage.A time-resolved scattering technique was used to measure sticking coefficient of H2, D2, N2, O2, CO, CH4, and CO2 on non-porous amorphous solid water (np-ASW) in the low coverage limit over a wide range of surface temperatures. We found that the time-resolved scattering technique is advantageous over the conventional King-Wells method that underestimates the sticking coefficient. Based on the measured values we suggest a useful general formula of the sticking coefficient as a function of grain temperature and molecule-surface binding energy.We measured the binding energy of N2, CO, O2, CH4, and CO2 on np-ASW, and of N2 and CO on porous amorphous solid water (p-ASW). We were able to measure binding energies down to a fraction of 1% of a layer, thus making these measurements more appropriate for astrochemistry than the existing values. We found that CO2 forms clusters on np-ASW surface even at very low coverage; this may help in explaining the segregation of CO2 in ices. The binding energies of N2, CO, O2, and CH4 on np-ASW decrease with coverage in the submonolayer regime. Their values in the low coverage limit are much higher than what is commonly used in gas-grain models. An empirical formula was used to describe the coverage dependence of the binding energies. We used the newly determined binding energy distributions in a simulation of gas-grain chemistry for cold dense clouds and hot core models. We found that owing to the higher value of desorption energy in the sub-monlayer regime a fraction of all these ices stays much longer and to higher temperature on the grain surface compared to the case using single value energies as currently done in astrochemical models.This work was supported in part by a grant to GV from NSF --- Astronomy & Astrophysics Division (#1311958)

Application of binding free energy calculations to prediction of binding modes and affinities of MDM2 and MDMX inhibitors.

PubMed

Lee, Hui Sun; Jo, Sunhwan; Lim, Hyun-Suk; Im, Wonpil

2012-07-23

Molecular docking is widely used to obtain binding modes and binding affinities of a molecule to a given target protein. Despite considerable efforts, however, prediction of both properties by docking remains challenging mainly due to protein's structural flexibility and inaccuracy of scoring functions. Here, an integrated approach has been developed to improve the accuracy of binding mode and affinity prediction and tested for small molecule MDM2 and MDMX antagonists. In this approach, initial candidate models selected from docking are subjected to equilibration MD simulations to further filter the models. Free energy perturbation molecular dynamics (FEP/MD) simulations are then applied to the filtered ligand models to enhance the ability in predicting the near-native ligand conformation. The calculated binding free energies for MDM2 complexes are overestimated compared to experimental measurements mainly due to the difficulties in sampling highly flexible apo-MDM2. Nonetheless, the FEP/MD binding free energy calculations are more promising for discriminating binders from nonbinders than docking scores. In particular, the comparison between the MDM2 and MDMX results suggests that apo-MDMX has lower flexibility than apo-MDM2. In addition, the FEP/MD calculations provide detailed information on the different energetic contributions to ligand binding, leading to a better understanding of the sensitivity and specificity of protein-ligand interactions.

Binding of two-electron metastable states in semiconductor quantum dots under a magnetic field

NASA Astrophysics Data System (ADS)

Garagiola, Mariano; Pont, Federico M.; Osenda, Omar

2018-04-01

Applying a strong enough magnetic field results in the binding of few-electron resonant states. The mechanism was proposed many years ago but its verification in laboratory conditions is far more recent. In this work we study the binding of two-electron resonant states. The electrons are confined in a cylindrical quantum dot which is embedded in a semiconductor wire. The geometry considered is similar to the one used in actual experimental setups. The low-energy two-electron spectrum is calculated numerically from an effective-mass approximation Hamiltonian modelling the system. Methods for binding threshold calculations in systems with one and two electrons are thoroughly studied; in particular, we use quantum information quantities to assess when the strong lateral confinement approximation can be used to obtain reliable low-energy spectra. For simplicity, only cases without bound states in the absence of an external field are considered. Under these conditions, the binding threshold for the one-electron case is given by the lowest Landau energy level. Moreover, the energy of the one-electron bounded resonance can be used to obtain the two-electron binding threshold. It is shown that for realistic values of the two-electron model parameters it is feasible to bind resonances with field strengths of a few tens of tesla.

Free energy calculations of glycosaminoglycan-protein interactions.

PubMed

Gandhi, Neha S; Mancera, Ricardo L

2009-10-01

Glycosaminoglycans (GAGs) are complex highly charged linear polysaccharides that have a variety of roles in biological processes. We report the first use of molecular dynamics (MD) free energy calculations using the MM/PBSA method to investigate the binding of GAGs to protein molecules, namely the platelet endothelial cell adhesion molecule 1 (PECAM-1) and annexin A2. Calculations of the free energy of the binding of heparin fragments of different sizes reveal the existence of a region of low GAG-binding affinity in domains 5-6 of PECAM-1 and a region of high affinity in domains 2-3, consistent with experimental data and ligand-protein docking studies. A conformational hinge movement between domains 2 and 3 was observed, which allows the binding of heparin fragments of increasing size (pentasaccharides to octasaccharides) with an increasingly higher binding affinity. Similar simulations of the binding of a heparin fragment to annexin A2 reveal the optimization of electrostatic and hydrogen bonding interactions with the protein and protein-bound calcium ions. In general, these free energy calculations reveal that the binding of heparin to protein surfaces is dominated by strong electrostatic interactions for longer fragments, with equally important contributions from van der Waals interactions and vibrational entropy changes, against a large unfavorable desolvation penalty due to the high charge density of these molecules.

Free-Energy-Based Protein Design: Re-Engineering Cellular Retinoic Acid Binding Protein II Assisted by the Moveable-Type Approach.

PubMed

Zhong, Haizhen A; Santos, Elizabeth M; Vasileiou, Chrysoula; Zheng, Zheng; Geiger, James H; Borhan, Babak; Merz, Kenneth M

2018-03-14

How to fine-tune the binding free energy of a small-molecule to a receptor site by altering the amino acid residue composition is a key question in protein engineering. Indeed, the ultimate solution to this problem, to chemical accuracy (±1 kcal/mol), will result in profound and wide-ranging applications in protein design. Numerous tools have been developed to address this question using knowledge-based models to more computationally intensive molecular dynamics simulations-based free energy calculations, but while some success has been achieved there remains room for improvement in terms of overall accuracy and in the speed of the methodology. Here we report a fast, knowledge-based movable-type (MT)-based approach to estimate the absolute and relative free energy of binding as influenced by mutations in a small-molecule binding site in a protein. We retrospectively validate our approach using mutagenesis data for retinoic acid binding to the Cellular Retinoic Acid Binding Protein II (CRABPII) system and then make prospective predictions that are borne out experimentally. The overall performance of our approach is supported by its success in identifying mutants that show high or even sub-nano-molar binding affinities of retinoic acid to the CRABPII system.

Calculation of Relative Binding Free Energy in the Water-Filled Active Site of Oligopeptide-Binding Protein A.

PubMed

Maurer, Manuela; de Beer, Stephanie B A; Oostenbrink, Chris

2016-04-15

The periplasmic oligopeptide binding protein A (OppA) represents a well-known example of water-mediated protein-ligand interactions. Here, we perform free-energy calculations for three different ligands binding to OppA, using a thermodynamic integration approach. The tripeptide ligands share a high structural similarity (all have the sequence KXK), but their experimentally-determined binding free energies differ remarkably. Thermodynamic cycles were constructed for the ligands, and simulations conducted in the bound and (freely solvated) unbound states. In the unbound state, it was observed that the difference in conformational freedom between alanine and glycine leads to a surprisingly slow convergence, despite their chemical similarity. This could be overcome by increasing the softness parameter during alchemical transformations. Discrepancies remained in the bound state however, when comparing independent simulations of the three ligands. These difficulties could be traced to a slow relaxation of the water network within the active site. Fluctuations in the number of water molecules residing in the binding cavity occur mostly on a timescale larger than the simulation time along the alchemical path. After extensive simulations, relative binding free energies that were converged to within thermal noise could be obtained, which agree well with available experimental data.

Calculation of Relative Binding Free Energy in the Water-Filled Active Site of Oligopeptide-Binding Protein A

PubMed Central

Maurer, Manuela; de Beer, Stephanie B. A.; Oostenbrink, Chris

2018-01-01

The periplasmic oligopeptide binding protein A (OppA) represents a well-known example of water-mediated protein-ligand interactions. Here, we perform free-energy calculations for three different ligands binding to OppA, using a thermodynamic integration approach. The tripeptide ligands share a high structural similarity (all have the sequence KXK), but their experimentally-determined binding free energies differ remarkably. Thermodynamic cycles were constructed for the ligands, and simulations conducted in the bound and (freely solvated) unbound states. In the unbound state, it was observed that the difference in conformational freedom between alanine and glycine leads to a surprisingly slow convergence, despite their chemical similarity. This could be overcome by increasing the softness parameter during alchemical transformations. Discrepancies remained in the bound state however, when comparing independent simulations of the three ligands. These difficulties could be traced to a slow relaxation of the water network within the active site. Fluctuations in the number of water molecules residing in the binding cavity occur mostly on a timescale larger than the simulation time along the alchemical path. After extensive simulations, relative binding free energies that were converged to within thermal noise could be obtained, which agree well with available experimental data. PMID:27092480

Distinguishing Binders from False Positives by Free Energy Calculations: Fragment Screening Against the Flap Site of HIV Protease

PubMed Central

2015-01-01

Molecular docking is a powerful tool used in drug discovery and structural biology for predicting the structures of ligand–receptor complexes. However, the accuracy of docking calculations can be limited by factors such as the neglect of protein reorganization in the scoring function; as a result, ligand screening can produce a high rate of false positive hits. Although absolute binding free energy methods still have difficulty in accurately rank-ordering binders, we believe that they can be fruitfully employed to distinguish binders from nonbinders and reduce the false positive rate. Here we study a set of ligands that dock favorably to a newly discovered, potentially allosteric site on the flap of HIV-1 protease. Fragment binding to this site stabilizes a closed form of protease, which could be exploited for the design of allosteric inhibitors. Twenty-three top-ranked protein–ligand complexes from AutoDock were subject to the free energy screening using two methods, the recently developed binding energy analysis method (BEDAM) and the standard double decoupling method (DDM). Free energy calculations correctly identified most of the false positives (≥83%) and recovered all the confirmed binders. The results show a gap averaging ≥3.7 kcal/mol, separating the binders and the false positives. We present a formula that decomposes the binding free energy into contributions from the receptor conformational macrostates, which provides insights into the roles of different binding modes. Our binding free energy component analysis further suggests that improving the treatment for the desolvation penalty associated with the unfulfilled polar groups could reduce the rate of false positive hits in docking. The current study demonstrates that the combination of docking with free energy methods can be very useful for more accurate ligand screening against valuable drug targets. PMID:25189630

Probing Carbohydrate Product Expulsion from a Processive Cellulase with Multiple Absolute Binding Free Energy Methods*

PubMed Central

Bu, Lintao; Beckham, Gregg T.; Shirts, Michael R.; Nimlos, Mark R.; Adney, William S.; Himmel, Michael E.; Crowley, Michael F.

2011-01-01

Understanding the enzymatic mechanism that cellulases employ to degrade cellulose is critical to efforts to efficiently utilize plant biomass as a sustainable energy resource. A key component of cellulase action on cellulose is product inhibition from monosaccharide and disaccharides in the product site of cellulase tunnel. The absolute binding free energy of cellobiose and glucose to the product site of the catalytic tunnel of the Family 7 cellobiohydrolase (Cel7A) of Trichoderma reesei (Hypocrea jecorina) was calculated using two different approaches: steered molecular dynamics (SMD) simulations and alchemical free energy perturbation molecular dynamics (FEP/MD) simulations. For the SMD approach, three methods based on Jarzynski's equality were used to construct the potential of mean force from multiple pulling trajectories. The calculated binding free energies, −14.4 kcal/mol using SMD and −11.2 kcal/mol using FEP/MD, are in good qualitative agreement. Analysis of the SMD pulling trajectories suggests that several protein residues (Arg-251, Asp-259, Asp-262, Trp-376, and Tyr-381) play key roles in cellobiose and glucose binding to the catalytic tunnel. Five mutations (R251A, D259A, D262A, W376A, and Y381A) were made computationally to measure the changes in free energy during the product expulsion process. The absolute binding free energies of cellobiose to the catalytic tunnel of these five mutants are −13.1, −6.0, −11.5, −7.5, and −8.8 kcal/mol, respectively. The results demonstrated that all of the mutants tested can lower the binding free energy of cellobiose, which provides potential applications in engineering the enzyme to accelerate the product expulsion process and improve the efficiency of biomass conversion. PMID:21454590

Studies on interaction of insect repellent compounds with odorant binding receptor proteins by in silico molecular docking approach.

PubMed

Gopal, J Vinay; Kannabiran, K

2013-12-01

The aim of the study was to identify the interactions between insect repellent compounds and target olfactory proteins. Four compounds, camphor (C10H16O), carvacrol (C10H14O), oleic acid (C18H34O2) and firmotox (C22H28O5) were chosen as ligands. Seven olfactory proteins of insects with PDB IDs: 3K1E, 1QWV, 1TUJ, 1OOF, 2ERB, 3R1O and OBP1 were chosen for docking analysis. Patch dock was used and pymol for visualizing the structures. The interactions of these ligands with few odorant binding proteins showed binding energies. The ligand camphor had showed a binding energy of -136 kcal/mol with OBP1 protein. The ligand carvacrol interacted with 1QWV and 1TUJ proteins with a least binding energy of -117.45 kcal/mol and -21.78 kcal/mol respectively. The ligand oleic acid interacted with 1OOF, 2ERB, 3R1O and OBP1 with least binding energies. Ligand firmotox interacted with OBP1 and showed least binding energies. Three ligands (camphor, oleic acid and firmotox) had one, two, three interactions with a single protein OBP1 of Nilaparvatha lugens (Rice pest). From this in silico study we identified the interaction patterns for insect repellent compounds with the target insect odarant proteins. The results of our study revealed that the chosen ligands showed hydrogen bond interactions with the target olfactory receptor proteins.

Studies of the mechanism of selectivity of protein tyrosine phosphatase 1B (PTP1B) bidentate inhibitors using molecular dynamics simulations and free energy calculations.

PubMed

Fang, Lei; Zhang, Huai; Cui, Wei; Ji, Mingjun

2008-10-01

Bidentate inhibitors of protein tyrosine phosphatase 1B (PTP1B) are considered as a group of ideal inhibitors with high binding potential and high selectivity in treating type II diabetes. In this paper, the binding models of five bidentate inhibitors to PTP1B, TCPTP, and SHP-2 were investigated and compared by using molecular dynamics (MD) simulations and free energy calculations. The binding free energies were computed using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) methodology. The calculation results show that the predicted free energies of the complexes are well consistent with the experimental data. The Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) free energy decomposition analysis indicates that the residues ARG24, ARG254, and GLN262 in the second binding site of PTP1B are essential for the high selectivity of inhibitors. Furthermore, the residue PHE182 close to the active site is also important for the selectivity and the binding affinity of the inhibitors. According to our analysis, it can be concluded that in most cases the polarity of the portion of the inhibitor that binds to the second binding site of the protein is positive to the affinity of the inhibitors while negative to the selectivity of the inhibitors. We expect that the information we obtained here can help to develop potential PTP1B inhibitors with more promising specificity.

Photoionization cross section and binding energy of single dopant in hollow cylindrical core/shell quantum dot

NASA Astrophysics Data System (ADS)

Feddi, E.; El-Yadri, M.; Dujardin, F.; Restrepo, R. L.; Duque, C. A.

2017-02-01

In this study, we have investigated the confined donor impurity in a hollow cylindrical-shell quantum dot. The charges are assumed to be completely confined to the interior of the shell with rigid walls. Within the framework of the effective-mass approximation and by using a simple variational approach, we have computed the donor binding energy as a function of the shell sizes in order to study the behavior of the electron-impurity attraction for a very small thickness. Our results show that the binding energy of a donor impurity placed at the center of cylindrical core/shell dots depends strongly on the shell size. The binding energy increases when the shell-wideness becomes smaller and shows the same behavior as in a simple cylindrical quantum dot. A special case has been studied, which corresponds to the ratio between the inner and outer radii near to one (a/b → 1) for which our model gives a non-significant behavior of the impurity binding energy. This fact implies the existence of a critical value (a/b) for which the binding energy of the donor impurity tends to the limit value of 4 effective Rydbergs as in a 2D quantum well. We also analyse the photoionization cross section considering only the in-plane incident radiation polarization. We determine its behavior as a function of photon energy, shell size, and donor position. The measurement of photoionization in such systems would be of great interest to understand the optical properties of carriers in quantum dots.

Metalloid Aluminum Clusters with Fluorine

DTIC Science & Technology

2016-12-01

molecular dynamics, binding energy , siesta code, density of states, projected density of states 15. NUMBER OF PAGES 69 16. PRICE CODE 17. SECURITY...high energy density compared to explosives, but typically release this energy slowly via diffusion-limited combustion. There is recent interest in using...examine the cluster binding energy and electronic structure. Partial fluorine substitution in a prototypical aluminum-cyclopentadienyl cluster results

Generalized Skyrme model with the loosely bound potential

NASA Astrophysics Data System (ADS)

Gudnason, Sven Bjarke; Zhang, Baiyang; Ma, Nana

2016-12-01

We study a generalization of the loosely bound Skyrme model which consists of the Skyrme model with a sixth-order derivative term—motivated by its fluidlike properties—and the second-order loosely bound potential—motivated by lowering the classical binding energies of higher-charged Skyrmions. We use the rational map approximation for the Skyrmion of topological charge B =4 , calculate the binding energy of the latter, and estimate the systematic error in using this approximation. In the parameter space that we can explore within the rational map approximation, we find classical binding energies as low as 1.8%, and once taking into account the contribution from spin-isospin quantization, we obtain binding energies as low as 5.3%. We also calculate the contribution from the sixth-order derivative term to the electric charge density and axial coupling.

Exploring the binding energy profiles of full agonists, partial agonists, and antagonists of the α7 nicotinic acetylcholine receptor.

PubMed

Tabassum, Nargis; Ma, Qianyun; Wu, Guanzhao; Jiang, Tao; Yu, Rilei

2017-09-01

Nicotinic acetylcholine receptors (nAChRs) belong to the Cys-loop receptor family and are important drug targets for the treatment of neurological diseases. However, the precise determinants of the binding efficacies of ligands for these receptors are unclear. Therefore, in this study, the binding energy profiles of various ligands (full agonists, partial agonists, and antagonists) were quantified by docking those ligands with structural ensembles of the α7 nAChR exhibiting different degrees of C-loop closure. This approximate treatment of interactions suggested that full agonists, partial agonists, and antagonists of the α7 nAChR possess distinctive binding energy profiles. Results from docking revealed that ligand binding efficacy may be related to the capacity of the ligand to stabilize conformational states with a closed C loop.

Evaluation of B3LYP, X3LYP, and M06-Class Density Functionals for Predicting the Binding Energies of Neutral, Protonated, and Deprotonated Water Clusters.

PubMed

Bryantsev, Vyacheslav S; Diallo, Mamadou S; van Duin, Adri C T; Goddard, William A

2009-04-14

In this paper we assess the accuracy of the B3LYP, X3LYP, and newly developed M06-L, M06-2X, and M06 functionals to predict the binding energies of neutral and charged water clusters including (H2O)n, n = 2-8, 20), H3O(+)(H2O)n, n = 1-6, and OH(-)(H2O)n, n = 1-6. We also compare the predicted energies of two ion hydration and neutralization reactions on the basis of the calculated binding energies. In all cases, we use as benchmarks calculated binding energies of water clusters extrapolated to the complete basis set limit of the second-order Møller-Plesset perturbation theory with the effects of higher order correlation estimated at the coupled-cluster theory with single, double, and perturbative triple excitations in the aug-cc-pVDZ basis set. We rank the accuracy of the functionals on the basis of the mean unsigned error (MUE) between calculated benchmark and density functional theory energies. The corresponding MUE (kcal/mol) for each functional is listed in parentheses. We find that M06-L (0.73) and M06 (0.84) give the most accurate binding energies using very extended basis sets such as aug-cc-pV5Z. For more affordable basis sets, the best methods for predicting the binding energies of water clusters are M06-L/aug-cc-pVTZ (1.24), B3LYP/6-311++G(2d,2p) (1.29), and M06/aug-cc-PVTZ (1.33). M06-L/aug-cc-pVTZ also gives more accurate energies for the neutralization reactions (1.38), whereas B3LYP/6-311++G(2d,2p) gives more accurate energies for the ion hydration reactions (1.69).

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.

PHOENIX: a scoring function for affinity prediction derived using high-resolution crystal structures and calorimetry measurements.

PubMed

Tang, Yat T; Marshall, Garland R

2011-02-28

Binding affinity prediction is one of the most critical components to computer-aided structure-based drug design. Despite advances in first-principle methods for predicting binding affinity, empirical scoring functions that are fast and only relatively accurate are still widely used in structure-based drug design. With the increasing availability of X-ray crystallographic structures in the Protein Data Bank and continuing application of biophysical methods such as isothermal titration calorimetry to measure thermodynamic parameters contributing to binding free energy, sufficient experimental data exists that scoring functions can now be derived by separating enthalpic (ΔH) and entropic (TΔS) contributions to binding free energy (ΔG). PHOENIX, a scoring function to predict binding affinities of protein-ligand complexes, utilizes the increasing availability of experimental data to improve binding affinity predictions by the following: model training and testing using high-resolution crystallographic data to minimize structural noise, independent models of enthalpic and entropic contributions fitted to thermodynamic parameters assumed to be thermodynamically biased to calculate binding free energy, use of shape and volume descriptors to better capture entropic contributions. A set of 42 descriptors and 112 protein-ligand complexes were used to derive functions using partial least-squares for change of enthalpy (ΔH) and change of entropy (TΔS) to calculate change of binding free energy (ΔG), resulting in a predictive r2 (r(pred)2) of 0.55 and a standard error (SE) of 1.34 kcal/mol. External validation using the 2009 version of the PDBbind "refined set" (n = 1612) resulted in a Pearson correlation coefficient (R(p)) of 0.575 and a mean error (ME) of 1.41 pK(d). Enthalpy and entropy predictions were of limited accuracy individually. However, their difference resulted in a relatively accurate binding free energy. While the development of an accurate and applicable scoring function was an objective of this study, the main focus was evaluation of the use of high-resolution X-ray crystal structures with high-quality thermodynamic parameters from isothermal titration calorimetry for scoring function development. With the increasing application of structure-based methods in molecular design, this study suggests that using high-resolution crystal structures, separating enthalpy and entropy contributions to binding free energy, and including descriptors to better capture entropic contributions may prove to be effective strategies toward rapid and accurate calculation of binding affinity.

Interaction entropy for protein-protein binding

NASA Astrophysics Data System (ADS)

Sun, Zhaoxi; Yan, Yu N.; Yang, Maoyou; Zhang, John Z. H.

2017-03-01

Protein-protein interactions are at the heart of signal transduction and are central to the function of protein machine in biology. The highly specific protein-protein binding is quantitatively characterized by the binding free energy whose accurate calculation from the first principle is a grand challenge in computational biology. In this paper, we show how the interaction entropy approach, which was recently proposed for protein-ligand binding free energy calculation, can be applied to computing the entropic contribution to the protein-protein binding free energy. Explicit theoretical derivation of the interaction entropy approach for protein-protein interaction system is given in detail from the basic definition. Extensive computational studies for a dozen realistic protein-protein interaction systems are carried out using the present approach and comparisons of the results for these protein-protein systems with those from the standard normal mode method are presented. Analysis of the present method for application in protein-protein binding as well as the limitation of the method in numerical computation is discussed. Our study and analysis of the results provided useful information for extracting correct entropic contribution in protein-protein binding from molecular dynamics simulations.

Interaction entropy for protein-protein binding.

PubMed

Sun, Zhaoxi; Yan, Yu N; Yang, Maoyou; Zhang, John Z H

2017-03-28

Protein-protein interactions are at the heart of signal transduction and are central to the function of protein machine in biology. The highly specific protein-protein binding is quantitatively characterized by the binding free energy whose accurate calculation from the first principle is a grand challenge in computational biology. In this paper, we show how the interactionentropy approach, which was recently proposed for protein-ligand binding free energy calculation, can be applied to computing the entropic contribution to the protein-protein binding free energy. Explicit theoretical derivation of the interactionentropy approach for protein-protein interaction system is given in detail from the basic definition. Extensive computational studies for a dozen realistic protein-protein interaction systems are carried out using the present approach and comparisons of the results for these protein-protein systems with those from the standard normal mode method are presented. Analysis of the present method for application in protein-protein binding as well as the limitation of the method in numerical computation is discussed. Our study and analysis of the results provided useful information for extracting correct entropic contribution in protein-protein binding from molecular dynamics simulations.

A density functional theory study of the correlation between analyte basicity, ZnPc adsorption strength, and sensor response.

PubMed

Tran, N L; Bohrer, F I; Trogler, W C; Kummel, A C

2009-05-28

Density functional theory (DFT) simulations were used to determine the binding strength of 12 electron-donating analytes to the zinc metal center of a zinc phthalocyanine molecule (ZnPc monomer). The analyte binding strengths were compared to the analytes' enthalpies of complex formation with boron trifluoride (BF(3)), which is a direct measure of their electron donating ability or Lewis basicity. With the exception of the most basic analyte investigated, the ZnPc binding energies were found to correlate linearly with analyte basicities. Based on natural population analysis calculations, analyte complexation to the Zn metal of the ZnPc monomer resulted in limited charge transfer from the analyte to the ZnPc molecule, which increased with analyte-ZnPc binding energy. The experimental analyte sensitivities from chemiresistor ZnPc sensor data were proportional to an exponential of the binding energies from DFT calculations consistent with sensitivity being proportional to analyte coverage and binding strength. The good correlation observed suggests DFT is a reliable method for the prediction of chemiresistor metallophthalocyanine binding strengths and response sensitivities.

Ab initio Study of Transition metal binding to the Prion Protein

NASA Astrophysics Data System (ADS)

Cox, Daniel L.; Singh, Rajiv R. P.; Pan, Jianping

2004-03-01

Fundamental understanding of the prion protein (PrP) is of critical public health importance in view of mad cow and chronic wasting diseases. In recent years, it has been shown that the normal form (PrP^c) binds copper^1), and the structure of the copper binding domain has been elaborated. Hypotheses about toxicity associated with binding of other metals (notably manganese) have been put forward, Accordingly, using the ab initio SIESTA density functional theory code^2), we calculated the binding energy E_B(M) of M-(PrP) complexes relative to initially uncomplexed M ions, with M=Cu,Ni,Zn,Mn and (PrP)^* the minimal binding domain. The binding energy trend is E_B(Ni)>E_B(Cu)>E_B(Zn)>E_B(Mn), consistent with recent experiments apart from the surprising stability of Ni. We will also present preliminary results for binding of initially complexed M ions. *-Supported by U.S. DOE, Office of Basic Energy Sciences, Division of Materials Research 1) G.S. Jackson et al., Proc. Nat. Acad. Sci. (USA) 98, 8531 (2001). 2) P. Ordejón, et al., Phys. Rev. B53, R10441 (1996); J.M. Soler et al., J. Phys. Cond. Matt. 14, 2745 (2002).

A Simple PB/LIE Free Energy Function Accurately Predicts the Peptide Binding Specificity of the Tiam1 PDZ Domain.

PubMed

Panel, Nicolas; Sun, Young Joo; Fuentes, Ernesto J; Simonson, Thomas

2017-01-01

PDZ domains generally bind short amino acid sequences at the C-terminus of target proteins, and short peptides can be used as inhibitors or model ligands. Here, we used experimental binding assays and molecular dynamics simulations to characterize 51 complexes involving the Tiam1 PDZ domain and to test the performance of a semi-empirical free energy function. The free energy function combined a Poisson-Boltzmann (PB) continuum electrostatic term, a van der Waals interaction energy, and a surface area term. Each term was empirically weighted, giving a Linear Interaction Energy or "PB/LIE" free energy. The model yielded a mean unsigned deviation of 0.43 kcal/mol and a Pearson correlation of 0.64 between experimental and computed free energies, which was superior to a Null model that assumes all complexes have the same affinity. Analyses of the models support several experimental observations that indicate the orientation of the α 2 helix is a critical determinant for peptide specificity. The models were also used to predict binding free energies for nine new variants, corresponding to point mutants of the Syndecan1 and Caspr4 peptides. The predictions did not reveal improved binding; however, they suggest that an unnatural amino acid could be used to increase protease resistance and peptide lifetimes in vivo . The overall performance of the model should allow its use in the design of new PDZ ligands in the future.

A Simple PB/LIE Free Energy Function Accurately Predicts the Peptide Binding Specificity of the Tiam1 PDZ Domain

PubMed Central

Panel, Nicolas; Sun, Young Joo; Fuentes, Ernesto J.; Simonson, Thomas

2017-01-01

PDZ domains generally bind short amino acid sequences at the C-terminus of target proteins, and short peptides can be used as inhibitors or model ligands. Here, we used experimental binding assays and molecular dynamics simulations to characterize 51 complexes involving the Tiam1 PDZ domain and to test the performance of a semi-empirical free energy function. The free energy function combined a Poisson-Boltzmann (PB) continuum electrostatic term, a van der Waals interaction energy, and a surface area term. Each term was empirically weighted, giving a Linear Interaction Energy or “PB/LIE” free energy. The model yielded a mean unsigned deviation of 0.43 kcal/mol and a Pearson correlation of 0.64 between experimental and computed free energies, which was superior to a Null model that assumes all complexes have the same affinity. Analyses of the models support several experimental observations that indicate the orientation of the α2 helix is a critical determinant for peptide specificity. The models were also used to predict binding free energies for nine new variants, corresponding to point mutants of the Syndecan1 and Caspr4 peptides. The predictions did not reveal improved binding; however, they suggest that an unnatural amino acid could be used to increase protease resistance and peptide lifetimes in vivo. The overall performance of the model should allow its use in the design of new PDZ ligands in the future. PMID:29018806

UO₂²⁺ uptake by proteins: understanding the binding features of the super uranyl binding protein and design of a protein with higher affinity.

PubMed

Odoh, Samuel O; Bondarevsky, Gary D; Karpus, Jason; Cui, Qiang; He, Chuan; Spezia, Riccardo; Gagliardi, Laura

2014-12-17

The capture of uranyl, UO2(2+), by a recently engineered protein (Zhou et al. Nat. Chem. 2014, 6, 236) with high selectivity and femtomolar sensitivity has been examined by a combination of density functional theory, molecular dynamics, and free-energy simulations. It was found that UO2(2+) is coordinated to five carboxylate oxygen atoms from four amino acid residues of the super uranyl binding protein (SUP). A network of hydrogen bonds between the amino acid residues coordinated to UO2(2+) and residues in its second coordination sphere also affects the protein's uranyl binding affinity. Free-energy simulations show how UO2(2+) capture is governed by the nature of the amino acid residues in the binding site, the integrity and strength of the second-sphere hydrogen bond network, and the number of water molecules in the first coordination sphere. Alteration of any of these three factors through mutations generally results in a reduction of the binding free energy of UO2(2+) to the aqueous protein as well as of the difference between the binding free energies of UO2(2+) and other ions (Ca(2+), Cu(2+), Mg(2+), and Zn(2+)), a proxy for the protein's selectivity over these ions. The results of our free-energy simulations confirmed the previously reported experimental results and allowed us to discover a mutant of SUP, specifically the GLU64ASP mutant, that not only binds UO2(2+) more strongly than SUP but that is also more selective for UO2(2+) over other ions. The predictions from the computations were confirmed experimentally.

Combined effects of an intense laser field, electric field and hydrostatic pressure on donor impurity states in zinc-blende InGaN/GaN quantum dots

NASA Astrophysics Data System (ADS)

Wang, Guangxin; Zhou, Rui; Duan, Xiuzhi

2016-07-01

The shallow-donor impurity states in cylindrical zinc-blende (ZB) In x Ga1- x N/GaN quantum dots (QDs) have been theoretically investigated, considering the combined effects of an intense laser field (ILF), an external electric field, and hydrostatic pressure. The numerical results show that for an on-center impurity in ZB In x Ga1- x N/GaN QD, (1) the ground-state binding energy of the donor impurity is a decreasing function of the laser-dressing parameter and/or the QD's height; (2) as the QD's radius decreases, the binding energy of the donor impurity increases at first, reaches a maximum value, and then drops rapidly; (3) the binding energy of the donor impurity is a decreasing function of the external electric field due to the Stark effect; (4) the binding energy of the donor impurity increases as the applied hydrostatic pressure becomes large. In addition, the position of the impurity ion was also found to have an important influence on the binding energy of the donor impurity. The physical reasons have been analyzed in detail.

Free Energy Landscape of Lipid Interactions with Regulatory Binding Sites on the Transmembrane Domain of the EGF Receptor.

PubMed

Hedger, George; Shorthouse, David; Koldsø, Heidi; Sansom, Mark S P

2016-08-25

Lipid molecules can bind to specific sites on integral membrane proteins, modulating their structure and function. We have undertaken coarse-grained simulations to calculate free energy profiles for glycolipids and phospholipids interacting with modulatory sites on the transmembrane helix dimer of the EGF receptor within a lipid bilayer environment. We identify lipid interaction sites at each end of the transmembrane domain and compute interaction free energy profiles for lipids with these sites. Interaction free energies ranged from ca. -40 to -4 kJ/mol for different lipid species. Those lipids (glycolipid GM3 and phosphoinositide PIP2) known to modulate EGFR function exhibit the strongest binding to interaction sites on the EGFR, and we are able to reproduce the preference for interaction with GM3 over other glycolipids suggested by experiment. Mutation of amino acid residues essential for EGFR function reduce the binding free energy of these key lipid species. The residues interacting with the lipids in the simulations are in agreement with those suggested by experimental (mutational) studies. This approach provides a generalizable tool for characterizing the interactions of lipids that bind to specific sites on integral membrane proteins.

Effective Mass Theory of 2D Excitons Revisited

NASA Astrophysics Data System (ADS)

Gonzalez, Joseph; Oleynik, Ivan

Two-dimensional (2D) semiconducting materials possess an exceptionally unique set of electronic and excitonic properties due to the combined effects of quantum and dielectric confinement. Reliable determination of exciton binding energies from both first-principles many-body perturbation theory (GW/BSE) and experiment is very challenging due to the enormous computational expense as well as the tremendous technical difficulties in experiment.. Very recently, effective mass theories of 2D excitons have been developed as an attractive alternative for inexpensive and accurate evaluation of the exciton binding energies. In this presentation, we evaluate two effective mass theory approaches by Velizhanin et al and Olsen et al in predicting exciton binding energies across a wide range of 2D materials. We specifically analyze the trends related to the varying screening lengths and exciton effective masses. We also extended the effective mass theory of 2D excitons to include effects of electron and hole mass anisotropies (mx ≠ my) , the latter showing a substantial influence on exciton binding energies. The recent predictions of exciton binding energies being independent of the exciton effective mass and a linear correlation with the band gap of a specific material are also critically reexamined.

Free Energy Landscape of Lipid Interactions with Regulatory Binding Sites on the Transmembrane Domain of the EGF Receptor

PubMed Central

2016-01-01

Lipid molecules can bind to specific sites on integral membrane proteins, modulating their structure and function. We have undertaken coarse-grained simulations to calculate free energy profiles for glycolipids and phospholipids interacting with modulatory sites on the transmembrane helix dimer of the EGF receptor within a lipid bilayer environment. We identify lipid interaction sites at each end of the transmembrane domain and compute interaction free energy profiles for lipids with these sites. Interaction free energies ranged from ca. −40 to −4 kJ/mol for different lipid species. Those lipids (glycolipid GM3 and phosphoinositide PIP2) known to modulate EGFR function exhibit the strongest binding to interaction sites on the EGFR, and we are able to reproduce the preference for interaction with GM3 over other glycolipids suggested by experiment. Mutation of amino acid residues essential for EGFR function reduce the binding free energy of these key lipid species. The residues interacting with the lipids in the simulations are in agreement with those suggested by experimental (mutational) studies. This approach provides a generalizable tool for characterizing the interactions of lipids that bind to specific sites on integral membrane proteins. PMID:27109430

Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

PubMed Central

Moraca, Federica; Amato, Jussara; Ortuso, Francesco; Artese, Anna; Novellino, Ettore; Alcaro, Stefano; Parrinello, Michele; Limongelli, Vittorio

2017-01-01

G-quadruplexes (G4s) are higher-order DNA structures typically present at promoter regions of genes and telomeres. Here, the G4 formation decreases the replicative DNA at each cell cycle, finally leading to apoptosis. The ability to control this mitotic clock, particularly in cancer cells, is fascinating and passes through a rational understanding of the ligand/G4 interaction. We demonstrate that an accurate description of the ligand/G4 binding mechanism is possible using an innovative free-energy method called funnel-metadynamics (FM), which we have recently developed to investigate ligand/protein interaction. Using FM simulations, we have elucidated the binding mechanism of the anticancer alkaloid berberine to the human telomeric G4 (d[AG3(T2AG3)3]), computing also the binding free-energy landscape. Two ligand binding modes have been identified as the lowest energy states. Furthermore, we have found prebinding sites, which are preparatory to reach the final binding mode. In our simulations, the ions and the water molecules have been explicitly represented and the energetic contribution of the solvent during ligand binding evaluated. Our theoretical results provide an accurate estimate of the absolute ligand/DNA binding free energy (ΔGb0 = −10.3 ± 0.5 kcal/mol) that we validated through steady-state fluorescence binding assays. The good agreement between the theoretical and experimental value demonstrates that FM is a most powerful method to investigate ligand/DNA interaction and can be a useful tool for the rational design also of G4 ligands. PMID:28232513

Essential slow degrees of freedom in protein-surface simulations: A metadynamics investigation.

PubMed

Prakash, Arushi; Sprenger, K G; Pfaendtner, Jim

2018-03-29

Many proteins exhibit strong binding affinities to surfaces, with binding energies much greater than thermal fluctuations. When modelling these protein-surface systems with classical molecular dynamics (MD) simulations, the large forces that exist at the protein/surface interface generally confine the system to a single free energy minimum. Exploring the full conformational space of the protein, especially finding other stable structures, becomes prohibitively expensive. Coupling MD simulations with metadynamics (enhanced sampling) has fast become a common method for sampling the adsorption of such proteins. In this paper, we compare three different flavors of metadynamics, specifically well-tempered, parallel-bias, and parallel-tempering in the well-tempered ensemble, to exhaustively sample the conformational surface-binding landscape of model peptide GGKGG. We investigate the effect of mobile ions and ion charge, as well as the choice of collective variable (CV), on the binding free energy of the peptide. We make the case for explicitly biasing ions to sample the true binding free energy of biomolecules when the ion concentration is high and the binding free energies of the solute and ions are similar. We also make the case for choosing CVs that apply bias to all atoms of the solute to speed up calculations and obtain the maximum possible amount of information about the system. Copyright © 2017 Elsevier Inc. All rights reserved.

10 CFR 851.7 - Requests for a binding interpretive ruling.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Requests for a binding interpretive ruling. 851.7 Section 851.7 Energy DEPARTMENT OF ENERGY WORKER SAFETY AND HEALTH PROGRAM General Provisions § 851.7 Requests... ruling, but a person may not act in reliance on an interpretive ruling that is administratively rescinded...

Thermodynamic Insights into Effects of Water Displacement and Rearrangement upon Ligand Modification using Molecular Dynamics Simulations.

PubMed

Wahl, Joel; Smiesko, Martin

2018-05-04

Computational methods, namely Molecular Dynamics Simulations (MD simulations) in combination with Inhomogeneous Fluid Solvation Theory (IFST) were used to retrospectively investigate various cases of ligand structure modifications that led to the displacement of binding site water molecules. Our findings are that the water displacement per se is energetically unfavorable in the discussed examples, and that it is merely the fine balance between change in protein-ligand interaction energy, ligand solvation free energies and binding site solvation free energies that determine if water displacement is favorable or not. We furthermore evaluated if we can reproduce experimental binding affinities by a computational approach combining changes in solvation free energies with changes in protein-ligand interaction energies and entropies. In two of the seven cases, this estimation led to large errors, implying that accurate predictions of relative binding free energies based on solvent thermodynamics is challenging. Still, MD simulations can provide insights into which water molecules can be targeted for displacement. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Acceptor binding energies in GaN and AlN

NASA Astrophysics Data System (ADS)

Mireles, Francisco; Ulloa, Sergio E.

1998-08-01

We employ effective-mass theory for degenerate hole bands to calculate the acceptor binding energies for Be, Mg, Zn, Ca, C, and Si substitutional acceptors in GaN and AlN. The calculations are performed through the 6×6 Rashba-Sheka-Pikus and the Luttinger-Kohn matrix Hamiltonians for wurtzite (WZ) and zinc-blende (ZB) crystal phases, respectively. An analytic representation for the acceptor pseudopotential is used to introduce the specific nature of the impurity atoms. The energy shift due to polaron effects is also considered in this approach. The ionization energy estimates are in very good agreement with those reported experimentally in WZ GaN. The binding energies for ZB GaN acceptors are all predicted to be shallower than the corresponding impurities in the WZ phase. The binding-energy dependence upon the crystal-field splitting in WZ GaN is analyzed. Ionization levels in AlN are found to have similar ``shallow'' values to those in GaN, but with some important differences which depend on the band structure parametrizations, especially the value of the crystal-field splitting used.

The Study of the Successive Metal-ligand Binding Energies for Fe(+), Fe(-), V(+) and Co(+)

NASA Technical Reports Server (NTRS)

Bauschlicher, Charles W., Jr.; Ricca, Alessandra; Maitre, Philippe; Langhoff, Stephen R. (Technical Monitor)

1994-01-01

The successive binding energies of CO and H2O to Fe(+), CO to Fe(-), and H2 to Co(+) and V(+) are presented. Overall the computed results are in good agreement with experiment. The trends in binding energies are analyzed in terms of metal to ligand donation, ligand to metal donation, ligand-ligand repulsion, and changes in the metal atom, such as hybridization, promotion, and spin multiplicity. The geometry and vibrational frequencies are also shown to be directly affected by these effects.

The Study Of The Successive Metal-Ligand Binding Energies For Fe+, Fe-, V+ and Co+

NASA Technical Reports Server (NTRS)

Bauschicher, Charles W., Jr.; Ricca, Alessandra; Maitre, Philippe; Langhoff, Stephen R. (Technical Monitor)

1995-01-01

The successive binding energies of CO and H2O to Fe(+), CO to Fe(-), and H2 to Co(+) and V(+) are presented. Overall the computed results are in good agreement with experiment. The trends in binding energies are analyzed in terms of metal to ligand donation, ligand to metal donation, ligand-ligand repulsion, and changes in the metal atom, such as hybridization, promotion, and spin multiplicity. The geometry and vibrational frequencies are also shown to be directly affected by these effects.

Role of tyrosine hot-spot residues at the interface of colicin E9 and immunity protein 9: a comparative free energy simulation study.

PubMed

Luitz, Manuel P; Zacharias, Martin

2013-03-01

The endonuclease activity of the bacterial colicin 9 enzyme is controlled by the specific and high-affinity binding of immunity protein 9 (Im9). Molecular dynamics simulation studies in explicit solvent were used to investigate the free energy change associated with the mutation of two hot-spot interface residues [tyrosine (Tyr): Tyr54 and Tyr55] of Im9 to Ala. In addition, the effect of several other mutations (Leu33Ala, Leu52Ala, Val34Ala, Val37Ala, Ser48Ala, and Ile53Ala) with smaller influence on binding affinity was also studied. Good qualitative agreement of calculated free energy changes and experimental data on binding affinity of the mutations was observed. The simulation studies can help to elucidate the molecular details on how the mutations influence protein-protein binding affinity. The role of solvent and conformational flexibility of the partner proteins was studied by comparing the results in the presence or absence of solvent and with or without positional restraints. Restriction of the conformational mobility of protein partners resulted in significant changes of the calculated free energies but of similar magnitude for isolated Im9 and for the complex and therefore in only modest changes of binding free energy differences. Although the overall binding free energy change was similar for the two Tyr-Ala mutations, the physical origin appeared to be different with solvation changes contributing significantly to the Tyr55Ala mutation and to a loss of direct protein-protein interactions dominating the free energy change due to the Tyr54Ala mutation. Copyright © 2012 Wiley Periodicals, Inc.

Trions in bulk and monolayer materials: Faddeev equations and hyperspherical harmonics.

PubMed

Filikhin, I; Kezerashvili, R Ya; Tsiklauri, Sh M; Vlahovic, B

2018-03-23

The negatively T - and positively T + charged trions in bulk and monolayer semiconductors are studied in the effective mass approximation within the framework of a potential model. The binding energies of trions in various semiconductors are calculated by employing the Faddeev equation with the Coulomb potential in 3D configuration space. Results of calculations of the binding energies for T - are consistent with previous computational studies, while the T + is unbound for all considered cases. The binding energies of trions in monolayer semiconductors are calculated using the method of hyperspherical harmonics by employing the Keldysh potential. It is shown that 2D T - and T + trions are bound and the binding energy of the positive trion is always greater than for the negative trion due to the heavier effective mass of holes. Our calculations demonstrate that screening effects play an important role in the formation of bound states of trions in 2D semiconductors.

Structure of Co(H2)n + Clusters, for n = 1-6

NASA Technical Reports Server (NTRS)

Bauschlicher, Charles W., Jr.; Maitre, Philippe

1995-01-01

The geometries and H2 binding energies have been determined for Co(H2)n (sup +), for n = 1-6. The binding energies are in good agreement with experiment. The shape of the clusters is used to explain the pairwise decrease in the binding energies. The bonding in CoH2 (sup +) and Co(H2)2 (sup +) is very similar and is enhanced by sd (sigma) hybridization. The next two H2 molecules add to the side of Co(H2)2 (sup +). These two additional H2 molecules cannot benefit from sd (sigma) hybridization and are less strongly bound. The addition of the fifth and sixth H2 molecules eliminates sd (sigma) hybridization as a mechanism for reducing Co-H2 repulsion. This coupled with the smaller Co to H2 (sigma *) donation results in another decrease in the binding energies.

Trions in bulk and monolayer materials: Faddeev equations and hyperspherical harmonics

NASA Astrophysics Data System (ADS)

Filikhin, I.; Kezerashvili, R. Ya; Tsiklauri, Sh M.; Vlahovic, B.

2018-03-01

The negatively T - and positively T + charged trions in bulk and monolayer semiconductors are studied in the effective mass approximation within the framework of a potential model. The binding energies of trions in various semiconductors are calculated by employing the Faddeev equation with the Coulomb potential in 3D configuration space. Results of calculations of the binding energies for T - are consistent with previous computational studies, while the T + is unbound for all considered cases. The binding energies of trions in monolayer semiconductors are calculated using the method of hyperspherical harmonics by employing the Keldysh potential. It is shown that 2D T - and T + trions are bound and the binding energy of the positive trion is always greater than for the negative trion due to the heavier effective mass of holes. Our calculations demonstrate that screening effects play an important role in the formation of bound states of trions in 2D semiconductors.

Prediction of cyclin-dependent kinase 2 inhibitor potency using the fragment molecular orbital method

PubMed Central

2011-01-01

Background The reliable and robust estimation of ligand binding affinity continues to be a challenge in drug design. Many current methods rely on molecular mechanics (MM) calculations which do not fully explain complex molecular interactions. Full quantum mechanical (QM) computation of the electronic state of protein-ligand complexes has recently become possible by the latest advances in the development of linear-scaling QM methods such as the ab initio fragment molecular orbital (FMO) method. This approximate molecular orbital method is sufficiently fast that it can be incorporated into the development cycle during structure-based drug design for the reliable estimation of ligand binding affinity. Additionally, the FMO method can be combined with approximations for entropy and solvation to make it applicable for binding affinity prediction for a broad range of target and chemotypes. Results We applied this method to examine the binding affinity for a series of published cyclin-dependent kinase 2 (CDK2) inhibitors. We calculated the binding affinity for 28 CDK2 inhibitors using the ab initio FMO method based on a number of X-ray crystal structures. The sum of the pair interaction energies (PIE) was calculated and used to explain the gas-phase enthalpic contribution to binding. The correlation of the ligand potencies to the protein-ligand interaction energies gained from FMO was examined and was seen to give a good correlation which outperformed three MM force field based scoring functions used to appoximate the free energy of binding. Although the FMO calculation allows for the enthalpic component of binding interactions to be understood at the quantum level, as it is an in vacuo single point calculation, the entropic component and solvation terms are neglected. For this reason a more accurate and predictive estimate for binding free energy was desired. Therefore, additional terms used to describe the protein-ligand interactions were then calculated to improve the correlation of the FMO derived values to experimental free energies of binding. These terms were used to account for the polar and non-polar solvation of the molecule estimated by the Poisson-Boltzmann equation and the solvent accessible surface area (SASA), respectively, as well as a correction term for ligand entropy. A quantitative structure-activity relationship (QSAR) model obtained by Partial Least Squares projection to latent structures (PLS) analysis of the ligand potencies and the calculated terms showed a strong correlation (r2 = 0.939, q2 = 0.896) for the 14 molecule test set which had a Pearson rank order correlation of 0.97. A training set of a further 14 molecules was well predicted (r2 = 0.842), and could be used to obtain meaningful estimations of the binding free energy. Conclusions Our results show that binding energies calculated with the FMO method correlate well with published data. Analysis of the terms used to derive the FMO energies adds greater understanding to the binding interactions than can be gained by MM methods. Combining this information with additional terms and creating a scaled model to describe the data results in more accurate predictions of ligand potencies than the absolute values obtained by FMO alone. PMID:21219630

Calculations of the binding affinities of protein-protein complexes with the fast multipole method

NASA Astrophysics Data System (ADS)

Kim, Bongkeun; Song, Jiming; Song, Xueyu

2010-09-01

In this paper, we used a coarse-grained model at the residue level to calculate the binding free energies of three protein-protein complexes. General formulations to calculate the electrostatic binding free energy and the van der Waals free energy are presented by solving linearized Poisson-Boltzmann equations using the boundary element method in combination with the fast multipole method. The residue level model with the fast multipole method allows us to efficiently investigate how the mutations on the active site of the protein-protein interface affect the changes in binding affinities of protein complexes. Good correlations between the calculated results and the experimental ones indicate that our model can capture the dominant contributions to the protein-protein interactions. At the same time, additional effects on protein binding due to atomic details are also discussed in the context of the limitations of such a coarse-grained model.

Onset of η-nuclear binding in a pionless EFT approach

NASA Astrophysics Data System (ADS)

Barnea, N.; Bazak, B.; Friedman, E.; Gal, A.

2017-08-01

ηNNN and ηNNNN bound states are explored in stochastic variational method (SVM) calculations within a pionless effective field theory (EFT) approach at leading order. The theoretical input consists of regulated NN and NNN contact terms, and a regulated energy dependent ηN contact term derived from coupled-channel models of the N* (1535) nucleon resonance. A self consistency procedure is applied to deal with the energy dependence of the ηN subthreshold input, resulting in a weak dependence of the calculated η-nuclear binding energies on the EFT regulator. It is found, in terms of the ηN scattering length aηN, that the onset of binding η 3He requires a minimal value of ReaηN close to 1 fm, yielding then a few MeV η binding in η 4He. The onset of binding η 4He requires a lower value of ReaηN, but exceeding 0.7 fm.

NMR Mapping of Protein Conformational Landscapes using Coordinated Behavior of Chemical Shifts upon Ligand Binding

PubMed Central

Cembran, Alessandro; Kim, Jonggul; Gao, Jiali; Veglia, Gianluigi

2014-01-01

Proteins exist as an ensemble of conformers that are distributed on free energy landscapes resembling folding funnels. While the most stable conformers populate low energy basins, protein function is often carried out through low-populated conformational states that occupy high energy basins. Ligand binding shifts the populations of these states, changing the distribution of these conformers. Understanding how the equilibrium among the states is altered upon ligand binding, interaction with other binding partners, and/or mutations and post-translational modifications is of critical importance for explaining allosteric signaling in proteins. Here, we propose a statistical analysis of the chemical shifts (CONCISE, COordiNated ChemIcal Shifts bEhavior) for the interpretation of protein conformational equilibria following linear trajectories of NMR chemical shifts. CONCISE enables one to quantitatively measure the population shifts associated with ligand titrations and estimate the degree of collectiveness of the protein residues’ response to ligand binding, giving a concise view of the structural transitions. The combination of CONCISE with thermocalorimetric and kinetic data allows one to depict a protein’s approximate conformational energy landscape. We tested this method with the catalytic subunit of cAMP-dependent protein kinase A, a ubiquitous enzyme that undergoes conformational transitions upon both nucleotide and pseudo-substrate binding. When complemented with chemical shift covariance analysis (CHESCA), this new method offers both collective response and residue-specific correlations for ligand binding to proteins. PMID:24604024

Binding Free Energies of Host-Guest Systems by Nonequilibrium Alchemical Simulations with Constrained Dynamics: Theoretical Framework.

PubMed

Giovannelli, Edoardo; Procacci, Piero; Cardini, Gianni; Pagliai, Marco; Volkov, Victor; Chelli, Riccardo

2017-12-12

The fast-switching decoupling method is a powerful nonequilibrium technique to compute absolute binding free energies of ligand-receptor complexes (Sandberg et al., J. Chem. Theory Comput. 2014, 11, 423-435). Inspired by the theory of noncovalent binding association of Gilson and co-workers (Biophys. J. 1997, 72, 1047-1069), we develop two approaches, termed binded-domain and single-point alchemical-path schemes (BiD-AP and SiP-AP), based on the possibility of performing alchemical trajectories during which the ligand is constrained to fixed positions relative to the receptor. The BiD-AP scheme exploits a recent generalization of nonequilibrium work theorems to estimate the free energy difference between the coupled and uncoupled states of the ligand-receptor complex. With respect to the fast-switching decoupling method without constraints, BiD-AP prevents the ligand from leaving the binding site, but still requires an estimate of the positional binding-site volume, which may not be a simple task. On the other side, the SiP-AP scheme allows avoidance of the calculation of the binding-site volume by introducing an additional equilibrium simulation of ligand and receptor in the bound state. In the companion article (DOI: 10.1021/acs.jctc.7b00595), we show that the extra computational effort required by SiP-AP leads to a significant improvement of accuracy in the free energy estimates.

Ligand recognition by RAR and RXR receptors: binding and selectivity.

PubMed

Sussman, Fredy; de Lera, Angel R

2005-10-06

Fundamental biological functions, most notably embriogenesis, cell growth, cell differentiation, and cell apoptosis, are in part regulated by a complex genomic network that starts with the binding (and activation) of retinoids to their cognate receptors, members of the superfamily of nuclear receptors. We have studied ligand recognition of retinoic receptors (RXRalpha and RARgamma) using a molecular-mechanics-based docking method. The protocol used in this work is able to rank the affinity of pairs of ligands for a single retinoid receptor, the highest values corresponding to those that adapt better to the shape of the binding site and generate the optimal set of electrostatic and apolar interactions with the receptor. Moreover, our studies shed light onto some of the energetic contributions to retinoid receptor ligand selectivity. In this regard we show that there is a difference in polarity between the binding site regions that anchor the carboxylate in RAR and RXR, which translates itself into large differences in the energy of interaction of both receptors with the same ligand. We observe that the latter energy change is canceled off by the solvation energy penalty upon binding. This energy compensation is borne out as well by experiments that address the effect of site-directed mutagenesis on ligand binding to RARgamma. The hypothesis that the difference in binding site polarity might be exploited to build RXR-selective ligands is tested with some compounds having a thiazolidinedione anchoring group.

Donor states in inverse opals

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

Mahan, G. D.

We calculate the binding energy of an electron bound to a donor in a semiconductor inverse opal. Inverse opals have two kinds of cavities, which we call octahedral and tetrahedral, according to their group symmetry. We put the donor in the center of each of these two cavities and obtain the binding energy. The binding energies become very large when the inverse opal is made from templates with small spheres. For spheres less than 50 nm in diameter, the donor binding can increase to several times its unconfined value. Then electrons become tightly bound to the donor and are unlikelymore » to be thermally activated to the semiconductor conduction band. This conclusion suggests that inverse opals will be poor conductors.« less

a New Phenomenological Formula for Ground-State Binding Energies

NASA Astrophysics Data System (ADS)

Gangopadhyay, G.

A phenomenological formula based on liquid drop model has been proposed for ground-state binding energies of nuclei. The effect due to bunching of single particle levels has been incorporated through a term resembling the one-body Hamiltonian. The effect of n-p interaction has been included through a function of valence nucleons. A total of 50 parameters has been used in the present calculation. The root mean square (r.m.s.) deviation for the binding energy values for 2140 nuclei comes out to be 0.376 MeV, and that for 1091 alpha decay energies is 0.284 MeV. The correspondence with the conventional liquid drop model is discussed.

Photoinduced Bandgap Renormalization and Exciton Binding Energy Reduction in WS2.

PubMed

Cunningham, Paul D; Hanbicki, Aubrey T; McCreary, Kathleen M; Jonker, Berend T

2017-12-26

Strong Coulomb attraction in monolayer transition metal dichalcogenides gives rise to tightly bound excitons and many-body interactions that dominate their optoelectronic properties. However, this Coulomb interaction can be screened through control of the surrounding dielectric environment as well as through applied voltage, which provides a potential means of tuning the bandgap, exciton binding energy, and emission wavelength. Here, we directly show that the bandgap and exciton binding energy can be optically tuned by means of the intensity of the incident light. Using transient absorption spectroscopy, we identify a sub-picosecond decay component in the excited-state dynamics of WS 2 that emerges for incident photon energies above the A-exciton resonance, which originates from a nonequilibrium population of charge carriers that form excitons as they cool. The generation of this charge-carrier population exhibits two distinct energy thresholds. The higher threshold is coincident with the onset of continuum states and therefore provides a direct optical means of determining both the bandgap and exciton binding energy. Using this technique, we observe a reduction in the exciton binding energy from 310 ± 30 to 220 ± 20 meV as the excitation density is increased from 3 × 10 11 to 1.2 × 10 12 photons/cm 2 . This reduction is due to dynamic dipolar screening of Coulomb interactions by excitons, which is the underlying physical process that initiates bandgap renormalization and leads to the insulator-metal transition in monolayer transition metal dichalcogenides.

Assessing the Accuracy of Density Functional and Semiempirical Wave Function Methods for Water Nanoparticles: Comparing Binding and Relative Energies of (H2O)16 and (H2O)17 to CCSD(T) Results.

PubMed

Leverentz, Hannah R; Qi, Helena W; Truhlar, Donald G

2013-02-12

The binding energies and relative conformational energies of five configurations of the water 16-mer are computed using 61 levels of density functional (DF) theory, 12 methods combining DF theory with molecular mechanics damped dispersion (DF-MM), seven semiempirical-wave function (SWF) methods, and five methods combining SWF theory with molecular mechanics damped dispersion (SWF-MM). The accuracies of the computed energies are assessed by comparing them to recent high-level ab initio results; this assessment is more relevant to bulk water than previous tests on small clusters because a 16-mer is large enough to have water molecules that participate in more than three hydrogen bonds. We find that for water 16-mer binding energies the best DF, DF-MM, SWF, and SWF-MM methods (and their mean unsigned errors in kcal/mol) are respectively M06-2X (1.6), ωB97X-D (2.3), SCC-DFTB-γ(h) (35.2), and PM3-D (3.2). We also mention the good performance of CAM-B3LYP (1.8), M05-2X (1.9), and TPSSLYP (3.0). In contrast, for relative energies of various water nanoparticle 16-mer structures, the best methods (and mean unsigned errors in kcal/mol), in the same order of classes of methods, are SOGGA11-X (0.3), ωB97X-D (0.2), PM6 (0.4), and PMOv1 (0.6). We also mention the good performance of LC-ωPBE-D3 (0.3) and ωB97X (0.4). When both relative and binding energies are taken into consideration, the best methods overall (out of the 85 tested) are M05-2X without molecular mechanics and ωB97X-D when molecular mechanics corrections are included; with considerably higher average errors and considerably lower cost, the best SWF or SWF-MM method is PMOv1. We use six of the best methods for binding energies of the water 16-mers to calculate the binding energies of water hexamers and water 17-mers to test whether these methods are also reliable for binding energy calculations on other types of water clusters.

Postprocessing of docked protein-ligand complexes using implicit solvation models.

PubMed

Lindström, Anton; Edvinsson, Lotta; Johansson, Andreas; Andersson, C David; Andersson, Ida E; Raubacher, Florian; Linusson, Anna

2011-02-28

Molecular docking plays an important role in drug discovery as a tool for the structure-based design of small organic ligands for macromolecules. Possible applications of docking are identification of the bioactive conformation of a protein-ligand complex and the ranking of different ligands with respect to their strength of binding to a particular target. We have investigated the effect of implicit water on the postprocessing of binding poses generated by molecular docking using MM-PB/GB-SA (molecular mechanics Poisson-Boltzmann and generalized Born surface area) methodology. The investigation was divided into three parts: geometry optimization, pose selection, and estimation of the relative binding energies of docked protein-ligand complexes. Appropriate geometry optimization afforded more accurate binding poses for 20% of the complexes investigated. The time required for this step was greatly reduced by minimizing the energy of the binding site using GB solvation models rather than minimizing the entire complex using the PB model. By optimizing the geometries of docking poses using the GB(HCT+SA) model then calculating their free energies of binding using the PB implicit solvent model, binding poses similar to those observed in crystal structures were obtained. Rescoring of these poses according to their calculated binding energies resulted in improved correlations with experimental binding data. These correlations could be further improved by applying the postprocessing to several of the most highly ranked poses rather than focusing exclusively on the top-scored pose. The postprocessing protocol was successfully applied to the analysis of a set of Factor Xa inhibitors and a set of glycopeptide ligands for the class II major histocompatibility complex (MHC) A(q) protein. These results indicate that the protocol for the postprocessing of docked protein-ligand complexes developed in this paper may be generally useful for structure-based design in drug discovery.

High-Affinity Quasi-Specific Sites in the Genome: How the DNA-Binding Proteins Cope with Them

PubMed Central

Chakrabarti, J.; Chandra, Navin; Raha, Paromita; Roy, Siddhartha

2011-01-01

Many prokaryotic transcription factors home in on one or a few target sites in the presence of a huge number of nonspecific sites. Our analysis of λ-repressor in the Escherichia coli genome based on single basepair substitution experiments shows the presence of hundreds of sites having binding energy within 3 Kcal/mole of the OR1 binding energy, and thousands of sites with binding energy above the nonspecific binding energy. The effect of such sites on DNA-based processes has not been fully explored. The presence of such sites dramatically lowers the occupation probability of the specific site far more than if the genome were composed of nonspecific sites only. Our Brownian dynamics studies show that the presence of quasi-specific sites results in very significant kinetic effects as well. In contrast to λ-repressor, the E. coli genome has orders of magnitude lower quasi-specific sites for GalR, an integral transcription factor, thus causing little competition for the specific site. We propose that GalR and perhaps repressors of the same family have evolved binding modes that lead to much smaller numbers of quasi-specific sites to remove the untoward effects of genomic DNA. PMID:21889449

Evaluation of water displacement energetics in protein binding sites with grid cell theory.

PubMed

Gerogiokas, G; Southey, M W Y; Mazanetz, M P; Heifetz, A; Hefeitz, A; Bodkin, M; Law, R J; Michel, J

2015-04-07

Excess free energies, enthalpies and entropies of water in protein binding sites were computed via classical simulations and Grid Cell Theory (GCT) analyses for three pairs of congeneric ligands in complex with the proteins scytalone dehydratase, p38α MAP kinase and EGFR kinase respectively. Comparative analysis is of interest since the binding modes for each ligand pair differ in the displacement of one binding site water molecule, but significant variations in relative binding affinities are observed. Protocols that vary in their use of restraints on protein and ligand atoms were compared to determine the influence of protein-ligand flexibility on computed water structure and energetics, and to assess protocols for routine analyses of protein-ligand complexes. The GCT-derived binding affinities correctly reproduce experimental trends, but the magnitude of the predicted changes in binding affinities is exaggerated with respect to results from a previous Monte Carlo Free Energy Perturbation study. Breakdown of the GCT water free energies into enthalpic and entropic components indicates that enthalpy changes dominate the observed variations in energetics. In EGFR kinase GCT analyses revealed that replacement of a pyrimidine by a cyanopyridine perturbs water energetics up three hydration shells away from the ligand.

Calculating binding free energies of host-guest systems using the AMOEBA polarizable force field.

PubMed

Bell, David R; Qi, Rui; Jing, Zhifeng; Xiang, Jin Yu; Mejias, Christopher; Schnieders, Michael J; Ponder, Jay W; Ren, Pengyu

2016-11-09

Molecular recognition is of paramount interest in many applications. Here we investigate a series of host-guest systems previously used in the SAMPL4 blind challenge by using molecular simulations and the AMOEBA polarizable force field. The free energy results computed by Bennett's acceptance ratio (BAR) method using the AMOEBA polarizable force field ranked favorably among the entries submitted to the SAMPL4 host-guest competition [Muddana, et al., J. Comput.-Aided Mol. Des., 2014, 28, 305-317]. In this work we conduct an in-depth analysis of the AMOEBA force field host-guest binding thermodynamics by using both BAR and the orthogonal space random walk (OSRW) methods. The binding entropy-enthalpy contributions are analyzed for each host-guest system. For systems of inordinate binding entropy-enthalpy values, we further examine the hydrogen bonding patterns and configurational entropy contribution. The binding mechanism of this series of host-guest systems varies from ligand to ligand, driven by enthalpy and/or entropy changes. Convergence of BAR and OSRW binding free energy methods is discussed. Ultimately, this work illustrates the value of molecular modelling and advanced force fields for the exploration and interpretation of binding thermodynamics.

Estimating Atomic Contributions to Hydration and Binding Using Free Energy Perturbation.

PubMed

Irwin, Benedict W J; Huggins, David J

2018-06-12

We present a general method called atom-wise free energy perturbation (AFEP), which extends a conventional molecular dynamics free energy perturbation (FEP) simulation to give the contribution to a free energy change from each atom. AFEP is derived from an expansion of the Zwanzig equation used in the exponential averaging method by defining that the system total energy can be partitioned into contributions from each atom. A partitioning method is assumed and used to group terms in the expansion to correspond to individual atoms. AFEP is applied to six example free energy changes to demonstrate the method. Firstly, the hydration free energies of methane, methanol, methylamine, methanethiol, and caffeine in water. AFEP highlights the atoms in the molecules that interact favorably or unfavorably with water. Finally AFEP is applied to the binding free energy of human immunodeficiency virus type 1 protease to lopinavir, and AFEP reveals the contribution of each atom to the binding free energy, indicating candidate areas of the molecule to improve to produce a more strongly binding inhibitor. FEP gives a single value for the free energy change and is already a very useful method. AFEP gives a free energy change for each "part" of the system being simulated, where part can mean individual atoms, chemical groups, amino acids, or larger partitions depending on what the user is trying to measure. This method should have various applications in molecular dynamics studies of physical, chemical, or biochemical phenomena, specifically in the field of computational drug discovery.

Is Einstein the Father of the Atomic Bomb

NASA Astrophysics Data System (ADS)

Lustig, Harry

2009-05-01

Soon after the American atomic bombs were dropped on Hiroshima and Nagasaki, the notion took hold in the popular mind that Albert Einstein was ``the father of the bomb.'' The claim of paternity rests on the belief that E=mc2 is what makes the release of enormous amounts of energy in the fission process possible and that the atomic bomb could not have been built without it. This is a misapprehension. Most physicists have known that all along. Nevertheless in his reaction to the opera Dr. Atomic, a prominent physicist claimed that Einstein's discovery that matter can be transformed into energy ``is precisely what made the bomb possible.'' In fact what makes the fission reaction and one of its applications,the atomic bomb, possible is the smaller binding energies of fission products compared to the binding energies of the nuclei that undergo fission.The binding energies of nuclei are a well understood consequence of the numbers and arrangements of protons and neutrons in the nucleus and of quantum-mechanical effects. The realization that composite systems have binding energies predates relativity. In the 19th century they were ascribed to potential and other forms of energy that reside in the system. With Einstein they became rest mass energy. While E=mc2 is not the cause of fission, measuring the masses of the participants in the reaction does permit an easy calculation of the kinetic energy that is released.

Tropomyosin movement on F-actin during muscle activation explained by energy landscapes

PubMed Central

Orzechowski, Marek; Moore, Jeffrey R.; Fischer, Stefan; Lehman, William

2014-01-01

Muscle contraction is regulated by tropomyosin movement across the thin filament surface, which exposes or blocks myosin-binding sites on actin. Recent atomic structures of F-actin-tropomyosin have yielded the positions of tropomyosin on myosin-free and myosin-decorated actin. Here, the repositioning of α-tropomyosin between these locations on F-actin was systematically examined by optimizing the energy of the complex for a wide range of tropomyosin positions on F-actin. The resulting energy landscape provides a full-map of the F-actin surface preferred by tropomyosin, revealing a broad energy basin associated with the tropomyosin position that blocks myosin-binding. This is consistent with previously proposed low-energy oscillations of semi-rigid tropomyosin, necessary for shifting of tropomyosin following troponin-binding. In contrast, the landscape shows much less favorable energies when tropomyosin locates near its myosin-induced “open-state” position. This indicates that spontaneous movement of tropomyosin away from its energetic “ground-state” to the open-state is unlikely in absence of myosin. Instead, myosin-binding must drive tropomyosin toward the open-state to activate the thin filament. Additional energy landscapes were computed for disease-causing actin mutants that distort the topology of the actin-tropomyosin energy landscape, explaining their phenotypes. Thus, the computation of such energy landscapes offers a sensitive way to estimate the impact of mutations. PMID:24412204

Tropomyosin movement on F-actin during muscle activation explained by energy landscapes.

PubMed

Orzechowski, Marek; Moore, Jeffrey R; Fischer, Stefan; Lehman, William

2014-03-01

Muscle contraction is regulated by tropomyosin movement across the thin filament surface, which exposes or blocks myosin-binding sites on actin. Recent atomic structures of F-actin-tropomyosin have yielded the positions of tropomyosin on myosin-free and myosin-decorated actin. Here, the repositioning of α-tropomyosin between these locations on F-actin was systematically examined by optimizing the energy of the complex for a wide range of tropomyosin positions on F-actin. The resulting energy landscape provides a full-map of the F-actin surface preferred by tropomyosin, revealing a broad energy basin associated with the tropomyosin position that blocks myosin-binding. This is consistent with previously proposed low-energy oscillations of semi-rigid tropomyosin, necessary for shifting of tropomyosin following troponin-binding. In contrast, the landscape shows much less favorable energies when tropomyosin locates near its myosin-induced "open-state" position. This indicates that spontaneous movement of tropomyosin away from its energetic "ground-state" to the open-state is unlikely in absence of myosin. Instead, myosin-binding must drive tropomyosin toward the open-state to activate the thin filament. Additional energy landscapes were computed for disease-causing actin mutants that distort the topology of the actin-tropomyosin energy landscape, explaining their phenotypes. Thus, the computation of such energy landscapes offers a sensitive way to estimate the impact of mutations. Copyright © 2014 Elsevier Inc. All rights reserved.

Variational calculation of ground-state energy of iron atoms and condensed matter in strong magnetic fields. [at neutron star surfaces

NASA Technical Reports Server (NTRS)

Flowers, E. G.; Ruderman, M. A.; Lee, J.-F.; Sutherland, P. G.; Hillebrandt, W.; Mueller, E.

1977-01-01

Variational calculations of the binding energies of iron atoms and condensed matter in strong magnetic fields (greater than 10 to the 12th gauss). These calculations include the electron exchange energy. The cohesive energy of the condensed matter, which is the difference between these two binding energies, is of interest in pulsar theories and in the description of the surfaces of neutron stars. It is found that the cohesive energy ranges from 2.6 keV to 8.0 keV.

The Study of the Successive Metal-Ligand Binding Energies for Fe(sup +), Fe(sup -), V(sup +) and Co(sup +)

NASA Technical Reports Server (NTRS)

Bauschlicher, Charles W., Jr.; Ricca, Alessandra; Maitre, Philippe; Langhoff, Stephen R. (Technical Monitor)

1995-01-01

The successive binding energies of CO and H2O to Fe(sup +), CO to Fe(sup -), and H2 to Co(sup +) and V(sup +) are presented. Overall the computed results are in good agreement with experiment. The trends in binding energies are analyzed in terms of metal to ligand donation, ligand to metal donation, ligand-ligand repulsion, and changes in the metal atom, such as hybridization, promotion, and spin multiplicity. The geometry and vibrational frequencies are also shown to be directly affected by these effects.

Effect of H2 binding on the nonadiabatic transition probability between singlet and triplet states of the [NiFe]-hydrogenase active site.

PubMed

Kaliakin, Danil S; Zaari, Ryan R; Varganov, Sergey A

2015-02-12

We investigate the effect of H2 binding on the spin-forbidden nonadiabatic transition probability between the lowest energy singlet and triplet electronic states of [NiFe]-hydrogenase active site model, using a velocity averaged Landau-Zener theory. Density functional and multireference perturbation theories were used to provide parameters for the Landau-Zener calculations. It was found that variation of the torsion angle between the terminal thiolate ligands around the Ni center induces an intersystem crossing between the lowest energy singlet and triplet electronic states in the bare active site and in the active site with bound H2. Potential energy curves between the singlet and triplet minima along the torsion angle and H2 binding energies to the two spin states were calculated. Upon H2 binding to the active site, there is a decrease in the torsion angle at the minimum energy crossing point between the singlet and triplet states. The probability of nonadiabatic transitions at temperatures between 270 and 370 K ranges from 35% to 32% for the active site with bound H2 and from 42% to 38% for the bare active site, thus indicating the importance of spin-forbidden nonadiabatic pathways for H2 binding on the [NiFe]-hydrogenase active site.

Universal aspects of adhesion and atomic force microscopy

NASA Technical Reports Server (NTRS)

Banerjea, Amitava; Smith, John R.; Ferrante, John

1990-01-01

Adhesive energies are computed for flat and atomically sharp tips as a function of the normal distance to the substrate. The dependence of binding energies on tip shape is investigated. The magnitudes of the binding energies for the atomic force microscope are found to depend sensitively on tip material, tip shape and the sample site being probed. The form of the energy-distance curve, however, is universal and independent of these variables, including tip shape.

Δ isobars and nuclear saturation

NASA Astrophysics Data System (ADS)

Ekström, A.; Hagen, G.; Morris, T. D.; Papenbrock, T.; Schwartz, P. D.

2018-02-01

We construct a nuclear interaction in chiral effective field theory with explicit inclusion of the Δ -isobar Δ (1232 ) degree of freedom at all orders up to next-to-next-to-leading order (NNLO). We use pion-nucleon (π N ) low-energy constants (LECs) from a Roy-Steiner analysis of π N scattering data, optimize the LECs in the contact potentials up to NNLO to reproduce low-energy nucleon-nucleon scattering phase shifts, and constrain the three-nucleon interaction at NNLO to reproduce the binding energy and point-proton radius of 4He. For heavier nuclei we use the coupled-cluster method to compute binding energies, radii, and neutron skins. We find that radii and binding energies are much improved for interactions with explicit inclusion of Δ (1232 ) , while Δ -less interactions produce nuclei that are not bound with respect to breakup into α particles. The saturation of nuclear matter is significantly improved, and its symmetry energy is consistent with empirical estimates.

Energetic factors determining the binding of type I inhibitors to c-Met kinase: experimental studies and quantum mechanical calculations.

PubMed

Yu, Zhe; Ma, Yu-chi; Ai, Jing; Chen, Dan-qi; Zhao, Dong-mei; Wang, Xin; Chen, Yue-lei; Geng, Mei-yu; Xiong, Bing; Cheng, Mao-sheng; Shen, Jing-Kang

2013-11-01

To decipher the molecular interactions between c-Met and its type I inhibitors and to facilitate the design of novel c-Met inhibitors. Based on the prototype model inhibitor 1, four ligands with subtle differences in the fused aromatic rings were synthesized. Quantum chemistry was employed to calculate the binding free energy for each ligand. Symmetry-adapted perturbation theory (SAPT) was used to decompose the binding energy into several fundamental forces to elucidate the determinant factors. Binding free energies calculated from quantum chemistry were correlated well with experimental data. SAPT calculations showed that the predominant driving force for binding was derived from a sandwich π-π interaction with Tyr-1230. Arg-1208 was the differentiating factor, interacting with the 6-position of the fused aromatic ring system through the backbone carbonyl with a force pattern similar to hydrogen bonding. Therefore, a hydrogen atom must be attached at the 6-position, and changing the carbon atom to nitrogen caused unfavorable electrostatic interactions. The theoretical studies have elucidated the determinant factors involved in the binding of type I inhibitors to c-Met.

Cost Function Network-based Design of Protein-Protein Interactions: predicting changes in binding affinity.

PubMed

Viricel, Clément; de Givry, Simon; Schiex, Thomas; Barbe, Sophie

2018-02-20

Accurate and economic methods to predict change in protein binding free energy upon mutation are imperative to accelerate the design of proteins for a wide range of applications. Free energy is defined by enthalpic and entropic contributions. Following the recent progresses of Artificial Intelligence-based algorithms for guaranteed NP-hard energy optimization and partition function computation, it becomes possible to quickly compute minimum energy conformations and to reliably estimate the entropic contribution of side-chains in the change of free energy of large protein interfaces. Using guaranteed Cost Function Network algorithms, Rosetta energy functions and Dunbrack's rotamer library, we developed and assessed EasyE and JayZ, two methods for binding affinity estimation that ignore or include conformational entropic contributions on a large benchmark of binding affinity experimental measures. If both approaches outperform most established tools, we observe that side-chain conformational entropy brings little or no improvement on most systems but becomes crucial in some rare cases. as open-source Python/C ++ code at sourcesup.renater.fr/projects/easy-jayz. thomas.schiex@inra.fr and sophie.barbe@insa-toulouse.fr. Supplementary data are available at Bioinformatics online.

Binding free energy calculations to rationalize the interactions of huprines with acetylcholinesterase.

PubMed

Nascimento, Érica C M; Oliva, Mónica; Andrés, Juan

2018-05-01

In the present study, the binding free energy of a family of huprines with acetylcholinesterase (AChE) is calculated by means of the free energy perturbation method, based on hybrid quantum mechanics and molecular mechanics potentials. Binding free energy calculations and the analysis of the geometrical parameters highlight the importance of the stereochemistry of huprines in AChE inhibition. Binding isotope effects are calculated to unravel the interactions between ligands and the gorge of AChE. New chemical insights are provided to explain and rationalize the experimental results. A good correlation with the experimental data is found for a family of inhibitors with moderate differences in the enzyme affinity. The analysis of the geometrical parameters and interaction energy per residue reveals that Asp72, Glu199, and His440 contribute significantly to the network of interactions between active site residues, which stabilize the inhibitors in the gorge. It seems that a cooperative effect of the residues of the gorge determines the affinity of the enzyme for these inhibitors, where Asp72, Glu199, and His440 make a prominent contribution.

Adhesion of a bimetallic interface. Ph.D. Thesis - Case Western Reserve Univ.; [for Al, Mg, and Zn

NASA Technical Reports Server (NTRS)

Ferrante, J.

1978-01-01

The Hohenberg-Kohn and Kohn-Sham formalisms are used to examine binding (binding energy as a function of separation) for combinations of the simple metals Al(111), Zn(0001), Mg(0001), and Na(110) in contact. Similar metal contacts between Al, Zn, Mg, and Na are examined self-consistently in an ab initio calculation using the Kohn-Sham formalism. Crystallinity is included using the Aschroft pseudopotential via first order perturbation theory for the electron-ion interaction; and the ion-ion interaction is included exactly via a lattice sum. Binding energy was determined both in the local-density approximation and including gradient corrections to the exchange and correlation energy. Binding was found in all cases. In dissimilar metal contacts, interfacial bonding was greater than that in the weaker material predicting the possibility of metallic transfer. The nonzero position of the energy minimum in like metal contacts is explained in terms of consistency between the Ashcroft pseudopotential and the bulk charge density. Good agreement with experimental surface energies is obtained in the self-consistent calculation when nonlocal terms are included.

Binding free energy calculations to rationalize the interactions of huprines with acetylcholinesterase

NASA Astrophysics Data System (ADS)

Nascimento, Érica C. M.; Oliva, Mónica; Andrés, Juan

2018-03-01

In the present study, the binding free energy of a family of huprines with acetylcholinesterase (AChE) is calculated by means of the free energy perturbation method, based on hybrid quantum mechanics and molecular mechanics potentials. Binding free energy calculations and the analysis of the geometrical parameters highlight the importance of the stereochemistry of huprines in AChE inhibition. Binding isotope effects are calculated to unravel the interactions between ligands and the gorge of AChE. New chemical insights are provided to explain and rationalize the experimental results. A good correlation with the experimental data is found for a family of inhibitors with moderate differences in the enzyme affinity. The analysis of the geometrical parameters and interaction energy per residue reveals that Asp72, Glu199, and His440 contribute significantly to the network of interactions between active site residues, which stabilize the inhibitors in the gorge. It seems that a cooperative effect of the residues of the gorge determines the affinity of the enzyme for these inhibitors, where Asp72, Glu199, and His440 make a prominent contribution.

Binding free energy calculations to rationalize the interactions of huprines with acetylcholinesterase

NASA Astrophysics Data System (ADS)

Nascimento, Érica C. M.; Oliva, Mónica; Andrés, Juan

2018-05-01

In the present study, the binding free energy of a family of huprines with acetylcholinesterase (AChE) is calculated by means of the free energy perturbation method, based on hybrid quantum mechanics and molecular mechanics potentials. Binding free energy calculations and the analysis of the geometrical parameters highlight the importance of the stereochemistry of huprines in AChE inhibition. Binding isotope effects are calculated to unravel the interactions between ligands and the gorge of AChE. New chemical insights are provided to explain and rationalize the experimental results. A good correlation with the experimental data is found for a family of inhibitors with moderate differences in the enzyme affinity. The analysis of the geometrical parameters and interaction energy per residue reveals that Asp72, Glu199, and His440 contribute significantly to the network of interactions between active site residues, which stabilize the inhibitors in the gorge. It seems that a cooperative effect of the residues of the gorge determines the affinity of the enzyme for these inhibitors, where Asp72, Glu199, and His440 make a prominent contribution.

Properties of inhibitors of methane hydrate formation via molecular dynamics simulations.

PubMed

Anderson, Brian J; Tester, Jefferson W; Borghi, Gian Paolo; Trout, Bernhardt L

2005-12-21

Within the framework of a proposed two-step mechanism for hydrate inhibition, the energy of binding of four inhibitor molecules (PEO, PVP, PVCap, and VIMA) to a hydrate surface is estimated with molecular dynamic simulations. One key feature of this proposed mechanism is that the binding of an inhibitor molecule to the surface of an ensuing hydrate crystal disrupts growth and therein crystallization. It is found through the molecular dynamic simulations that inhibitor molecules that experimentally exhibit better inhibition strength also have higher free energies of binding, an indirect confirmation of our proposed mechanism. Inhibitors increasing in effectiveness, PEO < PVP < PVCap < VIMA, have increasingly negative (exothermic) binding energies of -0.2 < -20.6 < -37.5 < -45.8 kcal/mol and binding free energies of increasing favorability (+0.4 approximately = +0.5 < -9.4 < -15.1 kcal/mol). Furthermore, the effect of an inhibitor molecule on the local liquid water structure under hydrate-forming conditions was examined and correlated to the experimental effectiveness of the inhibitors. Two molecular characteristics that lead to strongly binding inhibitors were found: (1) a charge distribution on the edge of the inhibitor that mimics the charge separation in the water molecules on the surface of the hydrate and (2) the congruence of the size of the inhibitor with respect to the available space at the hydrate-surface binding site. Equipped with this molecular-level understanding of the process of hydrate inhibition via low-dosage kinetic hydrate inhibitors we can design new, more effective inhibitor molecules.

Computational study of Gleevec and G6G reveals molecular determinants of kinase inhibitor selectivity

DOE PAGES

Lin, Yen -Lin; Meng, Yilin; Huang, Lei; ...

2014-10-22

Gleevec is a potent inhibitor of Abl tyrosine kinase but not of the highly homologous c-Src kinase. Because the ligand binds to an inactive form of the protein in which an Asp-Phe-Gly structural motif along the activation loop adopts a so-called DFG-out conformation, it was suggested that binding specificity was controlled by a “conformational selection” mechanism. In this context, the binding affinity displayed by the kinase inhibitor G6G poses an intriguing challenge. Although it possesses a chemical core very similar to that of Gleevec, G6G is a potent inhibitor of both Abl and c-Src kinases. Both inhibitors bind to themore » DFG-out conformation of the kinases, which seems to be in contradiction with the conformational selection mechanism. To address this issue and display the hidden thermodynamic contributions affecting the binding selectivity, molecular dynamics free energy simulations with explicit solvent molecules were carried out. Relative to Gleevec, G6G forms highly favorable van der Waals dispersive interactions upon binding to the kinases via its triazine functional group, which is considerably larger than the corresponding pyridine moiety in Gleevec. Upon binding of G6G to c-Src, these interactions offset the unfavorable free energy cost of the DFG-out conformation. When binding to Abl, however, G6G experiences an unfavorable free energy penalty due to steric clashes with the phosphate-binding loop, yielding an overall binding affinity that is similar to that of Gleevec. Such steric clashes are absent when G6G binds to c-Src, due to the extended conformation of the phosphate-binding loop.« less

A molecular dynamics investigation of CDK8/CycC and ligand binding: conformational flexibility and implication in drug discovery

NASA Astrophysics Data System (ADS)

Cholko, Timothy; Chen, Wei; Tang, Zhiye; Chang, Chia-en A.

2018-05-01

Abnormal activity of cyclin-dependent kinase 8 (CDK8) along with its partner protein cyclin C (CycC) is a common feature of many diseases including colorectal cancer. Using molecular dynamics (MD) simulations, this study determined the dynamics of the CDK8-CycC system and we obtained detailed breakdowns of binding energy contributions for four type-I and five type-II CDK8 inhibitors. We revealed system motions and conformational changes that will affect ligand binding, confirmed the essentialness of CycC for inclusion in future computational studies, and provide guidance in development of CDK8 binders. We employed unbiased all-atom MD simulations for 500 ns on twelve CDK8-CycC systems, including apoproteins and protein-ligand complexes, then performed principal component analysis (PCA) and measured the RMSF of key regions to identify protein dynamics. Binding pocket volume analysis identified conformational changes that accompany ligand binding. Next, H-bond analysis, residue-wise interaction calculations, and MM/PBSA were performed to characterize protein-ligand interactions and find the binding energy. We discovered that CycC is vital for maintaining a proper conformation of CDK8 to facilitate ligand binding and that the system exhibits motion that should be carefully considered in future computational work. Surprisingly, we found that motion of the activation loop did not affect ligand binding. Type-I and type-II ligand binding is driven by van der Waals interactions, but electrostatic energy and entropic penalties affect type-II binding as well. Binding of both ligand types affects protein flexibility. Based on this we provide suggestions for development of tighter-binding CDK8 inhibitors and offer insight that can aid future computational studies.

Binding Preferences of Amino Acids for Gold Nanoparticles: A Molecular Simulation Study.

PubMed

Shao, Qing; Hall, Carol K

2016-08-09

A better understanding of the binding preference of amino acids for gold nanoparticles of different diameters could aid in the design of peptides that bind specifically to nanoparticles of a given diameter. Here we identify the binding preference of 19 natural amino acids for three gold nanoparticles with diameters of 1.0, 2.0, and 4.0 nm, and investigate the mechanisms that govern these preferences. We calculate potentials of mean force between 36 entities (19 amino acids and 17 side chains) and the three gold nanoparticles in explicit water using well-tempered metadynamics simulations. Comparing these potentials of mean force determines the amino acids' nanoparticle binding preferences and if these preferences are controlled by the backbone, the side chain, or both. Twelve amino acids prefer to bind to the 4.0 nm gold nanoparticle, and seven prefer to bind to the 2.0 nm one. We also use atomistic molecular dynamics simulations to investigate how water molecules near the nanoparticle influence the binding of the amino acids. The solvation shells of the larger nanoparticles have higher water densities than those of the smaller nanoparticles while the orientation distributions of the water molecules in the shells of all three nanoparticles are similar. The nanoparticle preferences of the amino acids depend on whether their binding free energy is determined mainly by their ability to replace or to reorient water molecules in the nanoparticle solvation shell. The amino acids whose binding free energy depends mainly on the replacement of water molecules are likely to prefer to bind to the largest nanoparticle and tend to have relatively simple side chain structures. Those whose binding free energy depends mainly on their ability to reorient water molecules prefer a smaller nanoparticle and tend to have more complex side chain structures.

Theoretical Insights into Methane C–H Bond Activation on Alkaline Metal Oxides

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

Aljama, Hassan; Nørskov, Jens K.; Abild-Pedersen, Frank

Here, we investigate the role of alkaline metal oxides (AMO) (MgO, CaO, and SrO) in activating the C–H bond in methane. We also use Density Functional Theory (DFT) and microkinetic modeling to study the catalytic elementary steps in breaking the C–H bond in methane and creating the methyl radical, a precursor prior to creating C2 products. We also study the effects of surface geometry on the catalytic activity of AMO by examining terrace and step sites. We observe that the process of activating methane depends strongly on the structure of the AMO. When the AMO surface is doped with anmore » alkali metal, the transition state (TS) structure has a methyl radical-like behavior, where the methyl radical interacts weakly with the AMO surface. In this case, the TS energy scales with the hydrogen binding energy. On pure AMO, the TS interacts with AMO surface oxygen as well as the metal atom on the surface, and consequently the TS energy scales with the binding energy of hydrogen and methyl. We study the activity of AMO using a mean-field microkinetic model. The results indicate that terrace sites have similar catalytic activity, with the exception of MgO(100). Step sites bind hydrogen more strongly, making them more active, and this confirms previously reported experimental results. We map the catalytic activity of AMO using a volcano plot with two descriptors: the methyl and the hydrogen binding energies, with the latter being a more significant descriptor. The microkinetic model results suggest that C–H bond dissociation is not always the rate-limiting step. At weak hydrogen binding, the reaction is limited by C–H bond activation. At strong hydrogen binding, the reaction is limited due to poisoning of the active site. We found an increase in activity of AMO as the basicity increased. Finally, the developed microkinetic model allows screening for improved catalysts using simple calculations of the hydrogen binding energy.« less

Theoretical Insights into Methane C–H Bond Activation on Alkaline Metal Oxides

DOE PAGES

Aljama, Hassan; Nørskov, Jens K.; Abild-Pedersen, Frank

2017-07-17

Here, we investigate the role of alkaline metal oxides (AMO) (MgO, CaO, and SrO) in activating the C–H bond in methane. We also use Density Functional Theory (DFT) and microkinetic modeling to study the catalytic elementary steps in breaking the C–H bond in methane and creating the methyl radical, a precursor prior to creating C2 products. We also study the effects of surface geometry on the catalytic activity of AMO by examining terrace and step sites. We observe that the process of activating methane depends strongly on the structure of the AMO. When the AMO surface is doped with anmore » alkali metal, the transition state (TS) structure has a methyl radical-like behavior, where the methyl radical interacts weakly with the AMO surface. In this case, the TS energy scales with the hydrogen binding energy. On pure AMO, the TS interacts with AMO surface oxygen as well as the metal atom on the surface, and consequently the TS energy scales with the binding energy of hydrogen and methyl. We study the activity of AMO using a mean-field microkinetic model. The results indicate that terrace sites have similar catalytic activity, with the exception of MgO(100). Step sites bind hydrogen more strongly, making them more active, and this confirms previously reported experimental results. We map the catalytic activity of AMO using a volcano plot with two descriptors: the methyl and the hydrogen binding energies, with the latter being a more significant descriptor. The microkinetic model results suggest that C–H bond dissociation is not always the rate-limiting step. At weak hydrogen binding, the reaction is limited by C–H bond activation. At strong hydrogen binding, the reaction is limited due to poisoning of the active site. We found an increase in activity of AMO as the basicity increased. Finally, the developed microkinetic model allows screening for improved catalysts using simple calculations of the hydrogen binding energy.« less

Molecular dynamics simulations of energy dissipation and non-thermal diffusion on amorphous solid water.

PubMed

Fredon, A; Cuppen, H M

2018-02-21

Molecules in space are synthesized via a large variety of gas-phase reactions, and reactions on dust-grain surfaces, where the surface acts as a catalyst. Especially, saturated, hydrogen-rich molecules are formed through surface chemistry where the interstellar grains act as a meeting place and absorbing energy. Here we present the results of thousands of molecular dynamics simulations to quantify the outcome of an energy dissipation process. Admolecules on top of an amorphous solid water surface have been given translational energy between 0.5 and 5 eV. Three different surface species are considered, CO 2 , H 2 O and CH 4 , spanning a range in binding energies, number of internal degrees of freedom and molecular weight. The results are compared against a previous study using a crystalline water ice surface. Possible outcomes of a dissipation process are adsorption - possibly after long-range diffusion-, desorption and desorption of a surface molecule. The three admolecules were found to bind at different locations on the surface, particularly in terms of height. Water preferably binds on top of the surface, whereas methane fills the nanopores on the surface. This has direct consequences for desorption, travelled distance, and kick-out probabilities. The admolecules are found to frequently travel several tens of angstroms before stabilizing on a binding site, allowing follow-up reactions en route. We present kick-out probabilities and we have been able to quantify the desorption probability which depends on the binding energy of the species, the translational excitation, and a factor that accounts for difference in binding site height. We provide expressions that can be incorporated in astrochemical models to predict grain surface formation and return into the gas phase of these products.

A Critical Review of Validation, Blind Testing, and Real- World Use of Alchemical Protein-Ligand Binding Free Energy Calculations.

PubMed

Abel, Robert; Wang, Lingle; Mobley, David L; Friesner, Richard A

2017-01-01

Protein-ligand binding is among the most fundamental phenomena underlying all molecular biology, and a greater ability to more accurately and robustly predict the binding free energy of a small molecule ligand for its cognate protein is expected to have vast consequences for improving the efficiency of pharmaceutical drug discovery. We briefly reviewed a number of scientific and technical advances that have enabled alchemical free energy calculations to recently emerge as a preferred approach, and critically considered proper validation and effective use of these techniques. In particular, we characterized a selection bias effect which may be important in prospective free energy calculations, and introduced a strategy to improve the accuracy of the free energy predictions. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Intermolecular symmetry-adapted perturbation theory study of large organic complexes.

PubMed

Heßelmann, Andreas; Korona, Tatiana

2014-09-07

Binding energies for the complexes of the S12L database by Grimme [Chem. Eur. J. 18, 9955 (2012)] were calculated using intermolecular symmetry-adapted perturbation theory combined with a density-functional theory description of the interacting molecules. The individual interaction energy decompositions revealed no particular change in the stabilisation pattern as compared to smaller dimer systems at equilibrium structures. This demonstrates that, to some extent, the qualitative description of the interaction of small dimer systems may be extrapolated to larger systems, a method that is widely used in force-fields in which the total interaction energy is decomposed into atom-atom contributions. A comparison of the binding energies with accurate experimental reference values from Grimme, the latter including thermodynamic corrections from semiempirical calculations, has shown a fairly good agreement to within the error range of the reference binding energies.

Insights into the functional role of protonation states in the HIV-1 protease-BEA369 complex: molecular dynamics simulations and free energy calculations.

PubMed

Chen, Jianzhong; Yang, Maoyou; Hu, Guodong; Shi, Shuhua; Yi, Changhong; Zhang, Qinggang

2009-10-01

The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method combined with molecular dynamics (MD) simulations were used to investigate the functional role of protonation in human immunodeficiency virus type 1 (HIV-1) protease complexed with the inhibitor BEA369. Our results demonstrate that protonation of two aspartic acids (Asp25/Asp25') has a strong influence on the dynamics behavior of the complex, the binding free energy of BEA369, and inhibitor-residue interactions. Relative binding free energies calculated using the MM-PBSA method show that protonation of Asp25 results in the strongest binding of BEA369 to HIV-1 protease. Inhibitor-residue interactions computed by the theory of free energy decomposition also indicate that protonation of Asp25 has the most favorable effect on binding of BEA369. In addition, hydrogen-bond analysis based on the trajectories of the MD simulations shows that protonation of Asp25 strongly influences the water-mediated link of a conserved water molecule, Wat301. We expect that the results of this study will contribute significantly to binding calculations for BEA369, and to the design of high affinity inhibitors.

An extension of the fenske-hall LCAO method for approximate calculations of inner-shell binding energies of molecules

NASA Astrophysics Data System (ADS)

Zwanziger, Ch.; Reinhold, J.

1980-02-01

The approximate LCAO MO method of Fenske and Hall has been extended to an all-election method allowing the calculation of inner-shell binding energies of molecules and their chemical shifts. Preliminary results are given.

Structure and electronic properties of ion pairs accompanying cyclic morpholinium cation and alkylphosphite anion based ionic liquids

NASA Astrophysics Data System (ADS)

Verma, Prakash L.; Singh, Priti; Gejji, Shridhar P.

2017-07-01

Molecular insights for the formation of ion pairs accompanying the cyclic ammonium cation based room temperature ionic liquids (RTILs) composed of alkyl substituted N-methylmorpholinium (RMMor) and alkylphosphite [(Rsbnd O)2PHdbnd O] (Rdbnd ethyl, butyl, hexyl, octyl) anion have been derived from the M06-2x level of theory. Electronic structures, binding energies, and spectral characteristics of the ion pairs underlying these RTILs have been characterized. The ion pair formation is largely governed by Csbnd H⋯O and other intermolecular interactions. Calculated binding energies increase with the increasing alkyl chain on either cation or alkylphosphite anion. The cation-anion binding reveals signature in the frequency down-(red) shift of the characteristic anionic Pdbnd O stretching whereas the Psbnd H stretching exhibits a shift in the opposite direction in vibrational spectra which has further been rationalized through molecular electron density topography. Correlations of measured electrochemical stability with the separation of frontier orbital energies and binding energies in the ion pairs have further been established.

Linear Scaling of the Exciton Binding Energy versus the Band Gap of Two-Dimensional Materials

NASA Astrophysics Data System (ADS)

Choi, Jin-Ho; Cui, Ping; Lan, Haiping; Zhang, Zhenyu

2015-08-01

The exciton is one of the most crucial physical entities in the performance of optoelectronic and photonic devices, and widely varying exciton binding energies have been reported in different classes of materials. Using first-principles calculations within the G W -Bethe-Salpeter equation approach, here we investigate the excitonic properties of two recently discovered layered materials: phosphorene and graphene fluoride. We first confirm large exciton binding energies of, respectively, 0.85 and 2.03 eV in these systems. Next, by comparing these systems with several other representative two-dimensional materials, we discover a striking linear relationship between the exciton binding energy and the band gap and interpret the existence of the linear scaling law within a simple hydrogenic picture. The broad applicability of this novel scaling law is further demonstrated by using strained graphene fluoride. These findings are expected to stimulate related studies in higher and lower dimensions, potentially resulting in a deeper understanding of excitonic effects in materials of all dimensionalities.

Experimentally Determined Binding Energies of Astrophysically Relevant Hydrocarbons in Pure and H2O-Layered Ices

NASA Astrophysics Data System (ADS)

Behmard, Aida; Graninger, Dawn; Fayolle, Edith; Oberg, Karin I.

2017-01-01

Small hydrocarbons represent an important organic reservoir in a variety of interstellar environments. Constraints on desorption temperatures and binding energies of hydrocarbons are thus necessary for accurate predictions of where and in which phase these molecules exist. Through a series of temperature programmed desorption experiments, we determined binding energies of 1, 2, and 3-carbon interstellar hydrocarbons (CH4, C2H2, C2H4, C2H6, C3H4, C3H6, and C3H8) in pure ices and in relation to water ice, the dominant ice constituent during star and planet formation. These empirically determined values can be used to inform observations and models of the molecular spatial distribution in protoplanetary disks, thus providing insight into planetesimal composition. In addition, knowledge of hydrocarbon binding energies will refine simulations of grain surface chemistry, allowing for better predictions of the chemical conditions that lead to the production of complex organic molecules vital for life.

Binding Energy calculation of GSK-3 protein of Human against some anti-diabetic compounds of Momordica charantia linn (Bitter melon)

PubMed Central

Hazarika, Ridip; Parida, Pratap; Neog, Bijoy; Yadav, Raj Narain Singh

2012-01-01

Diabetes is one of the major life threatening diseases worldwide. It creates major health problems in urban India. Glycogen Synthase Kinase-3 (GSK-3) protein of human is known for phosphorylating and inactivating glycogen synthase which also acts as a negative regulator in the hormonal control of glucose homeostasis. In traditional medicine, Momordica charantia is used as antidiabetic plant because of its hypoglycemic effect. Hence to block the active site of the GSK-3 protein three anti-diabetic compounds namely, charantin, momordenol & momordicilin were taken from Momordica charantia for docking study and calculation of binding energy. The aim of present investigation is to find the binding energy of three major insulin-like active compounds against glycogen synthase kinase-3 (GSK-3), one of the key proteins involved in carbohydrate metabolism, with the help of molecular docking using ExomeTM Horizon suite. The study recorded minimum binding energy by momordicilin in comparison to the others. PMID:22493531

Binding Energy calculation of GSK-3 protein of Human against some anti-diabetic compounds of Momordica charantia linn (Bitter melon).

PubMed

Hazarika, Ridip; Parida, Pratap; Neog, Bijoy; Yadav, Raj Narain Singh

2012-01-01

Diabetes is one of the major life threatening diseases worldwide. It creates major health problems in urban India. Glycogen Synthase Kinase-3 (GSK-3) protein of human is known for phosphorylating and inactivating glycogen synthase which also acts as a negative regulator in the hormonal control of glucose homeostasis. In traditional medicine, Momordica charantia is used as antidiabetic plant because of its hypoglycemic effect. Hence to block the active site of the GSK-3 protein three anti-diabetic compounds namely, charantin, momordenol & momordicilin were taken from Momordica charantia for docking study and calculation of binding energy. The aim of present investigation is to find the binding energy of three major insulin-like active compounds against glycogen synthase kinase-3 (GSK-3), one of the key proteins involved in carbohydrate metabolism, with the help of molecular docking using ExomeTM Horizon suite. The study recorded minimum binding energy by momordicilin in comparison to the others.

Calculation of Cyclodextrin Binding Affinities: Energy, Entropy, and Implications for Drug Design

PubMed Central

Chen, Wei; Chang, Chia-En; Gilson, Michael K.

2004-01-01

The second generation Mining Minima method yields binding affinities accurate to within 0.8 kcal/mol for the associations of α-, β-, and γ-cyclodextrin with benzene, resorcinol, flurbiprofen, naproxen, and nabumetone. These calculations require hours to a day on a commodity computer. The calculations also indicate that the changes in configurational entropy upon binding oppose association by as much as 24 kcal/mol and result primarily from a narrowing of energy wells in the bound versus the free state, rather than from a drop in the number of distinct low-energy conformations on binding. Also, the configurational entropy is found to vary substantially among the bound conformations of a given cyclodextrin-guest complex. This result suggests that the configurational entropy must be accounted for to reliably rank docked conformations in both host-guest and ligand-protein complexes. In close analogy with the common experimental observation of entropy-enthalpy compensation, the computed entropy changes show a near-linear relationship with the changes in mean potential plus solvation energy. PMID:15339804

Ion Binding Energies Determining Functional Transport of ClC Proteins

NASA Astrophysics Data System (ADS)

Yu, Tao; Guo, Xu; Zou, Xian-Wu; Sang, Jian-Ping

2014-06-01

The ClC-type proteins, a large family of chloride transport proteins ubiquitously expressed in biological organisms, have been extensively studied for decades. Biological function of ClC proteins can be reflected by analyzing the binding situation of Cl- ions. We investigate ion binding properties of ClC-ec1 protein with the atomic molecular dynamics simulation approach. The calculated electrostatic binding energy results indicate that Cl- at the central binding site Scen has more binding stability than the internal binding site Sint. Quantitative comparison between the latest experimental heat release data isothermal titration calorimetry (ITC) and our calculated results demonstrates that chloride ions prefer to bind at Scen than Sint in the wild-type ClC-ec1 structure and prefer to bind at Sext and Scen than Sint in mutant E148A/E148Q structures. Even though the chloride ions make less contribution to heat release when binding to Sint and are relatively unstable in the Cl- pathway, they are still part contributors for the Cl- functional transport. This work provides a guide rule to estimate the importance of Cl- at the binding sites and how chloride ions have influences on the function of ClC proteins.

Biochemical activity of a fluorescent dye rhodamine 6G: Molecular modeling, electrochemical, spectroscopic and thermodynamic studies.

PubMed

Al Masum, Abdulla; Chakraborty, Maharudra; Ghosh, Soumen; Laha, Dipranjan; Karmakar, Parimal; Islam, Md Maidul; Mukhopadhyay, Subrata

2016-11-01

Interaction of CT DNA with Rhodamine 6G (R6G) has been studied using molecular docking, electrochemical, spectroscopic and thermodynamic methods. From the study, it was illustrated that Rhodamine 6G binds to the minor groove of CT DNA. The binding was cooperative in nature. Circular voltametric study showed significant change in peak current and peak potential due to complexation. All the studies showed that the binding constant was in the order of 10 6 M -1 . Circular dichroic spectra showed significant conformational change on binding and DNA unwind during binding. Thermodynamic study showed that binding was favored by negative enthalpy and positive entropy change. From thermodynamic study it was also observed that several positive and negative free energies played significant role during binding and the unfavorable conformational free energy change was overcame by highly negative hydrophobic and salt dependent free energy changes. The experimental results were further validated using molecular docking study and the effect of structure on binding has been studied theoretically. From docking study it was found that the hydrophobic interaction and hydrogen bonds played a significant role during binding. The dye was absorbed by cell and this phenomenon was studied using fluorescent microscope. Cell survivability test showed that the dye active against Human Breast Cancer cells MDA-MB 468. ROS study showed that the activity is due to the production of reactive oxygen. Copyright © 2016 Elsevier B.V. All rights reserved.

A novel BRET-based binding assay for interaction studies of relaxin family peptide receptor 3 with its ligands.

PubMed

Wang, Jia-Hui; Shao, Xiao-Xia; Hu, Meng-Jun; Wei, Dian; Liu, Ya-Li; Xu, Zeng-Guang; Guo, Zhan-Yun

2017-05-01

Relaxin family peptide receptor 3 (RXFP3) is an A-class G protein-coupled receptor that is implicated in the regulation of food intake and stress response upon activation by its cognate agonist relaxin-3. To study its interaction with various ligands, we developed a novel bioluminescence resonance energy transfer (BRET)-based binding assay using the brightest NanoLuc as an energy donor and a newly developed cyan-excitable orange fluorescent protein (CyOFP) as an energy acceptor. An engineered CyOFP without intrinsic cysteine residues but with an introduced cysteine at the C-terminus was overexpressed in Escherichia coli and chemically conjugated to the A-chain N-terminus of an easily labeled chimeric R3/I5 peptide via an intermolecular disulfide linkage. After the CyOFP-conjugated R3/I5 bound to a shortened human RXFP3 (removal of 33 N-terminal residues) fused with the NanoLuc reporter at the N-terminus, high BRET signals were detected. Saturation binding and real-time binding assays demonstrated that this BRET pair retained high binding affinity with fast association/dissociation. Using this BRET pair, binding potencies of various ligands with RXFP3 were conveniently measured through competition binding assays. Thus, the novel BRET-based binding assay facilitates interaction studies of RXFP3 with various ligands. The engineered CyOFP without intrinsic cysteine residues may also be applied to other BRET-based binding assays in future studies.

The FTMap family of web servers for determining and characterizing ligand binding hot spots of proteins

PubMed Central

Kozakov, Dima; Grove, Laurie E.; Hall, David R.; Bohnuud, Tanggis; Mottarella, Scott; Luo, Lingqi; Xia, Bing; Beglov, Dmitri; Vajda, Sandor

2016-01-01

FTMap is a computational mapping server that identifies binding hot spots of macromolecules, i.e., regions of the surface with major contributions to the ligand binding free energy. To use FTMap, users submit a protein, DNA, or RNA structure in PDB format. FTMap samples billions of positions of small organic molecules used as probes and scores the probe poses using a detailed energy expression. Regions that bind clusters of multiple probe types identify the binding hot spots, in good agreement with experimental data. FTMap serves as basis for other servers, namely FTSite to predict ligand binding sites, FTFlex to account for side chain flexibility, FTMap/param to parameterize additional probes, and FTDyn to map ensembles of protein structures. Applications include determining druggability of proteins, identifying ligand moieties that are most important for binding, finding the most bound-like conformation in ensembles of unliganded protein structures, and providing input for fragment based drug design. FTMap is more accurate than classical mapping methods such as GRID and MCSS, and is much faster than the more recent approaches to protein mapping based on mixed molecular dynamics. Using 16 probe molecules, the FTMap server finds the hot spots of an average size protein in less than an hour. Since FTFlex performs mapping for all low energy conformers of side chains in the binding site, its completion time is proportionately longer. PMID:25855957

In silico evolution of the Drosophila gap gene regulatory sequence under elevated mutational pressure.

PubMed

Chertkova, Aleksandra A; Schiffman, Joshua S; Nuzhdin, Sergey V; Kozlov, Konstantin N; Samsonova, Maria G; Gursky, Vitaly V

2017-02-07

Cis-regulatory sequences are often composed of many low-affinity transcription factor binding sites (TFBSs). Determining the evolutionary and functional importance of regulatory sequence composition is impeded without a detailed knowledge of the genotype-phenotype map. We simulate the evolution of regulatory sequences involved in Drosophila melanogaster embryo segmentation during early development. Natural selection evaluates gene expression dynamics produced by a computational model of the developmental network. We observe a dramatic decrease in the total number of transcription factor binding sites through the course of evolution. Despite a decrease in average sequence binding energies through time, the regulatory sequences tend towards organisations containing increased high affinity transcription factor binding sites. Additionally, the binding energies of separate sequence segments demonstrate ubiquitous mutual correlations through time. Fewer than 10% of initial TFBSs are maintained throughout the entire simulation, deemed 'core' sites. These sites have increased functional importance as assessed under wild-type conditions and their binding energy distributions are highly conserved. Furthermore, TFBSs within close proximity of core sites exhibit increased longevity, reflecting functional regulatory interactions with core sites. In response to elevated mutational pressure, evolution tends to sample regulatory sequence organisations with fewer, albeit on average, stronger functional transcription factor binding sites. These organisations are also shaped by the regulatory interactions among core binding sites with sites in their local vicinity.

The Modified Hartmann Potential Effects on γ-rigid Bohr Hamiltonian

NASA Astrophysics Data System (ADS)

Suparmi, A.; Cari, C.; Nur Pratiwi, Beta

2018-04-01

In this paper, we present the solution of Bohr Hamiltonian in the case of γ-rigid for the modified Hartmann potential. The modified Hartmann potential was formed from the original Hartmann potential, consists of β function and θ function. By using the separation method, the three-dimensional Bohr Hamiltonian equation was reduced into three one-dimensional Schrodinger-like equation which was solved analytically. The results for the wavefunction were shown in mathematically, while for the binding energy was solved numerically. The numerical binding energy for the presence of the modified Hartmann potential is lower than the binding energy value in the absence of modified Hartmann potential effect.

Docking, molecular dynamics, binding energy-MM-PBSA studies of naphthofuran derivatives to identify potential dual inhibitors against BACE-1 and GSK-3β.

PubMed

Kumar, Akhil; Srivastava, Gaurava; Negi, Arvind S; Sharma, Ashok

2018-01-19

BACE-1 and GSK-3β both are potential therapeutic drug targets for Alzheimer's disease. Recently, both these targets received attention for designing dual inhibitors. Till now only two scaffolds (triazinone and curcumin) derivatives have been reported as BACE-1 and GSK-3β dual inhibitors. In our previous work, we have reported first in class dual inhibitor for BACE-1 and GSK-3β. In this study, we have explored other naphthofuran derivatives for their potential to inhibit BACE-1 and GSK-3β through docking, molecular dynamics, binding energy (MM-PBSA). These computational methods were performed to estimate the binding affinity of naphthofuran derivatives towards the BACE-1 and GSK-3β. In the docking results, two derivatives (NS7 and NS9) showed better binding affinity as compared to previously reported inhibitors. Hydrogen bond occupancy of NS7 and NS9 generated from MD trajectories showed good interaction with the flap residues Gln73, Thr72 of BACE-1 and Arg141, Thr138 residues of GSK-3β. MM-PBSA and energy decomposition per residue revealed different components of binding energy and relative importance of amino acid involved in binding. The results showed that the binding of inhibitors was majorly governed by the hydrophobic interactions and suggesting that hydrophobic interactions might be the key to design dual inhibitors for BACE1-1 and GSK-3β. Distance between important pair of amino acid residues indicated that BACE-1 and GSK-3β adopt closed conformation and become inactive after ligand binding. The results suggested that naphthofuran derivatives might act as dual inhibitor against BACE-1 and GSK-3β.

Ligand deconstruction: Why some fragment binding positions are conserved and others are not

PubMed Central

Kozakov, Dima; Hall, David R.; Jehle, Stefan; Luo, Lingqi; Ochiana, Stefan O.; Jones, Elizabeth V.; Pollastri, Michael; Allen, Karen N.; Whitty, Adrian; Vajda, Sandor

2015-01-01

Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots—regions of the protein where interactions with a ligand contribute substantial binding free energy—the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even when other parts of the ligand are removed. This hypothesis is supported by eight case studies. The condition helps identify whether a protein is suitable for FBDD, predicts the size of fragments required for screening, and determines whether a fragment hit can be extended into a higher affinity ligand. Our results show that ligand binding sites can usefully be thought of in terms of an anchor site, which is the top-ranked hot spot and dominates the free energy of binding, surrounded by a number of weaker satellite sites that confer improved affinity and selectivity for a particular ligand and that it is the intrinsic binding potential of the protein surface that determines whether it can serve as a robust binding site for a suitably optimized ligand. PMID:25918377

The Role of Pectin in Pb Binding by Carrot Peel Biosorbents: Isoterm Adsorption Study

NASA Astrophysics Data System (ADS)

Hastuti, B.; Totiana, F.; Winiasih, R.

2018-04-01

Cheaply and abundantly biosorption available materials such as carrot peels can be a cost-efficient method for removing heavy metals from wastewater. To investigate the role pectin plays in metal binding by carrot peels, commerce pectin was compared. FTIR spectra confirmed the presence of carboxyl and hydroxyl groups in commerce pectin and carrot pectin. Isoterm experiments showed that all materials could remove Pb (II) ion. All of materials binding Pb (II) follow Freundlich models adsorption. The commerce pectin bindsPb (II) by involving energy 16.6 KJ/mole whereas pectin from carrot peel involves energy 21.09 KJ/mole. It indicates that commerce pectin binds the Pb (II) by physics adsorption whereas pectin from carrot peel by physics and chemical adsorption.

Dual binding in cohesin-dockerin complexes: the energy landscape and the role of short, terminal segments of the dockerin module.

PubMed

Wojciechowski, Michał; Różycki, Bartosz; Huy, Pham Dinh Quoc; Li, Mai Suan; Bayer, Edward A; Cieplak, Marek

2018-03-22

The assembly of the polysaccharide degradating cellulosome machinery is mediated by tight binding between cohesin and dockerin domains. We have used an empirical model known as FoldX as well as molecular mechanics methods to determine the free energy of binding between a cohesin and a dockerin from Clostridium thermocellum in two possible modes that differ by an approximately 180° rotation. Our studies suggest that the full-length wild-type complex exhibits dual binding at room temperature, i.e., the two modes of binding have comparable probabilities at equilibrium. The ability to bind in the two modes persists at elevated temperatures. However, single-point mutations or truncations of terminal segments in the dockerin result in shifting the equilibrium towards one of the binding modes. Our molecular dynamics simulations of mechanical stretching of the full-length wild-type cohesin-dockerin complex indicate that each mode of binding leads to two kinds of stretching pathways, which may be mistakenly taken as evidence of dual binding.

Methylene blue binding to DNA with alternating AT base sequence: minor groove binding is favored over intercalation.

PubMed

Rohs, Remo; Sklenar, Heinz

2004-04-01

The results presented in this paper on methylene blue (MB) binding to DNA with AT alternating base sequence complement the data obtained in two former modeling studies of MB binding to GC alternating DNA. In the light of the large amount of experimental data for both systems, this theoretical study is focused on a detailed energetic analysis and comparison in order to understand their different behavior. Since experimental high-resolution structures of the complexes are not available, the analysis is based on energy minimized structural models of the complexes in different binding modes. For both sequences, four different intercalation structures and two models for MB binding in the minor and major groove have been proposed. Solvent electrostatic effects were included in the energetic analysis by using electrostatic continuum theory, and the dependence of MB binding on salt concentration was investigated by solving the non-linear Poisson-Boltzmann equation. We find that the relative stability of the different complexes is similar for the two sequences, in agreement with the interpretation of spectroscopic data. Subtle differences, however, are seen in energy decompositions and can be attributed to the change from symmetric 5'-YpR-3' intercalation to minor groove binding with increasing salt concentration, which is experimentally observed for the AT sequence at lower salt concentration than for the GC sequence. According to our results, this difference is due to the significantly lower non-electrostatic energy for the minor groove complex with AT alternating DNA, whereas the slightly lower binding energy to this sequence is caused by a higher deformation energy of DNA. The energetic data are in agreement with the conclusions derived from different spectroscopic studies and can also be structurally interpreted on the basis of the modeled complexes. The simple static modeling technique and the neglect of entropy terms and of non-electrostatic solute-solvent interactions, which are assumed to be nearly constant for the compared complexes of MB with DNA, seem to be justified by the results.

Free energy component analysis for drug design: a case study of HIV-1 protease-inhibitor binding.

PubMed

Kalra, P; Reddy, T V; Jayaram, B

2001-12-06

A theoretically rigorous and computationally tractable methodology for the prediction of the free energies of binding of protein-ligand complexes is presented. The method formulated involves developing molecular dynamics trajectories of the enzyme, the inhibitor, and the complex, followed by a free energy component analysis that conveys information on the physicochemical forces driving the protein-ligand complex formation and enables an elucidation of drug design principles for a given receptor from a thermodynamic perspective. The complexes of HIV-1 protease with two peptidomimetic inhibitors were taken as illustrative cases. Four-nanosecond-level all-atom molecular dynamics simulations using explicit solvent without any restraints were carried out on the protease-inhibitor complexes and the free proteases, and the trajectories were analyzed via a thermodynamic cycle to calculate the binding free energies. The computed free energies were seen to be in good accord with the reported data. It was noted that the net van der Waals and hydrophobic contributions were favorable to binding while the net electrostatics, entropies, and adaptation expense were unfavorable in these protease-inhibitor complexes. The hydrogen bond between the CH2OH group of the inhibitor at the scissile position and the catalytic aspartate was found to be favorable to binding. Various implicit solvent models were also considered and their shortcomings discussed. In addition, some plausible modifications to the inhibitor residues were attempted, which led to better binding affinities. The generality of the method and the transferability of the protocol with essentially no changes to any other protein-ligand system are emphasized.

A method for predicting individual residue contributions to enzyme specificity and binding-site energies, and its application to MTH1.

PubMed

Stewart, James J P

2016-11-01

A new method for predicting the energy contributions to substrate binding and to specificity has been developed. Conventional global optimization methods do not permit the subtle effects responsible for these properties to be modeled with sufficient precision to allow confidence to be placed in the results, but by making simple alterations to the model, the precisions of the various energies involved can be improved from about ±2 kcal mol -1 to ±0.1 kcal mol -1 . This technique was applied to the oxidized nucleotide pyrophosphohydrolase enzyme MTH1. MTH1 is unusual in that the binding and reaction sites are well separated-an advantage from a computational chemistry perspective, as it allows the energetics involved in docking to be modeled without the need to consider any issues relating to reaction mechanisms. In this study, two types of energy terms were investigated: the noncovalent interactions between the binding site and the substrate, and those responsible for discriminating between the oxidized nucleotide 8-oxo-dGTP and the normal dGTP. Both of these were investigated using the semiempirical method PM7 in the program MOPAC. The contributions of the individual residues to both the binding energy and the specificity of MTH1 were calculated by simulating the effect of mutations. Where comparisons were possible, all calculated results were in agreement with experimental observations. This technique provides fresh insight into the binding mechanism that enzymes use for discriminating between possible substrates.

Molecular investigation of active binding site of isoniazid (INH) and insight into resistance mechanism of S315T-MtKatG in Mycobacterium tuberculosis.

PubMed

Srivastava, Gaurava; Tripathi, Shubhandra; Kumar, Akhil; Sharma, Ashok

2017-07-01

Multi drug resistant tuberculosis is a major threat for mankind. Resistance against Isoniazid (INH), targeting MtKatG protein, is one of the most commonly occurring resistances in MDR TB strains. S315T-MtKatG mutation is widely reported for INH resistance. Despite having knowledge about the mechanism of INH, exact binding site of INH to MtKatG is still uncertain and proposed to have three presumable binding sites (site-1, site-2, and site-3). In the current study docking, molecular dynamics simulation, binding free energy estimation, principal component analysis and free energy landscape analysis were performed to get molecular level details of INH binding site on MtKatG, and to probe the effect of S315T mutation on INH binding. Molecular docking and MD analysis suggested site-1 as active binding site of INH, where the effects of S315T mutation were observed on both access tunnel as well as molecular interaction between INH and its neighboring residues. MMPBSA also supported site-1 as potential binding site with lowest binding energy of -44.201 kJ/mol. Moreover, PCA and FEL revealed that S315T mutation not only reduces the dimension of heme access tunnel but also showed that extra methyl group at 315 position altered heme cavity, enforcing heme group distantly from INH, and thus preventing INH activation. The present study not only investigated the active binding site of INH but also provides a new insight about the conformational changes in the binding site of S315T-MtKatG. Copyright © 2017 Elsevier Ltd. All rights reserved.

Structure and binding energy of the H2S dimer at the CCSD(T) complete basis set limit.

PubMed

Lemke, Kono H

2017-06-21

This study presents results for the binding energy and geometry of the H 2 S dimer which have been computed using Møller-Plesset perturbation theory (MP2, MP4) and coupled cluster (CCSD, CCSD(T)) calculations with basis sets up to aug-cc-pV5Z. Estimates of D e , E ZPE , D o , and dimer geometry have been obtained at each level of theory by taking advantage of the systematic convergence behavior toward the complete basis set (CBS) limit. The CBS limit binding energy values of D e are 1.91 (MP2), 1.75 (MP4), 1.41 (CCSD), and 1.69 kcal/mol (CCSD[T]). The most accurate values for the equilibrium S-S distance r SS (without counterpoise correction) are 4.080 (MP2/aug-cc-pV5Z), 4.131 (MP4/aug-cc-pVQZ), 4.225 (CCSD/aug-cc-pVQZ), and 4.146 Å (CCSD(T)/aug-cc-pVQZ). This study also evaluates the effect of counterpoise correction on the H 2 S dimer geometry and binding energy. As regards the structure of (H 2 S) 2 , MPn, CCSD, and CCSD(T) level values of r SS , obtained by performing geometry optimizations on the counterpoise-corrected potential energy surface, converge systematically to CBS limit values of 4.099 (MP2), 4.146 (MP4), 4.233 (CCSD), and 4.167 Å (CCSD(T)). The corresponding CBS limit values of the equilibrium binding energy D e are 1.88 (MP2), 1.76 (MP4), 1.41 (CCSD), and 1.69 kcal/mol (CCSD(T)), the latter in excellent agreement with the measured binding energy value of 1.68 ± 0.02 kcal/mol reported by Ciaffoni et al. [Appl. Phys. B 92, 627 (2008)]. Combining CBS electronic binding energies D e with E ZPE predicted by CCSD(T) vibrational second-order perturbation theory calculations yields D o = 1.08 kcal/mol, which is around 0.6 kcal/mol smaller than the measured value of 1.7 ± 0.3 kcal/mol. Overall, the results presented here demonstrate that the application of high level calculations, in particular CCSD(T), in combination with augmented correlation consistent basis sets provides valuable insight into the structure and energetics of the hydrogen sulfide dimer.

Structure and binding energy of the H2S dimer at the CCSD(T) complete basis set limit

NASA Astrophysics Data System (ADS)

Lemke, Kono H.

2017-06-01

This study presents results for the binding energy and geometry of the H2S dimer which have been computed using Møller-Plesset perturbation theory (MP2, MP4) and coupled cluster (CCSD, CCSD(T)) calculations with basis sets up to aug-cc-pV5Z. Estimates of De, EZPE, Do, and dimer geometry have been obtained at each level of theory by taking advantage of the systematic convergence behavior toward the complete basis set (CBS) limit. The CBS limit binding energy values of De are 1.91 (MP2), 1.75 (MP4), 1.41 (CCSD), and 1.69 kcal/mol (CCSD[T]). The most accurate values for the equilibrium S-S distance rSS (without counterpoise correction) are 4.080 (MP2/aug-cc-pV5Z), 4.131 (MP4/aug-cc-pVQZ), 4.225 (CCSD/aug-cc-pVQZ), and 4.146 Å (CCSD(T)/aug-cc-pVQZ). This study also evaluates the effect of counterpoise correction on the H2S dimer geometry and binding energy. As regards the structure of (H2S)2, MPn, CCSD, and CCSD(T) level values of rSS, obtained by performing geometry optimizations on the counterpoise-corrected potential energy surface, converge systematically to CBS limit values of 4.099 (MP2), 4.146 (MP4), 4.233 (CCSD), and 4.167 Å (CCSD(T)). The corresponding CBS limit values of the equilibrium binding energy De are 1.88 (MP2), 1.76 (MP4), 1.41 (CCSD), and 1.69 kcal/mol (CCSD(T)), the latter in excellent agreement with the measured binding energy value of 1.68 ± 0.02 kcal/mol reported by Ciaffoni et al. [Appl. Phys. B 92, 627 (2008)]. Combining CBS electronic binding energies De with EZPE predicted by CCSD(T) vibrational second-order perturbation theory calculations yields Do = 1.08 kcal/mol, which is around 0.6 kcal/mol smaller than the measured value of 1.7 ± 0.3 kcal/mol. Overall, the results presented here demonstrate that the application of high level calculations, in particular CCSD(T), in combination with augmented correlation consistent basis sets provides valuable insight into the structure and energetics of the hydrogen sulfide dimer.

Accurate, robust and reliable calculations of Poisson-Boltzmann binding energies

PubMed Central

Nguyen, Duc D.; Wang, Bao

2017-01-01

Poisson-Boltzmann (PB) model is one of the most popular implicit solvent models in biophysical modeling and computation. The ability of providing accurate and reliable PB estimation of electrostatic solvation free energy, ΔGel, and binding free energy, ΔΔGel, is important to computational biophysics and biochemistry. In this work, we investigate the grid dependence of our PB solver (MIBPB) with SESs for estimating both electrostatic solvation free energies and electrostatic binding free energies. It is found that the relative absolute error of ΔGel obtained at the grid spacing of 1.0 Å compared to ΔGel at 0.2 Å averaged over 153 molecules is less than 0.2%. Our results indicate that the use of grid spacing 0.6 Å ensures accuracy and reliability in ΔΔGel calculation. In fact, the grid spacing of 1.1 Å appears to deliver adequate accuracy for high throughput screening. PMID:28211071

A comparison of the coupled cluster and internally contracted averaged coupled-pair functional levels of theory for the calculation of the MCH2(+) binding energies for M = Sc to Cu

NASA Technical Reports Server (NTRS)

Bauschlicher, Charles W., Jr.; Partridge, Harry; Scuseria, Gustavo E.

1992-01-01

The correlation contribution to the M-C binding energy for the MCH2(+) systems can exceed 100 kcal/mol. At the self-consistent field (SCF) level, these systems can be more than 50 kcal/mol above the fragment energies. In spite of the poor zeroth-order reference, the coupled cluster single and double excitation method with a perturbational estimate of triple excitations, CCSD(T), method is shown to provide an accurate description of these systems. The maximum difference between the CCSD(T) and internally contracted averaged coupled-pair functional binding energies is 1.5 kcal/mol for CrCH2(+), with the remaining systems agreeing to within 1.0 kcal/mol.

A look at ligand binding thermodynamics in drug discovery.

PubMed

Claveria-Gimeno, Rafael; Vega, Sonia; Abian, Olga; Velazquez-Campoy, Adrian

2017-04-01

Drug discovery is a challenging endeavor requiring the interplay of many different research areas. Gathering information on ligand binding thermodynamics may help considerably in reducing the risk within a high uncertainty scenario, allowing early rejection of flawed compounds and pushing forward optimal candidates. In particular, the free energy, the enthalpy, and the entropy of binding provide fundamental information on the intermolecular forces driving such interaction. Areas covered: The authors review the current status and recent developments in the application of ligand binding thermodynamics in drug discovery. The thermodynamic binding profile (Gibbs energy, enthalpy, and entropy of binding) can be used for lead selection and optimization (binding enthalpy, selectivity, and adaptability). Expert opinion: Binding thermodynamics provides fundamental information on the forces driving the formation of the drug-target complex. It has been widely accepted that binding thermodynamics may be used as a decision criterion along the ligand optimization process in drug discovery and development. In particular, the binding enthalpy may be used as a guide when selecting and optimizing compounds over a set of potential candidates. However, this has been recently called into question by arguing certain difficulties and in the light of certain experimental examples.

Fluorescence Analysis of Sulfonamide Binding to Carbonic Anhydrase

ERIC Educational Resources Information Center

Wang, Sheila C.; Zamble, Deborah B.

2006-01-01

A practical laboratory experiment is described that illustrates the application of fluorescence resonance energy transfer to the study of protein-ligand binding. The affinities of wild-type and mutant human carbonic anhydrase II for dansylamide were determined by monitoring the increase in ligand fluorescence that occurs due to energy transfer…

Energetic factors determining the binding of type I inhibitors to c-Met kinase: experimental studies and quantum mechanical calculations

PubMed Central

Yu, Zhe; Ma, Yu-chi; Ai, Jing; Chen, Dan-qi; Zhao, Dong-mei; Wang, Xin; Chen, Yue-lei; Geng, Mei-yu; Xiong, Bing; Cheng, Mao-sheng; Shen, Jing-kang

2013-01-01

Aim: To decipher the molecular interactions between c-Met and its type I inhibitors and to facilitate the design of novel c-Met inhibitors. Methods: Based on the prototype model inhibitor 1, four ligands with subtle differences in the fused aromatic rings were synthesized. Quantum chemistry was employed to calculate the binding free energy for each ligand. Symmetry-adapted perturbation theory (SAPT) was used to decompose the binding energy into several fundamental forces to elucidate the determinant factors. Results: Binding free energies calculated from quantum chemistry were correlated well with experimental data. SAPT calculations showed that the predominant driving force for binding was derived from a sandwich π–π interaction with Tyr-1230. Arg-1208 was the differentiating factor, interacting with the 6-position of the fused aromatic ring system through the backbone carbonyl with a force pattern similar to hydrogen bonding. Therefore, a hydrogen atom must be attached at the 6-position, and changing the carbon atom to nitrogen caused unfavorable electrostatic interactions. Conclusion: The theoretical studies have elucidated the determinant factors involved in the binding of type I inhibitors to c-Met. PMID:24056705

Theoretical insights into effects of molar ratios on stabilities, mechanical properties and detonation performance of CL-20/RDX cocrystal explosives by molecular dynamics simulation

NASA Astrophysics Data System (ADS)

Hang, Gui-yun; Yu, Wen-li; Wang, Tao; Wang, Jin-tao; Li, Zhen

2017-08-01

The CL-20/RDX cocrystal models with different molar ratios were established by substitution method and molecular dynamics (MD) simulation method was applied to investigate the influences of molar ratios on mechanical properties, stabilities and detonation performance of cocrystal explosives. The crystal parameters, structures, binding energies, mechanical properties and some detonation parameters of different cocrystal explosives were got and compared. The results illustrate that the molar ratio has a direct influence on properties of cocrystal explosive and each of the cocrystal model holds different mechanical properties, binding energies and detonation parameters. The mechanical properties of CL-20/RDX cocrystal explosive can be effectively improved and the cocrystal model with molar ratio in 1:1 has the best mechanical properties. Besides, it has the highest binding energy, so the stability and compatibility is the best. The detonation parameters show that the cocrystal explosive has better detonation performance than RDX. In a word, the cocrystal explosive with molar ratio in 1:1 has the best mechanical properties, highest binding energy and excellent energy density and detonation performance, it is quite promising and can satisfy the requirements of high energy density compounds (HEDC). This paper could offer some theoretical instructions and novel insights for the CL-20 cocrystal explosive designing.

Mechanism of energy conversion and transfer in bioluminescence. Final report. [Sea pansy Renilla reniformis

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

Cormier, M.J.

1979-01-01

Bioluminescence in the sea pansy, Renilla reniformis, a marine anthozoan coelenterate, is a complex process involving the participation of three proteins specific to anthozoan coelenterate-type systems. These are: (1) the luciferin binding protein, (2) the enzyme luciferase, and (3) the green-fluorescent protein. Each of these have been purified and characterized and the structure of luciferin has been confirmed by synthesis. Luciferin binding protein (BP-LH/sub 2/) is a specific substrate binding protein which binds one molecule of coelenterate-type luciferin per molecule of protein and which then releases luciferin in the presence of Ca/sup + +/. Luciferase is the enzyme which catalyzesmore » oxidation (by O/sub 2/) of coelenterate-type luciferin, leading to the production of CO/sub 2/ and enzyme-bound, excited-state oxyluciferin. Oxyluciferin may then emit blue light by a direct de-excitation pathway or may transfer excitation energy to the green-fluorescent protein (GFP). GFP is a non-catalytic accessory protein which accepts excitation energy from oxyluciferin, by radiationless energy transfer, and then emits green bioluminescence. The Renilla bioluminescence system is thus the first radiationless energy transfer system the individual components of which have been purified to homogeneity, characterized, and then reassembled in vitro with restoration of the energy transfer function.« less

Interfacial disorder drives charge separation in molecular semiconductors

NASA Astrophysics Data System (ADS)

Willard, Adam

One of the fundamental microscopic processes in photocurrent generation is the dissociation of neutral photo-excitations (i.e., Frenkel excitons) into free charge carriers (i.e., electrons and holes). This process requires the physical separation of oppositely charged electrons and holes, which are held to together by an attractive electrostatic binding energy. In traditional inorganic-based photovoltaic (PV) materials, this binding energy is generally small and easily overcome, however, in organic-based PVs (OPVs) the exciton binding energy can significantly exceed thermal energies. The inability of bound charges to overcome this large binding energy has been implicated as a primary source of efficiency loss in OPVs. Here I present results from our recent efforts to explore the role of static molecular disorder in mediating this process. Using a simple lattice model of exciton dynamics we demonstrate that random spatial variations in the energetic landscape can mitigate the attractive Coulomb interaction between electrons and holes. We show that this effect manifests as a reduction in the free energy barrier for exciton dissociation that grows more pronounced with increasing disorder. By considering the competition between this thermodynamic effect and the disorder-induced slowing of dissociation kinetics we demonstrate that exciton dissociation yields are expected to depend non-monotonically on the degree of static disorder.

Energy bands and acceptor binding energies of GaN

NASA Astrophysics Data System (ADS)

Xia, Jian-Bai; Cheah, K. W.; Wang, Xiao-Liang; Sun, Dian-Zhao; Kong, Mei-Ying

1999-04-01

The energy bands of zinc-blende and wurtzite GaN are calculated with the empirical pseudopotential method, and the pseudopotential parameters for Ga and N atoms are given. The calculated energy bands are in agreement with those obtained by the ab initio method. The effective-mass theory for the semiconductors of wurtzite structure is established, and the effective-mass parameters of GaN for both structures are given. The binding energies of acceptor states are calculated by solving strictly the effective-mass equations. The binding energies of donor and acceptor are 24 and 142 meV for the zinc-blende structure, 20 and 131, and 97 meV for the wurtzite structure, respectively, which are consistent with recent experimental results. It is proposed that there are two kinds of acceptor in wurtzite GaN. One kind is the general acceptor such as C, which substitutes N, which satisfies the effective-mass theory. The other kind of acceptor includes Mg, Zn, Cd, etc., the binding energy of these acceptors is deviated from that given by the effective-mass theory. In this report, wurtzite GaN is grown by the molecular-beam epitaxy method, and the photoluminescence spectra were measured. Three main peaks are assigned to the donor-acceptor transitions from two kinds of acceptors. Some of the transitions were identified as coming from the cubic phase of GaN, which appears randomly within the predominantly hexagonal material.

Structure-based prediction of free energy changes of binding of PTP1B inhibitors

NASA Astrophysics Data System (ADS)

Wang, Jing; Ling Chan, Shek; Ramnarayan, Kal

2003-08-01

The goals were (1) to understand the driving forces in the binding of small molecule inhibitors to the active site of PTP1B and (2) to develop a molecular mechanics-based empirical free energy function for compound potency prediction. A set of compounds with known activities was docked onto the active site. The related energy components and molecular surface areas were calculated. The bridging water molecules were identified and their contributions were considered. Linear relationships were explored between the above terms and the binding free energies of compounds derived based on experimental inhibition constants. We found that minimally three terms are required to give rise to a good correlation (0.86) with predictive power in five-group cross-validation test (q2 = 0.70). The dominant terms are the electrostatic energy and non-electrostatic energy stemming from the intra- and intermolecular interactions of solutes and from those of bridging water molecules in complexes.

Self-energy effect and Coulomb potential modulation of the exciton in monolayer MoS2 on polar substrate

NASA Astrophysics Data System (ADS)

Wang, Zi-Wu; Xiao, Yao; Li, Run-Ze; Li, Wei-Ping; Li, Zhi-Qing

2017-11-01

We theoretically investigate the correction of exciton binding energy in monolayer MoS2 resulting from the exciton couples with surface optical (SO) phonons induced by polar substrate. The total correction of binding energy can be divided into the self-energy effect and modification of Coulomb potential using the unitary transformation method. We find that both the self-energy and Coulomb potential vary from tens of meV to several hundreds of meV depending on the cut-off wave vector of SO phonon modes, polarizability of substrate materials and internal distance between the monolayer MoS2 and polar substrate. An effective Coulomb potential is obtained by combining the modified term into the Coulomb potential. This potentially could be widely used in various two-dimensional materials. Our theoretical results not only propose the ways to externally control the exciton binding energy in experiment, but also enrich the understanding of the exciton properties in the dielectric environment.

Simple method for determining binding energies of fullerene and complex atomic negative ions

NASA Astrophysics Data System (ADS)

Felfli, Zineb; Msezane, Alfred

2017-04-01

A robust potential which embeds fully the vital core polarization interaction has been used in the Regge pole method to explore low-energy electron scattering from C60, Eu and Nb through the total cross sections (TCSs) calculations. From the characteristic dramatically sharp resonances in the TCSs manifesting negative ion formation in these systems, we extracted the binding energies for the C60, Euand Nbanions they are found to be in outstanding agreement with the measured electron affinities of C60, Eu and Nb. Common among these considered systems, including the standard atomic Au is the formation of their ground state negative ions at the second Ramsauer-Townsend (R-T) minima of their TCSs. Indeed, this is a signature of all the fullerenes and complex atoms considered thus far. Shape resonances, R-T minima and binding energies of the resultant anions are presented. This work was supported by U.S. DOE, Basic Energy Sciences, Office of Energy Research.

Simultaneous observation of free and defect-bound excitons in CH3NH3PbI3 using four-wave mixing spectroscopy

NASA Astrophysics Data System (ADS)

March, Samuel A.; Clegg, Charlotte; Riley, Drew B.; Webber, Daniel; Hill, Ian G.; Hall, Kimberley C.

2016-12-01

Solar cells incorporating organic-inorganic perovskite, which may be fabricated using low-cost solution-based processing, have witnessed a dramatic rise in efficiencies yet their fundamental photophysical properties are not well understood. The exciton binding energy, central to the charge collection process, has been the subject of considerable controversy due to subtleties in extracting it from conventional linear spectroscopy techniques due to strong broadening tied to disorder. Here we report the simultaneous observation of free and defect-bound excitons in CH3NH3PbI3 films using four-wave mixing (FWM) spectroscopy. Due to the high sensitivity of FWM to excitons, tied to their longer coherence decay times than unbound electron- hole pairs, we show that the exciton resonance energies can be directly observed from the nonlinear optical spectra. Our results indicate low-temperature binding energies of 13 meV (29 meV) for the free (defect-bound) exciton, with the 16 meV localization energy for excitons attributed to binding to point defects. Our findings shed light on the wide range of binding energies (2-55 meV) reported in recent years.

Bonding in the first-row diatomic molecules within the local spin-density approximation

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

Painter, G.S.; Averill, F.W.

1982-08-15

The Hohenberg-Kohn-Sham density-functional equations in the local spin-density approximation (LSDA) have been solved with essentially no loss of accuracy for dimers of the first row of the Periodic Table with the use of a fully-self-consistent spin-polarized Gaussian-orbital approach. Spectroscopic constants (binding energies, equilibrium separations, and ground-state vibrational frequencies) have been derived from the calculated potential-energy curves. Intercomparison of results obtained using the exchange-correlation functionals of Slater (scaled exchange or X..cap alpha..), Gunnarsson and Lundqvist (GL), and Vosko, Wilk, and Nusair (VWN) permits assessment of the relative merits of each and serves to identify general shortcomings in the LSDA. Basic trendsmore » are similar for each functional, but the treatment of the spin dependence of the exchange-correlation energy in the GL and VWN functionals yields a variation of the binding energy across the series which is more systematic than that in the X..cap alpha.. approximation. Agreement between the present results and those of Dunlap, Connolly, and Sabin in the X..cap alpha.., approximation confirms the accuracy of the variational charge-density-fit procedure used in the latter work. The refinements in correlation treatment within the VWN functional are reflected in improvements in binding energies which are only slight for most dimers in the series. This behavior is attributed to the error remaining in the exchange channel within the LSDA and demonstrates the necessity for self-interaction corrections for more accurate binding-energy determinations. Within the current LSDA, absolute accuracies of the VWN functional for the first-row dimers are within 2.3 eV for binding energies, 0.07 a.u. for bond lengths, and approx.200 cm/sup -1/ for vibrational frequencies.« less

Free Energy Perturbation Hamiltonian Replica-Exchange Molecular Dynamics (FEP/H-REMD) for Absolute Ligand Binding Free Energy Calculations.

PubMed

Jiang, Wei; Roux, Benoît

2010-07-01

Free Energy Perturbation with Replica Exchange Molecular Dynamics (FEP/REMD) offers a powerful strategy to improve the convergence of free energy computations. In particular, it has been shown previously that a FEP/REMD scheme allowing random moves within an extended replica ensemble of thermodynamic coupling parameters "lambda" can improve the statistical convergence in calculations of absolute binding free energy of ligands to proteins [J. Chem. Theory Comput. 2009, 5, 2583]. In the present study, FEP/REMD is extended and combined with an accelerated MD simulations method based on Hamiltonian replica-exchange MD (H-REMD) to overcome the additional problems arising from the existence of kinetically trapped conformations within the protein receptor. In the combined strategy, each system with a given thermodynamic coupling factor lambda in the extended ensemble is further coupled with a set of replicas evolving on a biased energy surface with boosting potentials used to accelerate the inter-conversion among different rotameric states of the side chains in the neighborhood of the binding site. Exchanges are allowed to occur alternatively along the axes corresponding to the thermodynamic coupling parameter lambda and the boosting potential, in an extended dual array of coupled lambda- and H-REMD simulations. The method is implemented on the basis of new extensions to the REPDSTR module of the biomolecular simulation program CHARMM. As an illustrative example, the absolute binding free energy of p-xylene to the nonpolar cavity of the L99A mutant of T4 lysozyme was calculated. The tests demonstrate that the dual lambda-REMD and H-REMD simulation scheme greatly accelerates the configurational sampling of the rotameric states of the side chains around the binding pocket, thereby improving the convergence of the FEP computations.

Docking and Hydropathic Scoring of Polysubstituted Pyrrole Compounds with Anti-Tubulin Activity

PubMed Central

Tripathi, Ashutosh; Fornabaio, Micaela; Kellogg, Glen E.; Gupton, John T.; Gewirtz, David A.; Yeudall, W. Andrew; Vega, Nina E.; Mooberry, Susan L.

2008-01-01

Compounds that bind at the colchicine site of tubulin have drawn considerable attention with studies indicating that these agents suppress microtubule dynamics and inhibit tubulin polymerization. Data for eighteen polysubstituted pyrrole compounds are reported, including antiproliferative activity against human MDA-MB-435 cells and calculated free energies of binding following docking the compounds into models of αβ-tubulin. These docking calculations coupled with HINT interaction analyses are able to represent the complex structures and the binding modes of inhibitors such that calculated and measured free energies of binding correlate with an r2 of 0.76. Structural analysis of the binding pocket identifies important intermolecular contacts that mediate binding. As seen experimentally, the complex with JG-03-14 (3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2- carboxylic acid ethyl ester) is the most stable. These results illuminate the binding process and should be valuable in the design of new pyrrole-based colchicine site inhibitors as these compounds have very accessible syntheses. PMID:18083520

Experimental measurement of binding energy, selectivity, and allostery using fluctuation theorems.

PubMed

Camunas-Soler, Joan; Alemany, Anna; Ritort, Felix

2017-01-27

Thermodynamic bulk measurements of binding reactions rely on the validity of the law of mass action and the assumption of a dilute solution. Yet, important biological systems such as allosteric ligand-receptor binding, macromolecular crowding, or misfolded molecules may not follow these assumptions and may require a particular reaction model. Here we introduce a fluctuation theorem for ligand binding and an experimental approach using single-molecule force spectroscopy to determine binding energies, selectivity, and allostery of nucleic acids and peptides in a model-independent fashion. A similar approach could be used for proteins. This work extends the use of fluctuation theorems beyond unimolecular folding reactions, bridging the thermodynamics of small systems and the basic laws of chemical equilibrium. Copyright © 2017, American Association for the Advancement of Science.

Magnetic properties and core electron binding energies of liquid water

NASA Astrophysics Data System (ADS)

Galamba, N.; Cabral, Benedito J. C.

2018-01-01

The magnetic properties and the core and inner valence electron binding energies of liquid water are investigated. The adopted methodology relies on the combination of molecular dynamics and electronic structure calculations. Born-Oppenheimer molecular dynamics with the Becke and Lee-Yang-Parr functionals for exchange and correlation, respectively, and includes an empirical correction (BLYP-D3) functional and classical molecular dynamics with the TIP4P/2005-F model were carried out. The Keal-Tozer functional was applied for predicting magnetic shielding and spin-spin coupling constants. Core and inner valence electron binding energies in liquid water were calculated with symmetry adapted cluster-configuration interaction. The relationship between the magnetic shielding constant σ(17O), the role played by the oxygen atom as a proton acceptor and donor, and the tetrahedral organisation of liquid water are investigated. The results indicate that the deshielding of the oxygen atom in water is very dependent on the order parameter (q) describing the tetrahedral organisation of the hydrogen bond network. The strong sensitivity of magnetic properties on changes of the electronic density in the nuclei environment is illustrated by a correlation between σ(17O) and the energy gap between the 1a1[O1s] (core) and the 2a1 (inner valence) orbitals of water. Although several studies discussed the eventual connection between magnetic properties and core electron binding energies, such a correlation could not be clearly established. Here, we demonstrate that for liquid water this correlation exists although involving the gap between electron binding energies of core and inner valence orbitals.

Ab initio investigation on the valence and dipole-bound states of CNa - and SiNa -

NASA Astrophysics Data System (ADS)

Kalcher, Josef; Sax, Alexander F.

2000-08-01

CNa - and SiNa - have been studied by the CAS-ACPF method. The 3Σ- ground states have binding energies of 5420 and 7517 cm -1, respectively. The 5Σ- excited states are 494 and 1551 cm -1 above the respective ground states. The 1Δ , 3Π , and 1Π valence-excited states for SiNa - should be at least metastable. CNa - and SiNa - possess dipole-bound 5Σ- and 3Σ- states. Binding energies of these states in CNa - are 217 and 236 cm -1, respectively. SiNa - has two stable 5Σ- dipole-bound states, whose binding energies are 246 and 118 cm -1, respectively.

Three-body Coulomb bound states

NASA Technical Reports Server (NTRS)

Bhatia, A. K.; Drachman, Richard J.

1987-01-01

The binding energies of three-particle systems containing two electrons and one positive particle of mass M are reexamined in an attempt to understand the approximate proportionality of the 1Se ground-state binding energies of the reduced masses, as pointed out by Botero and Green (1986). The contribution to the energy of the mass-polarization term is evaluated. No fundamental principle is involved, since the mass polarization merely decreases somewhat as the mass of the positive particle is reduced below the proton mass. In the case of the excited 3Pe state, this reduction is not sufficient to allow binding when M approaches the electron mass. Some properties of the recently observed negative muonium ion (e/-/ mu/+/ e/-/) are also computed.

Ligand-protein docking using a quantum stochastic tunneling optimization method.

PubMed

Mancera, Ricardo L; Källblad, Per; Todorov, Nikolay P

2004-04-30

A novel hybrid optimization method called quantum stochastic tunneling has been recently introduced. Here, we report its implementation within a new docking program called EasyDock and a validation with the CCDC/Astex data set of ligand-protein complexes using the PLP score to represent the ligand-protein potential energy surface and ScreenScore to score the ligand-protein binding energies. When taking the top energy-ranked ligand binding mode pose, we were able to predict the correct crystallographic ligand binding mode in up to 75% of the cases. By using this novel optimization method run times for typical docking simulations are significantly shortened. Copyright 2004 Wiley Periodicals, Inc. J Comput Chem 25: 858-864, 2004

Optimization of binding electrostatics: Charge complementarity in the barnase-barstar protein complex

PubMed Central

lee, Lee-Peng; Tidor, Bruce

2001-01-01

Theoretical and experimental studies have shown that the large desolvation penalty required for polar and charged groups frequently precludes their involvement in electrostatic interactions that contribute strongly to net stability in the folding or binding of proteins in aqueous solution near room temperature. We have previously developed a theoretical framework for computing optimized electrostatic interactions and illustrated use of the algorithm with simplified geometries. Given a receptor and model assumptions, the method computes the ligand-charge distribution that provides the most favorable balance of desolvation and interaction effects on binding. In this paper the method has been extended to treat complexes using actual molecular shapes. The barnase-barstar protein complex was investigated with barnase treated as a target receptor. The atomic point charges of barstar were varied to optimize the electrostatic binding free energy. Barnase and natural barstar form a tight complex (Kd ∼ 10−14 M) with many charged and polar groups near the interface that make this a particularly relevant system for investigating the role of electrostatic effects on binding. The results show that sets of barstar charges (resulting from optimization with different constraints) can be found that give rise to relatively large predicted improvements in electrostatic binding free energy. Principles for enhancing the effect of electrostatic interactions in molecular binding in aqueous environments are discussed in light of the optima. Our findings suggest that, in general, the enhancements in electrostatic binding free energy resulting from modification of polar and charged groups can be substantial. Moreover, a recently proposed definition of electrostatic complementarity is shown to be a useful tool for examining binding interfaces. Finally, calculational results suggest that wild-type barstar is closer to being affinity optimized than is barnase for their mutual binding, consistent with the known roles of these proteins. PMID:11266622

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.

Insights into the effects of mutations on Cren7-DNA binding using molecular dynamics simulations and free energy calculations.

PubMed

Chen, Lin; Zheng, Qing-Chuan; Zhang, Hong-Xing

2015-02-28

A novel, highly conserved chromatin protein, Cren7 is involved in regulating essential cellular processes such as transcription, replication and repair. Although mutations in the DNA-binding loop of Cren7 destabilize the structure and reduce DNA-binding activity, the details are not very clear. Focusing on the specific Cren7-dsDNA complex (PDB code ), we applied molecular dynamics (MD) simulations and the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculations to explore the structural and dynamic effects of W26A, L28A, and K53A mutations in comparison to the wild-type protein. The energetic analysis indicated that the intermolecular van der Waals interaction and nonpolar solvation energy play an important role in the binding process of Cren7 and dsDNA. Compared with the wild type Cren7, all the studied mutants W26A, L28A, and K53A have obviously reduced binding free energies with dsDNA in the reduction of the polar and/or nonpolar interactions. These results further elucidated the previous experiments to understand the Cren7-DNA interaction comprehensively. Our work also would provide support for an understanding of the interactions of proteins with nucleic acids.

Accurate Wavelength Measurement of High-Energy Gamma Rays from the 35Cl(n,{gamma}) Reactions

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

Belgya, T.; Molnar, G.L.; Mutti, P.

2005-05-24

The energies of eight gamma rays in the 36Cl level scheme have been measured with high precision using the 35Cl(n,{gamma}) reaction and the GAMS4 spectrometer. From these energies, a skeleton decay scheme for 36Cl was constructed, and the binding energy of 36Cl was determined to higher precision than previously. It is shown that using this new information, binding energy determination from Ge detector experiments for other nuclei can also be made with higher precision than now available. The measurement of additional weaker 36Cl gamma rays is continuing.

Electrostatic Interactions in Aminoglycoside-RNA Complexes

PubMed Central

Kulik, Marta; Goral, Anna M.; Jasiński, Maciej; Dominiak, Paulina M.; Trylska, Joanna

2015-01-01

Electrostatic interactions often play key roles in the recognition of small molecules by nucleic acids. An example is aminoglycoside antibiotics, which by binding to ribosomal RNA (rRNA) affect bacterial protein synthesis. These antibiotics remain one of the few valid treatments against hospital-acquired infections by Gram-negative bacteria. It is necessary to understand the amplitude of electrostatic interactions between aminoglycosides and their rRNA targets to introduce aminoglycoside modifications that would enhance their binding or to design new scaffolds. Here, we calculated the electrostatic energy of interactions and its per-ring contributions between aminoglycosides and their primary rRNA binding site. We applied either the methodology based on the exact potential multipole moment (EPMM) or classical molecular mechanics force field single-point partial charges with Coulomb formula. For EPMM, we first reconstructed the aspherical electron density of 12 aminoglycoside-RNA complexes from the atomic parameters deposited in the University at Buffalo Databank. The University at Buffalo Databank concept assumes transferability of electron density between atoms in chemically equivalent vicinities and allows reconstruction of the electron densities from experimental structural data. From the electron density, we then calculated the electrostatic energy of interaction using EPMM. Finally, we compared the two approaches. The calculated electrostatic interaction energies between various aminoglycosides and their binding sites correlate with experimentally obtained binding free energies. Based on the calculated energetic contributions of water molecules mediating the interactions between the antibiotic and rRNA, we suggest possible modifications that could enhance aminoglycoside binding affinity. PMID:25650932

Electronic wave function and binding effects in M-shell ionization of gold by protons

NASA Astrophysics Data System (ADS)

Pajek, M.; Banaś, D.; Jabłoński, Ł.; Mukoyama, T.

2018-02-01

The measured M-X-ray production cross sections for protons, which are used in the particle induced X-ray emission (PIXE) technique, are systematically underestimated for low impact energies by the ECPSSR and ECUSAR theories. These theories, which are based on the plane wave Born approximation (PWBA) and use the screened hydrogenic wave functions, include corrections for the projectile Coulomb deflection and electron relativistic and binding effects. In the present paper, in order to interpret the observed disagreement at low impact energies, the systematic calculations of the M-shell ionization cross sections for gold were performed using the semiclassical (SCA) and the binary encounter (BEA) approximations in order to identify a role of the electronic wave function and electron binding effects. In these calculations the different wave functions, from nonrelativistic hydrogenic to selfconsistent Dirac-Hartree-Fock, were considered and the binding effect was treated within extreme separated- (SA) and united-atoms (UA) limits. The results are discussed in details and the observed discrepancies are attributed to inadequate description of the electron binding effect at the lowest impact energies for which the molecular approach is required.

Structure-affinity relationships for the binding of actinomycin D to DNA

NASA Astrophysics Data System (ADS)

Gallego, José; Ortiz, Angel R.; de Pascual-Teresa, Beatriz; Gago, Federico

1997-03-01

Molecular models of the complexes between actinomycin D and 14 different DNA hexamers were built based on the X-ray crystal structure of the actinomycin-d(GAAGCTTC)2 complex. The DNA sequences included the canonical GpC binding step flanked by different base pairs, nonclassical binding sites such as GpG and GpT, and sites containing 2,6-diamino- purine. A good correlation was found between the intermolecular interaction energies calculated for the refined complexes and the relative preferences of actinomycin binding to standard and modified DNA. A detailed energy decomposition into van der Waals and electrostatic components for the interactions between the DNA base pairs and either the chromophore or the peptidic part of the antibiotic was performed for each complex. The resulting energy matrix was then subjected to principal component analysis, which showed that actinomycin D discriminates among different DNA sequences by an interplay of hydrogen bonding and stacking interactions. The structure-affinity relationships for this important antitumor drug are thus rationalized and may be used to advantage in the design of novel sequence-specific DNA-binding agents.

Binding energies of benzene on coinage metal surfaces: Equal stability on different metals

NASA Astrophysics Data System (ADS)

Maaß, Friedrich; Jiang, Yingda; Liu, Wei; Tkatchenko, Alexandre; Tegeder, Petra

2018-06-01

Interfaces between organic molecules and inorganic solids adapt a prominent role in fundamental science, catalysis, molecular sensors, and molecular electronics. The molecular adsorption geometry, which is dictated by the strength of lateral and vertical interactions, determines the electronic structure of the molecule/substrate system. In this study, we investigate the binding properties of benzene on the noble metal surfaces Au(111), Ag(111), and Cu(111), respectively, using temperature-programmed desorption and first-principles calculations that account for non-locality of both electronic exchange and correlation effects. In the monolayer regime, we observed for all three systems a decrease of the binding energy with increasing coverage due to repulsive adsorbate/adsorbate interactions. Although the electronic properties of the noble metal surfaces are rather different, the binding strength of benzene on these surfaces is equal within the experimental error (accuracy of 0.05 eV), in excellent agreement with our calculations. This points toward the existence of a universal trend for the binding energy of aromatic molecules resulting from a subtle balance between Pauli repulsion and many-body van der Waals attraction.

Tension-induced binding of semiflexible biopolymers

NASA Astrophysics Data System (ADS)

Benetatos, Panayotis; von der Heydt, Alice; Zippelius, Annette

2015-03-01

We investigate theoretically the effect of polymer tension on the collective behaviour of reversible cross-links. We use a model of two parallel-aligned, weakly-bending wormlike chains with a regularly spaced sequence of binding sites subjected to a tensile force. Reversible cross-links attach and detach at the binding sites with an affinity controlled by a chemical potential. In a mean-field approach, we calculate the free energy of the system and we show the emergence of a free energy barrier which controls the reversible (un)binding. The tension affects the conformational entropy of the chains which competes with the binding energy of the cross-links. This competition gives rise to a sudden increase in the fraction of bound sites as the polymer tension increases. The force-induced first-order transition in the number of cross-links implies a sudden force-induced stiffening of the effective stretching modulus of the polymers. This mechanism may be relevant to the formation and stress-induced strengthening of stress fibers in the cytoskeleton. We acknowledge support by the Deutsche Forschungsgemeinschaft (DFG) via grant SFB-937/A1.

Calculating the sensitivity and robustness of binding free energy calculations to force field parameters

PubMed Central

Rocklin, Gabriel J.; Mobley, David L.; Dill, Ken A.

2013-01-01

Binding free energy calculations offer a thermodynamically rigorous method to compute protein-ligand binding, and they depend on empirical force fields with hundreds of parameters. We examined the sensitivity of computed binding free energies to the ligand’s electrostatic and van der Waals parameters. Dielectric screening and cancellation of effects between ligand-protein and ligand-solvent interactions reduce the parameter sensitivity of binding affinity by 65%, compared with interaction strengths computed in the gas-phase. However, multiple changes to parameters combine additively on average, which can lead to large changes in overall affinity from many small changes to parameters. Using these results, we estimate that random, uncorrelated errors in force field nonbonded parameters must be smaller than 0.02 e per charge, 0.06 Å per radius, and 0.01 kcal/mol per well depth in order to obtain 68% (one standard deviation) confidence that a computed affinity for a moderately-sized lead compound will fall within 1 kcal/mol of the true affinity, if these are the only sources of error considered. PMID:24015114

Nuclear Cartography: Patterns in Binding Energies and Subatomic Structure

ERIC Educational Resources Information Center

Simpson, E. C.; Shelley, M.

2017-01-01

Nuclear masses and binding energies are some of the first nuclear properties met in high school physics, and can be used to introduce radioactive decays, fusion, and fission. With relatively little extension, they can also illustrate fundamental concepts in nuclear physics, such as shell structure and pairing, and to discuss how the elements…

Functional asymmetry in the lysyl-tRNA synthetase explored by molecular dynamics, free energy calculations and experiment

PubMed Central

Hughes, Samantha J; Tanner, Julian A; Hindley, Alison D; Miller, Andrew D; Gould, Ian R

2003-01-01

Background Charging of transfer-RNA with cognate amino acid is accomplished by the aminoacyl-tRNA synthetases, and proceeds through an aminoacyl adenylate intermediate. The lysyl-tRNA synthetase has evolved an active site that specifically binds lysine and ATP. Previous molecular dynamics simulations of the heat-inducible Escherichia coli lysyl-tRNA synthetase, LysU, have revealed differences in the binding of ATP and aspects of asymmetry between the nominally equivalent active sites of this dimeric enzyme. The possibility that this asymmetry results in different binding affinities for the ligands is addressed here by a parallel computational and biochemical study. Results Biochemical experiments employing isothermal calorimetry, steady-state fluorescence and circular dichroism are used to determine the order and stoichiometries of the lysine and nucleotide binding events, and the associated thermodynamic parameters. An ordered mechanism of substrate addition is found, with lysine having to bind prior to the nucleotide in a magnesium dependent process. Two lysines are found to bind per dimer, and trigger a large conformational change. Subsequent nucleotide binding causes little structural rearrangement and crucially only occurs at a single catalytic site, in accord with the simulations. Molecular dynamics based free energy calculations of the ATP binding process are used to determine the binding affinities of each site. Significant differences in ATP binding affinities are observed, with only one active site capable of realizing the experimental binding free energy. Half-of-the-sites models in which the nucleotide is only present at one active site achieve their full binding potential irrespective of the subunit choice. This strongly suggests the involvement of an anti-cooperative mechanism. Pathways for relaying information between the two active sites are proposed. Conclusions The asymmetry uncovered here appears to be a common feature of oligomeric aminoacyl-tRNA synthetases, and may play an important functional role. We suggest a manner in which catalytic efficiency could be improved by LysU operating in an alternating sites mechanism. PMID:12787471

Binding Energy Calculation of Patchouli Alcohol Isomer Cyclooxygenase Complexes Suggested as COX-1/COX-2 Selective Inhibitor

PubMed Central

Mahdi, Chanif; Nurdiana, Nurdiana; Kikuchi, Takheshi; Fatchiyah, Fatchiyah

2014-01-01

To understand the structural features that dictate the selectivity of the two isoforms of the prostaglandin H2 synthase (PGHS/COX), the three-dimensional (3D) structure of COX-1/COX-2 was assessed by means of binding energy calculation of virtual molecular dynamic with using ligand alpha-Patchouli alcohol isomers. Molecular interaction studies with COX-1 and COX-2 were done using the molecular docking tools by Hex 8.0. Interactions were further visualized by using Discovery Studio Client 3.5 software tool. The binding energy of molecular interaction was calculated by AMBER12 and Virtual Molecular Dynamic 1.9.1 software. The analysis of the alpha-Patchouli alcohol isomer compounds showed that all alpha-Patchouli alcohol isomers were suggested as inhibitor of COX-1 and COX-2. Collectively, the scoring binding energy calculation (with PBSA Model Solvent) of alpha-Patchouli alcohol isomer compounds (CID442384, CID6432585, CID3080622, CID10955174, and CID56928117) was suggested as candidate for a selective COX-1 inhibitor and CID521903 as nonselective COX-1/COX-2. PMID:25484897

Determination of layer-dependent exciton binding energies in few-layer black phosphorus

PubMed Central

Zhang, Guowei; Chaves, Andrey; Huang, Shenyang; Wang, Fanjie; Xing, Qiaoxia; Low, Tony; Yan, Hugen

2018-01-01

The attraction between electrons and holes in semiconductors forms excitons, which largely determine the optical properties of the hosting material, and hence the device performance, especially for low-dimensional systems. Mono- and few-layer black phosphorus (BP) are emerging two-dimensional (2D) semiconductors. Despite its fundamental importance and technological interest, experimental investigation of exciton physics has been rather limited. We report the first systematic measurement of exciton binding energies in ultrahigh-quality few-layer BP by infrared absorption spectroscopy, with layer (L) thickness ranging from 2 to 6 layers. Our experiments allow us to determine the exciton binding energy, decreasing from 213 meV (2L) to 106 meV (6L). The scaling behavior with layer numbers can be well described by an analytical model, which takes into account the nonlocal screening effect. Extrapolation to free-standing monolayer yields a large binding energy of ~800 meV. Our study provides insights into 2D excitons and their crossover from 2D to 3D, and demonstrates that few-layer BP is a promising high-quality optoelectronic material for potential infrared applications. PMID:29556530

Pressure-induced increase of exciton-LO-phonon coupling in a ZnCdSe/ZnSe quantum well

NASA Astrophysics Data System (ADS)

Guo, Z. Z.; Liang, X. X.; Ban, S. L.

2003-07-01

The possibility of pressure-induced increase of exciton-LO-phonon coupling in ZnCdSe/ZnSe quantum wells is studied. The ground state binding energies of the heavy hole excitons are calculated using a variational method with consideration of the electron-phonon interaction and the pressure dependence of the parameters. The results show that for quantum wells with intermediate well width, the exciton binding energy and the LO-phonon energy may coincide in the course of pressure increasing, resulting in the increase of exciton-LO-phonon coupling. It is also found that among the pressure-dependent parameters, the influence of the lattice constant is the most important one. The changes of both the effective masses and the dielectric constants have obvious effects on the exciton binding energy, but their influences are counterbalanced.

Relative Binding Free Energy Calculations in Drug Discovery: Recent Advances and Practical Considerations.

PubMed

Cournia, Zoe; Allen, Bryce; Sherman, Woody

2017-12-26

Accurate in silico prediction of protein-ligand binding affinities has been a primary objective of structure-based drug design for decades due to the putative value it would bring to the drug discovery process. However, computational methods have historically failed to deliver value in real-world drug discovery applications due to a variety of scientific, technical, and practical challenges. Recently, a family of approaches commonly referred to as relative binding free energy (RBFE) calculations, which rely on physics-based molecular simulations and statistical mechanics, have shown promise in reliably generating accurate predictions in the context of drug discovery projects. This advance arises from accumulating developments in the underlying scientific methods (decades of research on force fields and sampling algorithms) coupled with vast increases in computational resources (graphics processing units and cloud infrastructures). Mounting evidence from retrospective validation studies, blind challenge predictions, and prospective applications suggests that RBFE simulations can now predict the affinity differences for congeneric ligands with sufficient accuracy and throughput to deliver considerable value in hit-to-lead and lead optimization efforts. Here, we present an overview of current RBFE implementations, highlighting recent advances and remaining challenges, along with examples that emphasize practical considerations for obtaining reliable RBFE results. We focus specifically on relative binding free energies because the calculations are less computationally intensive than absolute binding free energy (ABFE) calculations and map directly onto the hit-to-lead and lead optimization processes, where the prediction of relative binding energies between a reference molecule and new ideas (virtual molecules) can be used to prioritize molecules for synthesis. We describe the critical aspects of running RBFE calculations, from both theoretical and applied perspectives, using a combination of retrospective literature examples and prospective studies from drug discovery projects. This work is intended to provide a contemporary overview of the scientific, technical, and practical issues associated with running relative binding free energy simulations, with a focus on real-world drug discovery applications. We offer guidelines for improving the accuracy of RBFE simulations, especially for challenging cases, and emphasize unresolved issues that could be improved by further research in the field.

The IκBα/NF-κB complex has two hot spots, one at either end of the interface

PubMed Central

Bergqvist, Simon; Ghosh, Gourisankar; Komives, Elizabeth A.

2008-01-01

IκBα binds to and inhibits the transcriptional activity of NF-κB family members via its ankyrin repeat (AR) domain. The binding affinity of IκBα with NF-κB(p50/p65) heterodimers and NF-κB(p65/65) homodimers is in the picomolar range, and in the cell, this results in long half-lives of the complexes. Direct binding experiments have been performed using surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) on a series of truncations and mutations in order to understand what regions of the interface are most important for the tight binding affinity of this complex. We previously showed that interactions between residues 305 and 321 of NF-κB(p65) with the first AR of IκBα are critical for the binding energy. Interactions in this region are responsible for more than 7 kcal/mol of the binding energy. Here we show equally drastic consequences for the binding energy occur upon truncation of even a few residues at the C terminus of IκBα. Thus, the interface actually has two hot spots, one at either end of the elongated and large surface of interaction. These results suggest a “squeeze” mechanism that leads to the extremely high affinity of the IκBα•NF-κB complex through stabilization of the ankyrin repeat domain. PMID:18824506

Structure-based multiscale approach for identification of interaction partners of PDZ domains.

PubMed

Tiwari, Garima; Mohanty, Debasisa

2014-04-28

PDZ domains are peptide recognition modules which mediate specific protein-protein interactions and are known to have a complex specificity landscape. We have developed a novel structure-based multiscale approach which identifies crucial specificity determining residues (SDRs) of PDZ domains from explicit solvent molecular dynamics (MD) simulations on PDZ-peptide complexes and uses these SDRs in combination with knowledge-based scoring functions for proteomewide identification of their interaction partners. Multiple explicit solvent simulations ranging from 5 to 50 ns duration have been carried out on 28 PDZ-peptide complexes with known binding affinities. MM/PBSA binding energy values calculated from these simulations show a correlation coefficient of 0.755 with the experimental binding affinities. On the basis of the SDRs of PDZ domains identified by MD simulations, we have developed a simple scoring scheme for evaluating binding energies for PDZ-peptide complexes using residue based statistical pair potentials. This multiscale approach has been benchmarked on a mouse PDZ proteome array data set by calculating the binding energies for 217 different substrate peptides in binding pockets of 64 different mouse PDZ domains. Receiver operating characteristic (ROC) curve analysis indicates that, the area under curve (AUC) values for binder vs nonbinder classification by our structure based method is 0.780. Our structure based method does not require experimental PDZ-peptide binding data for training.

Atomistic models for free energy evaluation of drug binding to membrane proteins.

PubMed

Durdagi, S; Zhao, C; Cuervo, J E; Noskov, S Y

2011-01-01

The binding of various molecules to integral membrane proteins with optimal affinity and specificity is central to normal function of cell. While membrane proteins represent about one third of the whole cell proteome, they are a majority of common drug targets. The quest for the development of computational models capable of accurate evaluation of binding affinities, decomposition of the binding into its principal components and thus mapping molecular mechanisms of binding remains one of the main goals of modern computational biophysics and related drug development. The primary scope of this review will be on the recent extension of computational methods for the study of drug binding to membrane proteins. Several examples of such applications will be provided ranging from secondary transporters to voltage gated channels. In this mini-review, we will provide a short summary on the breadth of different methods for binding affinity evaluation. These methods include molecular docking with docking scoring functions, molecular dynamics (MD) simulations combined with post-processing analysis using Molecular Mechanics/Poisson Boltzmann (Generalized Born) Surface Area (MM/PB(GB)SA), as well as direct evaluation of free energies from Free Energy Perturbation (FEP) with constraining schemes, and Potential of Mean Force (PMF) computations. We will compare advantages and shortcomings of popular techniques and provide discussion on the integrative strategies for drug development aimed at targeting membrane proteins.

Role of protein structure and the role of individual fingers in zinc finger protein-DNA recognition: a molecular dynamics simulation study and free energy calculations

NASA Astrophysics Data System (ADS)

Hamed, Mazen Y.

2018-05-01

Molecular dynamics and MM_GBSA energy calculations on various zinc finger proteins containing three and four fingers bound to their target DNA gave insights into the role of each finger in the DNA binding process as part of the protein structure. The wild type Zif 268 (PDB code: 1AAY) gave a ΔG value of - 76.1 (14) kcal/mol. Zinc fingers ZF1, ZF2 and ZF3 were mutated in one experiment and in another experiment one finger was cut and the rest of the protein was studied for binding. The ΔΔG values for the Zinc Finger protein with both ZF1 and ZF2 mutated was + 80 kcal/mol, while mutating only ZF1 the ΔΔG value was + 52 kcal/mol (relative to the wild type). Cutting ZF3 and studying the protein consisting only of ZF1 linked to ZF2 gave a ΔΔG value of + 68 kcal/mol. Upon cutting ZF1, the resulting ZF2 linked to ZF3 protein gave a ΔΔG value of + 41 kcal/mol. The above results shed light on the importance of each finger in the binding process, especially the role of ZF1 as the anchoring finger followed in importance by ZF2 and ZF3. The energy difference between the binding of the wild type protein Zif268 (1AAY) and that for individual finger binding to DNA according to the formula: ΔΔGlinkers, otherstructuralfactors = ΔGzif268 - (ΔGF1+F2+F3) gave a value = - 44.5 kcal/mol. This stabilization can be attributed to the contribution of linkers and other structural factors in the intact protein in the DNA binding process. DNA binding energies of variant proteins of the wild type Zif268 which differ in their ZF1 amino acid sequence gave evidence of a good relationship between binding energy and recognition and specificity, this finding confirms the reported vital role of ZF1 in the ZF protein scanning and anchoring to the target DNA sequence. The role of hydrogen bonds in both specific and nonspecific amino acid-DNA contacts is discussed in relation to mutations. The binding energies of variant Zinc Finger proteins confirmed the role of ZF1 in the recognition, specificity and anchoring of the zinc finger protein to DNA.

Role of protein structure and the role of individual fingers in zinc finger protein-DNA recognition: a molecular dynamics simulation study and free energy calculations.

PubMed

Hamed, Mazen Y

2018-05-03

Molecular dynamics and MM_GBSA energy calculations on various zinc finger proteins containing three and four fingers bound to their target DNA gave insights into the role of each finger in the DNA binding process as part of the protein structure. The wild type Zif 268 (PDB code: 1AAY) gave a ΔG value of - 76.1 (14) kcal/mol. Zinc fingers ZF1, ZF2 and ZF3 were mutated in one experiment and in another experiment one finger was cut and the rest of the protein was studied for binding. The ΔΔG values for the Zinc Finger protein with both ZF1 and ZF2 mutated was + 80 kcal/mol, while mutating only ZF1 the ΔΔG value was + 52 kcal/mol (relative to the wild type). Cutting ZF3 and studying the protein consisting only of ZF1 linked to ZF2 gave a ΔΔG value of + 68 kcal/mol. Upon cutting ZF1, the resulting ZF2 linked to ZF3 protein gave a ΔΔG value of + 41 kcal/mol. The above results shed light on the importance of each finger in the binding process, especially the role of ZF1 as the anchoring finger followed in importance by ZF2 and ZF3. The energy difference between the binding of the wild type protein Zif268 (1AAY) and that for individual finger binding to DNA according to the formula: ΔΔG linkers, otherstructuralfactors  = ΔG zif268  - (ΔG F1+F2+F3 ) gave a value = - 44.5 kcal/mol. This stabilization can be attributed to the contribution of linkers and other structural factors in the intact protein in the DNA binding process. DNA binding energies of variant proteins of the wild type Zif268 which differ in their ZF1 amino acid sequence gave evidence of a good relationship between binding energy and recognition and specificity, this finding confirms the reported vital role of ZF1 in the ZF protein scanning and anchoring to the target DNA sequence. The role of hydrogen bonds in both specific and nonspecific amino acid-DNA contacts is discussed in relation to mutations. The binding energies of variant Zinc Finger proteins confirmed the role of ZF1 in the recognition, specificity and anchoring of the zinc finger protein to DNA.

A first-principles study on adsorption behaviors of pristine and Li-decorated graphene sheets toward hydrazine molecules

NASA Astrophysics Data System (ADS)

Zeng, Huadong; Cheng, Xinlu; Wang, Wei

2018-03-01

The adsorption behaviors and properties of hydrazine (N2H4) molecules on pristine and Li-decorated graphene sheets were investigated by means of first-principles based on density functional theory. We systematically analyzed the optimal geometry, average binding energy, charge transfer, charge density difference and density of states of N2H4 molecules adsorbed on pristine and Li-decorated graphene sheets. It is found that the interaction between single N2H4 molecule and pristine graphene is weak physisorption with the low binding energy of -0.026 eV, suggesting that the pristine graphene sheet is insensitive to the presence of N2H4 molecule. However, it is markedly enhanced after lithium decoration with the high binding energy of -1.004 eV, verifying that the Li-decorated graphene sheet is significantly sensitive to detect N2H4 molecule. Meanwhile, the effects of the concentrations of N2H4 molecules on two different substrates were studied detailedly. For pristine graphene substrate, the average binding energy augments apparently with increasing the number of N2H4 molecules, which is mainly attributed to the van der Waals interactions and hydrogen bonds among N2H4 clusters. Li-decorated graphene sheet has still a strong affinity to N2H4 molecules despite the corresponding average binding energy emerges a contrary tendency. Overall, Li-decorated graphene sheet could be considered as a potential gas sensor in field of hydrazine molecules.

Prediction of FAD binding sites in electron transport proteins according to efficient radial basis function networks and significant amino acid pairs.

PubMed

Le, Nguyen-Quoc-Khanh; Ou, Yu-Yen

2016-07-30

Cellular respiration is a catabolic pathway for producing adenosine triphosphate (ATP) and is the most efficient process through which cells harvest energy from consumed food. When cells undergo cellular respiration, they require a pathway to keep and transfer electrons (i.e., the electron transport chain). Due to oxidation-reduction reactions, the electron transport chain produces a transmembrane proton electrochemical gradient. In case protons flow back through this membrane, this mechanical energy is converted into chemical energy by ATP synthase. The convert process is involved in producing ATP which provides energy in a lot of cellular processes. In the electron transport chain process, flavin adenine dinucleotide (FAD) is one of the most vital molecules for carrying and transferring electrons. Therefore, predicting FAD binding sites in the electron transport chain is vital for helping biologists understand the electron transport chain process and energy production in cells. We used an independent data set to evaluate the performance of the proposed method, which had an accuracy of 69.84 %. We compared the performance of the proposed method in analyzing two newly discovered electron transport protein sequences with that of the general FAD binding predictor presented by Mishra and Raghava and determined that the accuracy of the proposed method improved by 9-45 % and its Matthew's correlation coefficient was 0.14-0.5. Furthermore, the proposed method enabled reducing the number of false positives significantly and can provide useful information for biologists. We developed a method that is based on PSSM profiles and SAAPs for identifying FAD binding sites in newly discovered electron transport protein sequences. This approach achieved a significant improvement after we added SAAPs to PSSM features to analyze FAD binding proteins in the electron transport chain. The proposed method can serve as an effective tool for predicting FAD binding sites in electron transport proteins and can help biologists understand the functions of the electron transport chain, particularly those of FAD binding sites. We also developed a web server which identifies FAD binding sites in electron transporters available for academics.

An introduction to best practices in free energy calculations.

PubMed

Shirts, Michael R; Mobley, David L

2013-01-01

Free energy calculations are extremely useful for investigating small-molecule biophysical properties such as protein-ligand binding affinities and partition coefficients. However, these calculations are also notoriously difficult to implement correctly. In this chapter, we review standard methods for computing free energy via simulation, discussing current best practices and examining potential pitfalls for computational researchers performing them for the first time. We include a variety of examples and tips for how to set up and conduct these calculations, including applications to relative binding affinities and small-molecule solvation free energies.

Temperature dependent dispersion and electron-phonon coupling surface states on Be(1010)

NASA Astrophysics Data System (ADS)

Tang, Shu-Jung; Ismail; Sprunger, Philip; Plummer, Ward

2002-03-01

Temperature dependent dispersion and electron-phonon coupling surface states on Be(10-10) S.-J Tang*, Ismail* , P.T . Sprunger#, E. W. Plummer* * Department of Physics and Astronomy, University of Tennessee, Knoxville, TN37996 , # Center for Advanced Microstructures and Devices (CAMD), Louisiana State University The surface states dispersing in a large band gap from -A to -Γ in Be(10-10) were studied with high-resolution, angle-resolved photoemission. Spectra reveal that the two zone-boundary surface states, S1 and S2, behave significantly different with respect to band dispersion, the temperature dependence of binding energies, and the electron-phonon coupling. The band dispersion of S1 is purely free-electron like with the maximum binding energy of 0.37+-0.05 eV at -A and effective mass m*/m =0835. However, the maximum binding energy 2.74+-0.05 eV of the S2 is located 0.2Åaway from -A and disperses into the bulk band edge at a binding energy of 1.75+-0.05 eV. Temperature dependent data reveal that the binding energies of S1 and S2 at -A shift in opposite directions at the rate of (-0.61+-0.3)+- 10E-4 eV/K and (1.71+-0.8)+-10E-4 eV/K, respectively. Moreover, from the temperature-dependent spectral widths of the surface states S1 and S2 at , the electron-phonon coupling parameters,λ, have been determined. Unusually different, the coupling strength λ for S1 and S2 are 0.67+-0.03 and 0.51+-0.04, respectively. The differences between the electron-phonon coupling, temperature dependent binding energies, and dispersions between these two zone-centered surface states will be discussed in light unique bonding at the surface and localization.

Towards accurate free energy calculations in ligand protein-binding studies.

PubMed

Steinbrecher, Thomas; Labahn, Andreas

2010-01-01

Cells contain a multitude of different chemical reaction paths running simultaneously and quite independently next to each other. This amazing feat is enabled by molecular recognition, the ability of biomolecules to form stable and specific complexes with each other and with their substrates. A better understanding of this process, i.e. of the kinetics, structures and thermodynamic properties of biomolecule binding, would be invaluable in the study of biological systems. In addition, as the mode of action of many pharmaceuticals is based upon their inhibition or activation of biomolecule targets, predictive models of small molecule receptor binding are very helpful tools in rational drug design. Since the goal here is normally to design a new compound with a high inhibition strength, one of the most important thermodynamic properties is the binding free energy DeltaG(0). The prediction of binding constants has always been one of the major goals in the field of computational chemistry, because the ability to reliably assess a hypothetical compound's binding properties without having to synthesize it first would save a tremendous amount of work. The different approaches to this question range from fast and simple empirical descriptor methods to elaborate simulation protocols aimed at putting the computation of free energies onto a solid foundation of statistical thermodynamics. While the later methods are still not suited for the screenings of thousands of compounds that are routinely performed in computational drug design studies, they are increasingly put to use for the detailed study of protein ligand interactions. This review will focus on molecular mechanics force field based free energy calculations and their application to the study of protein ligand interactions. After a brief overview of other popular methods for the calculation of free energies, we will describe recent advances in methodology and a variety of exemplary studies of molecular dynamics simulation based free energy calculations.

On the Role of Water Models in Quantifying the Binding Free Energy of Highly Conserved Water Molecules in Proteins: The Case of Concanavalin A.

PubMed

Fadda, Elisa; Woods, Robert J

2011-10-11

The ability of ligands to displace conserved water molecules in protein binding sites is of significant interest in drug design and is particularly pertinent in the case of glycomimetic drugs. This concept was explored in previous work [ Clarke et al. J. Am. Chem. Soc. 2001 , 123 , 12238 - 12247 and Kadirvelraj et al. J. Am. Chem. Soc. 2008 , 130 , 16933 - 16942 ] for a highly conserved water molecule located in the binding site of the prototypic carbohydrate-binding protein Concanavalin A (Con A). A synthetic ligand was designed with the aim of displacing such water. While the synthetic ligand bound to Con A in an analogous manner to that of the natural ligand, crystallographic analysis demonstrated that it did not displace the conserved water. In order to quantify the affinity of this particular water for the Con A surface, we report here the calculated standard binding free energy for this water in both ligand-bound and free Con A, employing three popular water models: TIP3P, TIP4P, and TIP5P. Although each model was developed to perform well in simulations of bulk-phase water, the computed binding energies for the isolated water molecule displayed a high sensitivity to the model. Both molecular dynamics simulation and free energy results indicate that the choice of water model may greatly influence the characterization of surface water molecules as conserved (TIP5P) or not (TIP3P) in protein binding sites, an observation of considerable significance to rational drug design. Structural and theoretical aspects at the basis of the different behaviors are identified and discussed.

The effect of magnetic field on the impurity binding energy of shallow donor impurities in a Ga1−xInxNyAs1−y/GaAs quantum well

PubMed Central

2012-01-01

Using a variational approach, we have investigated the effects of the magnetic field, the impurity position, and the nitrogen and indium concentrations on impurity binding energy in a Ga1−xInxNyAs1−y/GaAs quantum well. Our calculations have revealed the dependence of impurity binding on the applied magnetic field, the impurity position, and the nitrogen and indium concentrations. PMID:23095253

INTERACTION OF INTERSTITIAL CLUSTERS WITH RHENIUM, OSMIUM, AND TANTALUM IN TUNGSTEN

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

Setyawan, Wahyu; Nandipati, Giridhar; Kurtz, Richard J.

2016-09-01

In the previous semi annual report, we explored the stability of interstitial clusters in W up to size seven. In this report, we study the binding of those clusters to Re, Os, and Ta atoms. For each cluster size, the three most stable configurations are considered to average the binding property. The average binding energy to a Re decreases from 0.79 eV for a size-1 cluster (a [111] dumbbell) to 0.65 eV for a size-7 cluster. For Os, the binding decreases from 1.61 eV for a [111] dumbbell to 1.34 eV for a size-7 cluster. Tantalum is repulsive to interstitialmore » clusters with binding energy ranges from -0.61 eV for a [111] dumbbell to -0.5 eV for a size-7 cluster.« less

Comparison of the interaction between lactoferrin and isomeric drugs

NASA Astrophysics Data System (ADS)

Guo, Ming; Lu, Xiaowang; Wang, Yan; Brodelius, Peter E.

2017-02-01

The binding properties of pentacyclic triterpenoid isomeric drugs, i.e. ursolic acid (UA) and oleanolic acid (OA), to bovine lactoferrin (BLF) have been studied by molecule modeling, fluorescence spectroscopy, UV-visible absorbance spectroscopy and infrared spectroscopy (IR). Molecular docking, performed to reveal the possible binding mode or mechanism, suggested that hydrophobic interaction and hydrogen bonding play important roles to stabilize the complex. The results of spectroscopic measurements showed that the two isomeric drugs both strongly quenched the intrinsic fluorescence of BLF through a static quenching procedure although some differences between UA and OA binding strength and non-radiation energy transfer occurred within the molecules. The number of binding sites was 3.44 and 3.10 for UA and OA, respectively, and the efficiency of Förster energy transfer provided a distance of 0.77 and 1.21 nm for UA and OA, respectively. The conformation transformation of BLF affected by the drugs conformed to the ;all-or-none; pattern. In addition, the changes of the ratios of α-helices, β-sheets and β-turns of BLF during the process of the interaction were obtained. The results of the experiments in combination with the calculations showed that there are two modes of pentacyclic triterpenoid binding to BLF instead of one binding mode only governed by the principle of the lowest bonding energy.

Binding of novel fullerene inhibitors to HIV-1 protease: insight through molecular dynamics and molecular mechanics Poisson-Boltzmann surface area calculations

NASA Astrophysics Data System (ADS)

Tzoupis, Haralambos; Leonis, Georgios; Durdagi, Serdar; Mouchlis, Varnavas; Mavromoustakos, Thomas; Papadopoulos, Manthos G.

2011-10-01

The objectives of this study include the design of a series of novel fullerene-based inhibitors for HIV-1 protease (HIV-1 PR), by employing two strategies that can also be applied to the design of inhibitors for any other target. Additionally, the interactions which contribute to the observed exceptionally high binding free energies were analyzed. In particular, we investigated: (1) hydrogen bonding (H-bond) interactions between specific fullerene derivatives and the protease, (2) the regions of HIV-1 PR that play a significant role in binding, (3) protease changes upon binding and (4) various contributions to the binding free energy, in order to identify the most significant of them. This study has been performed by employing a docking technique, two 3D-QSAR models, molecular dynamics (MD) simulations and the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. Our computed binding free energies are in satisfactory agreement with the experimental results. The suitability of specific fullerene derivatives as drug candidates was further enhanced, after ADMET (absorption, distribution, metabolism, excretion and toxicity) properties have been estimated to be promising. The outcomes of this study revealed important protein-ligand interaction patterns that may lead towards the development of novel, potent HIV-1 PR inhibitors.

Dispersion- and Exchange-Corrected Density Functional Theory for Sodium Ion Hydration.

PubMed

Soniat, Marielle; Rogers, David M; Rempe, Susan B

2015-07-14

A challenge in density functional theory is developing functionals that simultaneously describe intermolecular electron correlation and electron delocalization. Recent exchange-correlation functionals address those two issues by adding corrections important at long ranges: an atom-centered pairwise dispersion term to account for correlation and a modified long-range component of the electron exchange term to correct for delocalization. Here we investigate how those corrections influence the accuracy of binding free energy predictions for sodium-water clusters. We find that the dual-corrected ωB97X-D functional gives cluster binding energies closest to high-level ab initio methods (CCSD(T)). Binding energy decomposition shows that the ωB97X-D functional predicts the smallest ion-water (pairwise) interaction energy and larger multibody contributions for a four-water cluster than most other functionals - a trend consistent with CCSD(T) results. Also, ωB97X-D produces the smallest amounts of charge transfer and the least polarizable waters of the density functionals studied, which mimics the lower polarizability of CCSD. When compared with experimental binding free energies, however, the exchange-corrected CAM-B3LYP functional performs best (error <1 kcal/mol), possibly because of its parametrization to experimental formation enthalpies. For clusters containing more than four waters, "split-shell" coordination must be considered to obtain accurate free energies in comparison with experiment.

Converging free energies of binding in cucurbit[7]uril and octa-acid host-guest systems from SAMPL4 using expanded ensemble simulations

NASA Astrophysics Data System (ADS)

Monroe, Jacob I.; Shirts, Michael R.

2014-04-01

Molecular containers such as cucurbit[7]uril (CB7) and the octa-acid (OA) host are ideal simplified model test systems for optimizing and analyzing methods for computing free energies of binding intended for use with biologically relevant protein-ligand complexes. To this end, we have performed initially blind free energy calculations to determine the free energies of binding for ligands of both the CB7 and OA hosts. A subset of the selected guest molecules were those included in the SAMPL4 prediction challenge. Using expanded ensemble simulations in the dimension of coupling host-guest intermolecular interactions, we are able to show that our estimates in most cases can be demonstrated to fully converge and that the errors in our estimates are due almost entirely to the assigned force field parameters and the choice of environmental conditions used to model experiment. We confirm the convergence through the use of alternative simulation methodologies and thermodynamic pathways, analyzing sampled conformations, and directly observing changes of the free energy with respect to simulation time. Our results demonstrate the benefits of enhanced sampling of multiple local free energy minima made possible by the use of expanded ensemble molecular dynamics and may indicate the presence of significant problems with current transferable force fields for organic molecules when used for calculating binding affinities, especially in non-protein chemistries.

Converging free energies of binding in cucurbit[7]uril and octa-acid host-guest systems from SAMPL4 using expanded ensemble simulations.

PubMed

Monroe, Jacob I; Shirts, Michael R

2014-04-01

Molecular containers such as cucurbit[7]uril (CB7) and the octa-acid (OA) host are ideal simplified model test systems for optimizing and analyzing methods for computing free energies of binding intended for use with biologically relevant protein-ligand complexes. To this end, we have performed initially blind free energy calculations to determine the free energies of binding for ligands of both the CB7 and OA hosts. A subset of the selected guest molecules were those included in the SAMPL4 prediction challenge. Using expanded ensemble simulations in the dimension of coupling host-guest intermolecular interactions, we are able to show that our estimates in most cases can be demonstrated to fully converge and that the errors in our estimates are due almost entirely to the assigned force field parameters and the choice of environmental conditions used to model experiment. We confirm the convergence through the use of alternative simulation methodologies and thermodynamic pathways, analyzing sampled conformations, and directly observing changes of the free energy with respect to simulation time. Our results demonstrate the benefits of enhanced sampling of multiple local free energy minima made possible by the use of expanded ensemble molecular dynamics and may indicate the presence of significant problems with current transferable force fields for organic molecules when used for calculating binding affinities, especially in non-protein chemistries.

Thermodynamics of impurity-enhanced vacancy formation in metals

NASA Astrophysics Data System (ADS)

Bukonte, Laura; Ahlgren, Tommy; Heinola, Kalle

2017-01-01

Hydrogen induced vacancy formation in metals and metal alloys has been of great interest during the past couple of decades. The main reason for this phenomenon, often referred to as the superabundant vacancy formation, is the lowering of vacancy formation energy due to the trapping of hydrogen. By means of thermodynamics, we study the equilibrium vacancy formation in fcc metals (Pd, Ni, Co, and Fe) in correlation with the H amounts. The results of this study are compared and found to be in good agreement with experiments. For the accurate description of the total energy of the metal-hydrogen system, we take into account the binding energies of each trapped impurity, the vibrational entropy of defects, and the thermodynamics of divacancy formation. We demonstrate the effect of vacancy formation energy, the hydrogen binding, and the divacancy binding energy on the total equilibrium vacancy concentration. We show that the divacancy fraction gives the major contribution to the total vacancy fraction at high H fractions and cannot be neglected when studying superabundant vacancies. Our results lead to a novel conclusion that at high hydrogen fractions, superabundant vacancy formation takes place regardless of the binding energy between vacancies and hydrogen. We also propose the reason of superabundant vacancy formation mainly in the fcc phase. The equations obtained within this work can be used for any metal-impurity system, if the impurity occupies an interstitial site in the lattice.

The energy and work of a ligand-gated ion channel

PubMed Central

Auerbach, Anthony

2015-01-01

Ligand-gated ion channels are allosteric membrane proteins that isomerize between C(losed) and O(pen) conformations. A difference in affinity for ligands in the two shapes influences the C↔O ‘gating’ equilibrium constant. The energies associated with adult-type mouse neuromuscular nicotinic acetylcholine receptor-channel (AChR) gating have been measured by using single-channel electrophysiology. Without ligands the free energy, enthalpy and entropy of gating are ΔG0=+8.4, ΔH0=+10.9 and ΔS0=+2.4 kcal/mol (−100 mV, 23 °C). Many mutations throughout the protein change ΔG0, including natural ones that cause disease. Agonists and most mutations change approximately independently the ground state energy difference, so it is possible to forecast and engineer AChR responses simply by combining perturbations. The free energy of the low↔high affinity change for the neurotransmitter at each of two functionally-equivalent binding sites is ΔGBACh=−5.1 kcal/mol. ΔGBACh is set mainly by interactions of ACh with just three binding site aromatic groups. For a series of structurally-related agonists there is a correlation between the energies of low- and high-affinity binding, which implies that gating commences with the formation of the low affinity complex. Brief, intermediate states in binding and gating have been detected. Several proposals for the nature of the gating transition state energy landscape and the isomerization mechanism are discussed. PMID:23357172

Theoretical Study of Fe(CO)n-

NASA Technical Reports Server (NTRS)

Ricca, Alessandra; Baushlicher, Charles W., Jr.

1995-01-01

The structures and CO binding energies are computed for Fe(CO)n- using a hybrid density functional theory (DFT) approach. The structures and ground states can be explained in terms of maximizing the Fe to CO 2pi* donation and minimizing Fe-CO 5 sigma repulsion. The trends in the CO binding energies for Fe(CO)n- and the differences between the trends for Fe(CO)n- and Fe(CO)n are also explained. For Fe(CO)n-, the second, third, and fourth CO bonding energies are in good agreement with experiment, while the first is too small. The first CO binding is also too small using the coupled cluster singles and doubles approach including a perturbation estimate of the connected triple excitations.

Crown oxygen-doping graphene with embedded main-group metal atoms

NASA Astrophysics Data System (ADS)

Wu, Liyuan; Wang, Qian; Yang, Chuanghua; Quhe, Ruge; Guan, Pengfei; Lu, Pengfei

2018-02-01

Different main-group metal atoms embedded in crown oxygen-doping graphene (metal@OG) systems are studied by the density functional theory. The binding energies and electronic structures are calculated by using first-principles calculations. The binding energy of metal@OG system mainly depends on the electronegativity of the metal atom. The lower the value of the electronegativity, the larger the binding energy, indicating the more stable the system. The electronic structure of metal@OG arouses the emergence of bandgap and shift of Dirac point. It is shown that interaction between metal atom and crown oxygen-doping graphene leads to the graphene's stable n-doping, and the metal@OG systems are stable semiconducting materials, which can be used in technological applications.

Tight-binding calculation studies of vacancy and adatom defects in graphene

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

Zhang, Wei; Lu, Wen-Cai; Zhang, Hong-Xing

2016-02-19

Computational studies of complex defects in graphene usually need to deal with a larger number of atoms than the current first-principles methods can handle. We show a recently developed three-center tight-binding potential for carbon is very efficient for large scale atomistic simulations and can accurately describe the structures and energies of various defects in graphene. Using the three-center tight-binding potential, we have systematically studied the stable structures and formation energies of vacancy and embedded-atom defects of various sizes up to 4 vacancies and 4 embedded atoms in graphene. In conclusion, our calculations reveal low-energy defect structures and provide a moremore » comprehensive understanding of the structures and stability of defects in graphene.« less

Changes in the zero-point energy of the protons as the source of the binding energy of water to A-phase DNA.

PubMed

Reiter, G F; Senesi, R; Mayers, J

2010-10-01

The measured changes in the zero-point kinetic energy of the protons are entirely responsible for the binding energy of water molecules to A phase DNA at the concentration of 6  water molecules/base pair. The changes in kinetic energy can be expected to be a significant contribution to the energy balance in intracellular biological processes and the properties of nano-confined water. The shape of the momentum distribution in the dehydrated A phase is consistent with coherent delocalization of some of the protons in a double well potential, with a separation of the wells of 0.2 Å.

New Parameters for Higher Accuracy in the Computation of Binding Free Energy Differences upon Alanine Scanning Mutagenesis on Protein-Protein Interfaces.

PubMed

Simões, Inês C M; Costa, Inês P D; Coimbra, João T S; Ramos, Maria J; Fernandes, Pedro A

2017-01-23

Knowing how proteins make stable complexes enables the development of inhibitors to preclude protein-protein (P:P) binding. The identification of the specific interfacial residues that mostly contribute to protein binding, denominated as hot spots, is thus critical. Here, we refine an in silico alanine scanning mutagenesis protocol, based on a residue-dependent dielectric constant version of the Molecular Mechanics/Poisson-Boltzmann Surface Area method. We have used a large data set of structurally diverse P:P complexes to redefine the residue-dependent dielectric constants used in the determination of binding free energies. The accuracy of the method was validated through comparison with experimental data, considering the per-residue P:P binding free energy (ΔΔG binding ) differences upon alanine mutation. Different protocols were tested, i.e., a geometry optimization protocol and three molecular dynamics (MD) protocols: (1) one using explicit water molecules, (2) another with an implicit solvation model, and (3) a third where we have carried out an accelerated MD with explicit water molecules. Using a set of protein dielectric constants (within the range from 1 to 20) we showed that the dielectric constants of 7 for nonpolar and polar residues and 11 for charged residues (and histidine) provide optimal ΔΔG binding predictions. An overall mean unsigned error (MUE) of 1.4 kcal mol -1 relative to the experiment was achieved in 210 mutations only with geometry optimization, which was further reduced with MD simulations (MUE of 1.1 kcal mol -1 for the MD employing explicit solvent). This recalibrated method allows for a better computational identification of hot spots, avoiding expensive and time-consuming experiments or thermodynamic integration/ free energy perturbation/ uBAR calculations, and will hopefully help new drug discovery campaigns in their quest of searching spots of interest for binding small drug-like molecules at P:P interfaces.

Steered Molecular Dynamics for Investigating the Interactions Between Insulin Receptor Tyrosine Kinase (IRK) and Variants of Protein Tyrosine Phosphatase 1B (PTP1B).

PubMed

Nguyen, Hung; Do, Nhat; Phan, Tuyn; Pham, Tri

2018-02-01

The aim of this study is to use steered molecular dynamics to investigate the dissociation process between IRK and PTP1Bs for wild type and five mutants (consisting of p.D181E, p.D181A, p.Q262A, p.D181A-Y46F, and p.D181A-Q262A). The gained results are observed not only the unbinding mechanism of IRK-PTP1B complexes came from pulling force profile, number of hydrogen bonds, and interaction energy between IRK and PTP1Bs but also described PTP1B's point mutations could variably change its binding affinity towards IRK. Additionally, the binding free energy calculated by Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) is also revealed that electrostatic energy and polar solvation energy mainly made up the binding free energy of PTP1B-IRK complexes.

GMXPBSA 2.0: A GROMACS tool to perform MM/PBSA and computational alanine scanning

NASA Astrophysics Data System (ADS)

Paissoni, C.; Spiliotopoulos, D.; Musco, G.; Spitaleri, A.

2014-11-01

GMXPBSA 2.0 is a user-friendly suite of Bash/Perl scripts for streamlining MM/PBSA calculations on structural ensembles derived from GROMACS trajectories, to automatically calculate binding free energies for protein-protein or ligand-protein complexes. GMXPBSA 2.0 is flexible and can easily be customized to specific needs. Additionally, it performs computational alanine scanning (CAS) to study the effects of ligand and/or receptor alanine mutations on the free energy of binding. Calculations require only for protein-protein or protein-ligand MD simulations. GMXPBSA 2.0 performs different comparative analysis, including a posteriori generation of alanine mutants of the wild-type complex, calculation of the binding free energy values of the mutant complexes and comparison of the results with the wild-type system. Moreover, it compares the binding free energy of different complexes trajectories, allowing the study the effects of non-alanine mutations, post-translational modifications or unnatural amino acids on the binding free energy of the system under investigation. Finally, it can calculate and rank relative affinity to the same receptor utilizing MD simulations of proteins in complex with different ligands. In order to dissect the different MM/PBSA energy contributions, including molecular mechanic (MM), electrostatic contribution to solvation (PB) and nonpolar contribution to solvation (SA), the tool combines two freely available programs: the MD simulations software GROMACS and the Poisson-Boltzmann equation solver APBS. All the calculations can be performed in single or distributed automatic fashion on a cluster facility in order to increase the calculation by dividing frames across the available processors. The program is freely available under the GPL license.

Analysis of oxygen binding-energy variations for BaO on W

NASA Astrophysics Data System (ADS)

Haas, G. A.; Shih, A.; Mueller, D.; Thomas, R. E.

Interatomic Auger analyses have been made of different forms of BaO layers on W substrates. Variations in Auger spectroscopy energies of the Ba4dBa5pO2p interatomic Auger transition were found to be largely governed by the O2p binding energy of the BaO adsorbate. This was illustrated by comparing results of the Auger data values with values derived from O2p binding energies using ultraviolet photoelectron spectroscopy. Very good agreement was observed not only for the W<100> substrate but also for the W<110> substrate which showed two oxygen-induced electronics state. Variations in binding energy were noted for different states of BaO lattice formation and for different amounts of oxidation, ranging from the transition of Ba to BaO and continuing to the BaO 2 stoichiometry and beyond. Effects were also reported for adsorbate alignment and thermal activation (i.e., reduction) of the oxidized state. An empirical relationship was found suggesting that the more tightly bound the O2p states of the BaO adsorbate were, the lower its work function would be. This link between binding energy and work function was observed to be valid not only for cases of poisoning by oxidation, but held as well during reactivation by the subsequent reduction of the oxide. In addition, this relationship also appeared to predict the low work function obtained through the introduction of substances such as Sc to the BaO-W system. Possible qualitative reasons which might contribute to this are discussed in terms of enhanced dipole effects and shifts in band structure.

Exploring transition pathway and free-energy profile of large-scale protein conformational change by combining normal mode analysis and umbrella sampling molecular dynamics.

PubMed

Wang, Jinan; Shao, Qiang; Xu, Zhijian; Liu, Yingtao; Yang, Zhuo; Cossins, Benjamin P; Jiang, Hualiang; Chen, Kaixian; Shi, Jiye; Zhu, Weiliang

2014-01-09

Large-scale conformational changes of proteins are usually associated with the binding of ligands. Because the conformational changes are often related to the biological functions of proteins, understanding the molecular mechanisms of these motions and the effects of ligand binding becomes very necessary. In the present study, we use the combination of normal-mode analysis and umbrella sampling molecular dynamics simulation to delineate the atomically detailed conformational transition pathways and the associated free-energy landscapes for three well-known protein systems, viz., adenylate kinase (AdK), calmodulin (CaM), and p38α kinase in the absence and presence of respective ligands. For each protein under study, the transient conformations along the conformational transition pathway and thermodynamic observables are in agreement with experimentally and computationally determined ones. The calculated free-energy profiles reveal that AdK and CaM are intrinsically flexible in structures without obvious energy barrier, and their ligand binding shifts the equilibrium from the ligand-free to ligand-bound conformation (population shift mechanism). In contrast, the ligand binding to p38α leads to a large change in free-energy barrier (ΔΔG ≈ 7 kcal/mol), promoting the transition from DFG-in to DFG-out conformation (induced fit mechanism). Moreover, the effect of the protonation of D168 on the conformational change of p38α is also studied, which reduces the free-energy difference between the two functional states of p38α and thus further facilitates the conformational interconversion. Therefore, the present study suggests that the detailed mechanism of ligand binding and the associated conformational transition is not uniform for all kinds of proteins but correlated to their respective biological functions.

Insights into resistance mechanism of the macrolide biosensor protein MphR(A) binding to macrolide antibiotic erythromycin by molecular dynamics simulation

NASA Astrophysics Data System (ADS)

Feng, Tingting; Zhang, Yanjun; Ding, Jing-Na; Fan, Song; Han, Ju-Guang

2015-12-01

Macrolide biosensor protein MphR(A) has been known as a key regulatory protein in metabolite sensing and genetic expression regulating. MphR(A) protein binds to macrolide antibiotic erythromycin (Ery) and releases the gene operon, thus activates expression of the mphA gene and initiates Ery resistance. The two mutant amino acid residues (V66L and V126L) might potentially disrupt Ery binding to MphR(A). In these studies, the binding of macrolide antibiotic Ery to wild type (Wt) MphR(A) and double mutant (V66L/V126L) MphR(A) are explored by molecular dynamics simulations. Compared to the Apo-MphR(A) protein and Wt-MphR(A)-Ery complex, many interesting effects owing to the double mutant (V66L/V126L) are discovered. In the case of Ery, Helix I which plays an important role in transcription shows itself a right-hand α helix in Wt-MphR(A)-Ery, whereas the activated helix is broken down in double mutant-V66L/V126L-MphR(A)-Ery. The calculated results exhibit that the double mutant V66L/V126L reduces the binding affinity of the V66L/V126L-MphR(A) to Ery, resulting in the block of Ery resistance. The binding free energy decomposition analysis reveals that the decrease of the binding affinity for the variant V66L/V126L-MphR(A)-Ery is mainly attributed to the gas phase electrostatic energies. The residue Leu66, Thr154, and Arg122 enhance the binding affinity of V66L/V126L-MphR(A) to Ery. The residues Tyr103 and His147 contributes mainly to binding energies in the Wt-MphR(A)-Ery complex, whereas the two residues have no contribution to the binding free energy inV66L/V126L-MphR(A)-Ery complex. Our study gives useful insights into the nature of amino acids mutation effect, the mechanism of blocking drug resistance at the atomic level and the characteristics in binding affinity for Ery to double mutant (V66L/V126L) MphR(A), which will contribute to the design of more effective macrolide antibiotics.

Heat Capacity Changes and Disorder-to-Order Transitions in Allosteric Activation.

PubMed

Cressman, William J; Beckett, Dorothy

2016-01-19

Allosteric coupling in proteins is ubiquitous but incompletely understood, particularly in systems characterized by coupling over large distances. Binding of the allosteric effector, bio-5'-AMP, to the Escherichia coli biotin protein ligase, BirA, enhances the protein's dimerization free energy by -4 kcal/mol. Previous studies revealed that disorder-to-order transitions at the effector binding and dimerization sites, which are separated by 33 Å, are integral to functional coupling. Perturbations to the transition at the ligand binding site alter both ligand binding and coupled dimerization. Alanine substitutions in four loops on the dimerization surface yield a range of energetic effects on dimerization. A glycine to alanine substitution at position 142 in one of these loops results in a complete loss of allosteric coupling, disruption of the disorder-to-order transitions at both functional sites, and a decreased affinity for the effector. In this work, allosteric communication between the effector binding and dimerization surfaces in BirA was further investigated by performing isothermal titration calorimetry measurements on nine proteins with alanine substitutions in three dimerization surface loops. In contrast to BirAG142A, at 20 °C all variants bind to bio-5'-AMP with free energies indistinguishable from that measured for wild-type BirA. However, the majority of the variants exhibit altered heat capacity changes for effector binding. Moreover, the ΔCp values correlate with the dimerization free energies of the effector-bound proteins. These thermodynamic results, combined with structural information, indicate that allosteric activation of the BirA monomer involves formation of a network of intramolecular interactions on the dimerization surface in response to bio-5'-AMP binding at the distant effector binding site.

Automated docking of ligands to an artificial active site: augmenting crystallographic analysis with computer modeling

NASA Astrophysics Data System (ADS)

Rosenfeld, Robin J.; Goodsell, David S.; Musah, Rabi A.; Morris, Garrett M.; Goodin, David B.; Olson, Arthur J.

2003-08-01

The W191G cavity of cytochrome c peroxidase is useful as a model system for introducing small molecule oxidation in an artificially created cavity. A set of small, cyclic, organic cations was previously shown to bind in the buried, solvent-filled pocket created by the W191G mutation. We docked these ligands and a set of non-binders in the W191G cavity using AutoDock 3.0. For the ligands, we compared docking predictions with experimentally determined binding energies and X-ray crystal structure complexes. For the ligands, predicted binding energies differed from measured values by ± 0.8 kcal/mol. For most ligands, the docking simulation clearly predicted a single binding mode that matched the crystallographic binding mode within 1.0 Å RMSD. For 2 ligands, where the docking procedure yielded an ambiguous result, solutions matching the crystallographic result could be obtained by including an additional crystallographically observed water molecule in the protein model. For the remaining 2 ligands, docking indicated multiple binding modes, consistent with the original electron density, suggesting disordered binding of these ligands. Visual inspection of the atomic affinity grid maps used in docking calculations revealed two patches of high affinity for hydrogen bond donating groups. Multiple solutions are predicted as these two sites compete for polar hydrogens in the ligand during the docking simulation. Ligands could be distinguished, to some extent, from non-binders using a combination of two trends: predicted binding energy and level of clustering. In summary, AutoDock 3.0 appears to be useful in predicting key structural and energetic features of ligand binding in the W191G cavity.

Calculations of antiproton-nucleus quasi-bound states using the Paris N bar N potential

NASA Astrophysics Data System (ADS)

Hrtánková, Jaroslava; Mareš, Jiří

2018-01-01

An optical potential constructed using the p bar N scattering amplitudes derived from the 2009 version of the Paris N bar N potential is applied in calculations of p bar quasi-bound states in selected nuclei across the periodic table. A proper self-consistent procedure for treating energy dependence of the amplitudes in a nucleus appears crucial for evaluating p bar binding energies and widths. Particular attention is paid to the role of P-wave amplitudes. While the P-wave potential nearly does not affect calculated p bar binding energies, it reduces considerably the corresponding widths. The Paris S-wave potential supplemented by a phenomenological P-wave term yields in dynamical calculations p bar binding energies Bpbar ≈ 200 MeV and widths Γpbar ∼ 200- 230 MeV, which is very close to the values obtained within the RMF model consistent with p bar -atom data.

Methods for neutralizing anthrax or anthrax spores

DOEpatents

Sloan, Mark A; Vivekandanda, Jeevalatha; Holwitt, Eric A; Kiel, Johnathan L

2013-02-26

The present invention concerns methods, compositions and apparatus for neutralizing bioagents, wherein bioagents comprise biowarfare agents, biohazardous agents, biological agents and/or infectious agents. The methods comprise exposing the bioagent to an organic semiconductor and exposing the bioagent and organic semiconductor to a source of energy. Although any source of energy is contemplated, in some embodiments the energy comprises visible light, ultraviolet, infrared, radiofrequency, microwave, laser radiation, pulsed corona discharge or electron beam radiation. Exemplary organic semiconductors include DAT and DALM. In certain embodiments, the organic semiconductor may be attached to one or more binding moieties, such as an antibody, antibody fragment, or nucleic acid ligand. Preferably, the binding moiety has a binding affinity for one or more bioagents to be neutralized. Other embodiments concern an apparatus comprising an organic semiconductor and an energy source. In preferred embodiments, the methods, compositions and apparatus are used for neutralizing anthrax spores.

Cooper-pair size and binding energy for unconventional superconducting systems

NASA Astrophysics Data System (ADS)

Dinóla Neto, F.; Neto, Minos A.; Salmon, Octavio D. Rodriguez

2018-06-01

The main proposal of this paper is to analyze the size of the Cooper pairs composed by unbalanced mass fermions from different electronic bands along the BCS-BEC crossover and study the binding energy of the pairs. We are considering an interaction between fermions with different masses leading to an inter-band pairing. In addiction to the attractive interaction we have an hybridization term to couple both bands, which in general acts unfavorable for the pairing between the electrons. We get first order phase transitions as the hybridization breaks the Cooper pairs for the s-wave symmetry of the gap amplitude. The results show the dependence of the Cooper-pair size as a function of the hybridization for T = 0 . We also propose the structure of the binding energy of the inter-band system as a function of the two-bands quasi-particle energies.

Mechanical work makes important contributions to surface chemistry at steps.

PubMed

Francis, M F; Curtin, W A

2015-02-13

The effect of mechanical strain on the binding energy of adsorbates to late transition metals is believed to be entirely controlled by electronic factors, with tensile stress inducing stronger binding. Here we show, via computation, that mechanical strain of late transition metals can modify binding at stepped surfaces opposite to well-established trends on flat surfaces. The mechanism driving the trend is mechanical, arising from the relaxation of stored mechanical energy. The mechanical energy change can be larger than, and of opposite sign than, the energy changes due to electronic effects and leads to a violation of trends predicted by the widely accepted electronic 'd-band' model. This trend has a direct impact on catalytic activity, which is demonstrated here for methanation, where biaxial tension is predicted to shift the activity of nickel significantly, reaching the peak of the volcano plot and comparable to cobalt and ruthenium.

Site Identification by Ligand Competitive Saturation (SILCS) simulations for fragment-based drug design.

PubMed

Faller, Christina E; Raman, E Prabhu; MacKerell, Alexander D; Guvench, Olgun

2015-01-01

Fragment-based drug design (FBDD) involves screening low molecular weight molecules ("fragments") that correspond to functional groups found in larger drug-like molecules to determine their binding to target proteins or nucleic acids. Based on the principle of thermodynamic additivity, two fragments that bind nonoverlapping nearby sites on the target can be combined to yield a new molecule whose binding free energy is the sum of those of the fragments. Experimental FBDD approaches, like NMR and X-ray crystallography, have proven very useful but can be expensive in terms of time, materials, and labor. Accordingly, a variety of computational FBDD approaches have been developed that provide different levels of detail and accuracy.The Site Identification by Ligand Competitive Saturation (SILCS) method of computational FBDD uses all-atom explicit-solvent molecular dynamics (MD) simulations to identify fragment binding. The target is "soaked" in an aqueous solution with multiple fragments having different identities. The resulting computational competition assay reveals what small molecule types are most likely to bind which regions of the target. From SILCS simulations, 3D probability maps of fragment binding called "FragMaps" can be produced. Based on the probabilities relative to bulk, SILCS FragMaps can be used to determine "Grid Free Energies (GFEs)," which provide per-atom contributions to fragment binding affinities. For essentially no additional computational overhead relative to the production of the FragMaps, GFEs can be used to compute Ligand Grid Free Energies (LGFEs) for arbitrarily complex molecules, and these LGFEs can be used to rank-order the molecules in accordance with binding affinities.

Nanomechanical mapping of first binding steps of a virus to animal cells

NASA Astrophysics Data System (ADS)

Alsteens, David; Newton, Richard; Schubert, Rajib; Martinez-Martin, David; Delguste, Martin; Roska, Botond; Müller, Daniel J.

2017-02-01

Viral infection is initiated when a virus binds to cell surface receptors. Because the cell membrane is dynamic and heterogeneous, imaging living cells and simultaneously quantifying the first viral binding events is difficult. Here, we show an atomic force and confocal microscopy set-up that allows the surface receptor landscape of cells to be imaged and the virus binding events within the first millisecond of contact with the cell to be mapped at high resolution (<50 nm). We present theoretical approaches to contour the free-energy landscape of early binding events between an engineered virus and cell surface receptors. We find that the first bond formed between the viral glycoprotein and its cognate cell surface receptor has relatively low lifetime and free energy, but this increases as additional bonds form rapidly (≤1 ms). The formation of additional bonds occurs with positive allosteric modulation and the three binding sites of the viral glycoprotein are quickly occupied. Our quantitative approach can be readily applied to study the binding of other viruses to animal cells.

Capture and quality control mechanisms for ATP binding

PubMed Central

Li, Li; Martinis, Susan A.

2013-01-01

The catalytic events in members of the nucleotidylyl transferase superfamily are initiated by a millisecond binding of ATP in the active site. Through metadynamics simulations on a class I aminoacyl-tRNA synthetase (aaRSs), the largest group in the superfamily, we calculate the free energy landscape of ATP selection and binding. Mutagenesis studies and fluorescence spectroscopy validated the identification of the most populated intermediate states. The rapid first binding step involves formation of encounter complexes captured through a fly-casting mechanism that acts up on the triphosphate moiety of ATP. In the slower nucleoside binding step, a conserved histidine in the HxxH motif orients the incoming ATP through base-stacking interactions resulting in a deep minimum in the free energy surface. Mutation of this histidine significantly decreases the binding affinity measured experimentally and computationally. The metadynamics simulations further reveal an intermediate quality control state that the synthetases and most likely other members of the superfamily use to select ATP over other nucleoside triphosphates. PMID:23276298

Computational search for aflatoxin binding proteins

NASA Astrophysics Data System (ADS)

Wang, Ying; Liu, Jinfeng; Zhang, Lujia; He, Xiao; Zhang, John Z. H.

2017-10-01

Aflatoxin is one of the mycotoxins that contaminate various food products. Among various aflatoxin types (B1, B2, G1, G2 and M1), aflatoxin B1 is the most important and the most toxic one. In this study, through computational screening, we found that several proteins may bind specifically with different type of aflatoxins. Combination of theoretical methods including target fishing, molecular docking, molecular dynamics (MD) simulation, MM/PBSA calculation were utilized to search for new aflatoxin B1 binding proteins. A recently developed method for calculating entropic contribution to binding free energy called interaction entropy (IE) was employed to compute the binding free energy between the protein and aflatoxin B1. Through comprehensive comparison, three proteins, namely, trihydroxynaphthalene reductase, GSK-3b, and Pim-1 were eventually selected as potent aflatoxin B1 binding proteins. GSK-3b and Pim-1 are drug targets of cancers or neurological diseases. GSK-3b is the strongest binder for aflatoxin B1.

Capture and quality control mechanisms for adenosine-5'-triphosphate binding.

PubMed

Li, Li; Martinis, Susan A; Luthey-Schulten, Zaida

2013-04-24

The catalytic events in members of the nucleotidylyl transferase superfamily are initiated by a millisecond binding of ATP in the active site. Through metadynamics simulations on a class I aminoacyl-tRNA synthetase (aaRSs), the largest group in the superfamily, we calculate the free energy landscape of ATP selection and binding. Mutagenesis studies and fluorescence spectroscopy validated the identification of the most populated intermediate states. The rapid first binding step involves formation of encounter complexes captured through a fly casting mechanism that acts upon the triphosphate moiety of ATP. In the slower nucleoside binding step, a conserved histidine in the HxxH motif orients the incoming ATP through base-stacking interactions resulting in a deep minimum in the free energy surface. Mutation of this histidine significantly decreases the binding affinity measured experimentally and computationally. The metadynamics simulations further reveal an intermediate quality control state that the synthetases and most likely other members of the superfamily use to select ATP over other nucleoside triphosphates.

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.

Time-dependent density-functional tight-binding method with the third-order expansion of electron density

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

Nishimoto, Yoshio, E-mail: nishimoto.yoshio@fukui.kyoto-u.ac.jp

2015-09-07

We develop a formalism for the calculation of excitation energies and excited state gradients for the self-consistent-charge density-functional tight-binding method with the third-order contributions of a Taylor series of the density functional theory energy with respect to the fluctuation of electron density (time-dependent density-functional tight-binding (TD-DFTB3)). The formulation of the excitation energy is based on the existing time-dependent density functional theory and the older TD-DFTB2 formulae. The analytical gradient is computed by solving Z-vector equations, and it requires one to calculate the third-order derivative of the total energy with respect to density matrix elements due to the inclusion of themore » third-order contributions. The comparison of adiabatic excitation energies for selected small and medium-size molecules using the TD-DFTB2 and TD-DFTB3 methods shows that the inclusion of the third-order contributions does not affect excitation energies significantly. A different set of parameters, which are optimized for DFTB3, slightly improves the prediction of adiabatic excitation energies statistically. The application of TD-DFTB for the prediction of absorption and fluorescence energies of cresyl violet demonstrates that TD-DFTB3 reproduced the experimental fluorescence energy quite well.« less

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

Time-dependent density-functional tight-binding method with the third-order expansion of electron density.

PubMed

Nishimoto, Yoshio

2015-09-07

We develop a formalism for the calculation of excitation energies and excited state gradients for the self-consistent-charge density-functional tight-binding method with the third-order contributions of a Taylor series of the density functional theory energy with respect to the fluctuation of electron density (time-dependent density-functional tight-binding (TD-DFTB3)). The formulation of the excitation energy is based on the existing time-dependent density functional theory and the older TD-DFTB2 formulae. The analytical gradient is computed by solving Z-vector equations, and it requires one to calculate the third-order derivative of the total energy with respect to density matrix elements due to the inclusion of the third-order contributions. The comparison of adiabatic excitation energies for selected small and medium-size molecules using the TD-DFTB2 and TD-DFTB3 methods shows that the inclusion of the third-order contributions does not affect excitation energies significantly. A different set of parameters, which are optimized for DFTB3, slightly improves the prediction of adiabatic excitation energies statistically. The application of TD-DFTB for the prediction of absorption and fluorescence energies of cresyl violet demonstrates that TD-DFTB3 reproduced the experimental fluorescence energy quite well.

Effect of van der Waals interactions on the structural and binding properties of GaSe

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

Sarkisov, Sergey Y., E-mail: sarkisov@mail.tsu.ru; Kosobutsky, Alexey V., E-mail: kosobutsky@kemsu.ru; Kemerovo State University, Krasnaya 6, 650043 Kemerovo

The influence of van der Waals interactions on the lattice parameters, band structure, elastic moduli and binding energy of layered GaSe compound has been studied using projector-augmented wave method within density functional theory. We employed the conventional local/semilocal exchange-correlation functionals and recently developed van der Waals functionals which are able to describe dispersion forces. It is found that application of van der Waals density functionals allows to substantially increase the accuracy of calculations of the lattice constants a and c and interlayer distance in GaSe at ambient conditions and under hydrostatic pressure. The pressure dependences of the a-parameter, Ga–Ga, Ga–Semore » bond lengths and Ga–Ga–Se bond angle are characterized by a relatively low curvature, while c(p) has a distinct downward bowing due to nonlinear shrinking of the interlayer spacing. From the calculated binding energy curves we deduce the interlayer binding energy of GaSe, which is found to be in the range 0.172–0.197 eV/layer (14.2–16.2 meV/Å{sup 2}). - Highlights: • Effects of van der Waals interactions are analyzed using advanced density functionals. • Calculations with vdW-corrected functionals closely agree with experiment. • Interlayer binding energy of GaSe is estimated to be 14.2–16.2 meV/Å{sup 2}.« less

Dissociation free-energy profiles of specific and nonspecific DNA-protein complexes.

PubMed

Yonetani, Yoshiteru; Kono, Hidetoshi

2013-06-27

DNA-binding proteins recognize DNA sequences with at least two different binding modes: specific and nonspecific. Experimental structures of such complexes provide us a static view of the bindings. However, it is difficult to reveal further mechanisms of their target-site search and recognition only from static information because the transition process between the bound and unbound states is not clarified by static information. What is the difference between specific and nonspecific bindings? Here we performed adaptive biasing force molecular dynamics simulations with the specific and nonspecific structures of DNA-Lac repressor complexes to investigate the dissociation process. The resultant free-energy profiles showed that the specific complex has a sharp, deep well consistent with tight binding, whereas the nonspecific complex has a broad, shallow well consistent with loose binding. The difference in the well depth, ~5 kcal/mol, was in fair agreement with the experimentally obtained value and was found to mainly come from the protein conformational difference, particularly in the C-terminal tail. Also, the free-energy profiles were found to be correlated with changes in the number of protein-DNA contacts and that of surface water molecules. The derived protein spatial distributions around the DNA indicate that any large dissociation occurs rarely, regardless of the specific and nonspecific sites. Comparison of the free-energy barrier for sliding [~8.7 kcal/mol; Furini J. Phys. Chem. B 2010, 114, 2238] and that for dissociation (at least ~16 kcal/mol) calculated in this study suggests that sliding is much preferred to dissociation.

Energetics and kinetics of cooperative cofilin-actin filament interactions.

PubMed

Cao, Wenxiang; Goodarzi, Jim P; De La Cruz, Enrique M

2006-08-11

We have evaluated the thermodynamic parameters associated with cooperative cofilin binding to actin filaments, accounting for contributions of ion-linked equilibria, and determined the kinetic basis of cooperative cofilin binding. Ions weaken non-contiguous (isolated, non-cooperative) cofilin binding to an actin filament without affecting cooperative filament interactions. Non-contiguous cofilin binding is coupled to the dissociation of approximately 1.7 thermodynamically bound counterions. Counterion dissociation contributes approximately 40% of the total cofilin binding free energy (in the presence of 50 mM KCl). The non-contiguous and cooperative binding free energies are driven entirely by large, positive entropy changes, consistent with a cofilin-mediated increase in actin filament structural dynamics. The rate constant for cofilin binding to an isolated site on an actin filament is slow and likely to be limited by filament breathing. Cooperative cofilin binding arises from an approximately tenfold more rapid association rate constant and an approximately twofold slower dissociation rate constant. The more rapid association rate constant is presumably a consequence of cofilin-dependent changes in the average orientation of subdomain 2, subunit angular disorder and filament twist, which increase the accessibility of a neighboring cofilin-binding site on an actin filament. Cooperative association is more rapid than binding to an isolated site, but still slow for a second-order reaction, suggesting that cooperative binding is limited also by binding site accessibility. We suggest that the dissociation of actin-associated ions weakens intersubunit interactions in the actin filament lattice that enhance cofilin-binding site accessibility, favor cooperative binding and promote filament severing.

Mechanosensing Potentials Gate Fuel Consumption in a Bipedal DNA Nanowalker

NASA Astrophysics Data System (ADS)

Tee, Shern Ren; Hu, Xinpeng; Loh, Iong Ying; Wang, Zhisong

2018-03-01

A bipedal DNA nanowalker was recently reported to convert chemical energy into directional motion autonomously and efficiently. To elucidate its chemomechanical coupling mechanisms, three-dimensional molecular modeling is used to obtain coarse-grained foot-track binding potentials of the DNA nanowalker via unbiased and biased sampling techniques (for the potentials' basin and high-energy edges, respectively). The binding state that is protected against fuel-induced dissociation responds asymmetrically to forward versus backward forces, unlike the unprotected state, demonstrating a mechanosensing capability to gate fuel binding. Despite complex DNA mechanics, the foot-track potential exhibits a surprisingly neat three-part profile, offering some general guidelines to rationally design efficient nanowalkers. Subsequent modeling of the bipedal walker attached to the track gives estimates of the free energy for each bipedal state, showing how the mechanosensing foot-track binding breaks the symmetry between the rear and front feet, enabling the rear foot to be selectively dissociated by fuel and generating efficient chemomechanical coupling.

E-novo: an automated workflow for efficient structure-based lead optimization.

PubMed

Pearce, Bradley C; Langley, David R; Kang, Jia; Huang, Hongwei; Kulkarni, Amit

2009-07-01

An automated E-Novo protocol designed as a structure-based lead optimization tool was prepared through Pipeline Pilot with existing CHARMm components in Discovery Studio. A scaffold core having 3D binding coordinates of interest is generated from a ligand-bound protein structural model. Ligands of interest are generated from the scaffold using an R-group fragmentation/enumeration tool within E-Novo, with their cores aligned. The ligand side chains are conformationally sampled and are subjected to core-constrained protein docking, using a modified CHARMm-based CDOCKER method to generate top poses along with CDOCKER energies. In the final stage of E-Novo, a physics-based binding energy scoring function ranks the top ligand CDOCKER poses using a more accurate Molecular Mechanics-Generalized Born with Surface Area method. Correlation of the calculated ligand binding energies with experimental binding affinities were used to validate protocol performance. Inhibitors of Src tyrosine kinase, CDK2 kinase, beta-secretase, factor Xa, HIV protease, and thrombin were used to test the protocol using published ligand crystal structure data within reasonably defined binding sites. In-house Respiratory Syncytial Virus inhibitor data were used as a more challenging test set using a hand-built binding model. Least squares fits for all data sets suggested reasonable validation of the protocol within the context of observed ligand binding poses. The E-Novo protocol provides a convenient all-in-one structure-based design process for rapid assessment and scoring of lead optimization libraries.

Theoretical analysis of the time-resolved binary (e, 2e) binding energy spectra on three-body photodissociation of acetone at 195 nm

NASA Astrophysics Data System (ADS)

Yamazaki, M.; Nakayama, S.; Zhu, C. Y.; Takahashi, M.

2017-11-01

We report on theoretical progress in time-resolved (e, 2e) electron momentum spectroscopy of photodissociation dynamics of the deuterated acetone molecule at 195 nm. We have examined the predicted minimum energy reaction path to investigate whether associated (e, 2e) calculations meet the experimental results. A noticeable difference between the experiment and calculations has been found at around binding energy of 10 eV, suggesting that the observed difference may originate, at least partly, in ever-unconsidered non-minimum energy paths.

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

Efimov, V.; Tkachenko, E.G.

It is shown that the well-known correlation between the triton binding energy and the nd doublet scattering length (the so-called Phillips line), which is observed in calculations, can be explained by smallness of the characteristic energies of the problem: the binding energies of the triton and deuteron: on the energy scale of nuclear forces. Equivalently, the Phillips line is a consequence of the diffuse structure of the triton and deuteron. These conclusions are obtained on the basis of qualitative consideration of the problem, calculation of the above correlation in the zero and linear approximation, and comparison of the calculated resultsmore » with the Phillips line.« less

Dissociation kinetics of excited ions: PEPICO measurements of Os3(CO)12 - The 7-35 eV single ionization binding energy region.

PubMed

Schalk, Oliver; Josefsson, Ida; Geng, Ting; Richter, Robert; Sa'adeh, Hanan; Thomas, Richard D; Mucke, Melanie

2018-02-28

In this article, we study the photoinduced dissociation pathways of a metallocarbonyl, Os 3 (CO) 12 , in particular the consecutive loss of CO groups. To do so, we performed photoelectron-photoion coincidence (PEPICO) measurements in the single ionization binding energy region from 7 to 35 eV using 45-eV photons. Zero-energy ion appearance energies for the dissociation steps were extracted by modeling the PEPICO data using the statistical adiabatic channel model. Upon ionization to the excited ionic states above 13 eV binding energy, non-statistical behavior was observed and assigned to prompt CO loss. Double ionization was found to be dominated by the knockout process with an onset of 20.9 ± 0.4 eV. The oscillator strength is significantly larger for energies above 26.6 ± 0.4 eV, corresponding to one electron being ejected from the Os 3 center and one from the CO ligands. The cross section for double ionization was found to increase linearly up to 35 eV ionization energy, at which 40% of the generated ions are doubly charged.

Critical insight into the interaction of naringenin with human haemoglobin: A combined spectroscopic and computational modeling approaches

NASA Astrophysics Data System (ADS)

Maity, Subhajit; Chakraborty, Sandipan; Chakraborti, Abhay Sankar

2017-02-01

The present study demonstrates critical insight into the binding of a bioactive flavanone naringenin with normal human haemoglobin (NHb). Both spectrophotometric and spectrofluorimetric studies reveal that naringenin interacts with NHb. The binding affinity constant and number of binding sites appear to be approximately (1.5 ± 0.2) × 104 M-1 and 1, respectively. Static quenching seems to be an important factor in binding process, as evident from steady-state and time-resolved fluorescence spectroscopic studies. Far UV circular dichroism spectroscopy depicts that binding of naringenin to NHb causes no change in the secondary structure of the protein, which is also evident from Fourier transform infrared spectroscopic study. Free energy change (ΔG0) for naringenin-NHb interaction, determined by spectroscopic and isothermal calorimetric method, appears to be -5.67 kcal/mol and -6.90 kcal/mol, respectively, and is close to the docking energy -6.84 kcal/mol. Molecular docking suggests that naringenin binds near the cavity of the tetrameric heme protein, forming hydrogen bonds with surrounding amino acid residues. The binding site is away from the heme moieties, implicating naringenin binding does not affect the oxygen binding capacity of NHb, which makes the protein a suitable carrier of the flavonoid.

Structure and stability of fluorine-substituted benzene-argon complexes: The decisive role of exchange-repulsion and dispersion interactions

NASA Astrophysics Data System (ADS)

Tarakeshwar, P.; Kim, Kwang S.; Kraka, Elfi; Cremer, Dieter

2001-10-01

The van der Waals complexes benzene-argon (BAr), fluorobenzene-argon (FAr), p-difluorobenzene-argon (DAr) are investigated at the second-order Møller-Plesset (MP2) level of theory using the 6-31+G(d), cc-pVDZ, aug-cc-pVTZ, and [7s4p2d1f/4s3p1d/3s1p] basis sets. Geometries, binding energies, harmonic vibrational frequencies, and density distribution are calculated where basis set superposition errors are corrected with the counterpoise method. Binding energies turn out to be almost identical (MP2/[7s4p2d1f/4s3p1d/3s1p]: 408, 409, 408 cm-1) for BAr, FAr, and DAr. Vibrationally corrected binding energies (357, 351, 364 cm-1) agree well with experimental values (340, 344, and 339 cm-1). Symmetry adapted perturbation theory (SAPT) is used to decompose binding energies and to examine the influence of attractive and repulsive components. Fluorine substituents lead to a contraction of the π density of the benzene ring, thus reducing the destabilizing exchange-repulsion and exchange-induction effects. At the same time, both the polarizing power and the polarizability of the π-density of the benzene derivative decreases thus reducing stabilizing induction and dispersion interactions. Stabilizing and destabilizing interactions largely cancel each other out to give comparable binding energies. The equilibrium geometry of the Ar complex is also a result of the decisive influence of exchange-repulsion and dispersive interactions.

Hydrogen storage in engineered carbon nanospaces.

PubMed

Burress, Jacob; Kraus, Michael; Beckner, Matt; Cepel, Raina; Suppes, Galen; Wexler, Carlos; Pfeifer, Peter

2009-05-20

It is shown how appropriately engineered nanoporous carbons provide materials for reversible hydrogen storage, based on physisorption, with exceptional storage capacities (approximately 80 g H2/kg carbon, approximately 50 g H2/liter carbon, at 50 bar and 77 K). Nanopores generate high storage capacities (a) by having high surface area to volume ratios, and (b) by hosting deep potential wells through overlapping substrate potentials from opposite pore walls, giving rise to a binding energy nearly twice the binding energy in wide pores. Experimental case studies are presented with surface areas as high as 3100 m(2) g(-1), in which 40% of all surface sites reside in pores of width approximately 0.7 nm and binding energy approximately 9 kJ mol(-1), and 60% of sites in pores of width>1.0 nm and binding energy approximately 5 kJ mol(-1). The findings, including the prevalence of just two distinct binding energies, are in excellent agreement with results from molecular dynamics simulations. It is also shown, from statistical mechanical models, that one can experimentally distinguish between the situation in which molecules do (mobile adsorption) and do not (localized adsorption) move parallel to the surface, how such lateral dynamics affects the hydrogen storage capacity, and how the two situations are controlled by the vibrational frequencies of adsorbed hydrogen molecules parallel and perpendicular to the surface: in the samples presented, adsorption is mobile at 293 K, and localized at 77 K. These findings make a strong case for it being possible to significantly increase hydrogen storage capacities in nanoporous carbons by suitable engineering of the nanopore space.

Minimum Free Energy Path of Ligand-Induced Transition in Adenylate Kinase

PubMed Central

Matsunaga, Yasuhiro; Fujisaki, Hiroshi; Terada, Tohru; Furuta, Tadaomi; Moritsugu, Kei; Kidera, Akinori

2012-01-01

Large-scale conformational changes in proteins involve barrier-crossing transitions on the complex free energy surfaces of high-dimensional space. Such rare events cannot be efficiently captured by conventional molecular dynamics simulations. Here we show that, by combining the on-the-fly string method and the multi-state Bennett acceptance ratio (MBAR) method, the free energy profile of a conformational transition pathway in Escherichia coli adenylate kinase can be characterized in a high-dimensional space. The minimum free energy paths of the conformational transitions in adenylate kinase were explored by the on-the-fly string method in 20-dimensional space spanned by the 20 largest-amplitude principal modes, and the free energy and various kinds of average physical quantities along the pathways were successfully evaluated by the MBAR method. The influence of ligand binding on the pathways was characterized in terms of rigid-body motions of the lid-shaped ATP-binding domain (LID) and the AMP-binding (AMPbd) domains. It was found that the LID domain was able to partially close without the ligand, while the closure of the AMPbd domain required the ligand binding. The transition state ensemble of the ligand bound form was identified as those structures characterized by highly specific binding of the ligand to the AMPbd domain, and was validated by unrestrained MD simulations. It was also found that complete closure of the LID domain required the dehydration of solvents around the P-loop. These findings suggest that the interplay of the two different types of domain motion is an essential feature in the conformational transition of the enzyme. PMID:22685395

Free-energy relationships in ion channels activated by voltage and ligand

PubMed Central

Chowdhury, Sandipan

2013-01-01

Many ion channels are modulated by multiple stimuli, which allow them to integrate a variety of cellular signals and precisely respond to physiological needs. Understanding how these different signaling pathways interact has been a challenge in part because of the complexity of underlying models. In this study, we analyzed the energetic relationships in polymodal ion channels using linkage principles. We first show that in proteins dually modulated by voltage and ligand, the net free-energy change can be obtained by measuring the charge-voltage (Q-V) relationship in zero ligand condition and the ligand binding curve at highly depolarizing membrane voltages. Next, we show that the voltage-dependent changes in ligand occupancy of the protein can be directly obtained by measuring the Q-V curves at multiple ligand concentrations. When a single reference ligand binding curve is available, this relationship allows us to reconstruct ligand binding curves at different voltages. More significantly, we establish that the shift of the Q-V curve between zero and saturating ligand concentration is a direct estimate of the interaction energy between the ligand- and voltage-dependent pathway. These free-energy relationships were tested by numerical simulations of a detailed gating model of the BK channel. Furthermore, as a proof of principle, we estimate the interaction energy between the ligand binding and voltage-dependent pathways for HCN2 channels whose ligand binding curves at various voltages are available. These emerging principles will be useful for high-throughput mutagenesis studies aimed at identifying interaction pathways between various regulatory domains in a polymodal ion channel. PMID:23250866

Rapid and Reliable Binding Affinity Prediction of Bromodomain Inhibitors: A Computational Study

PubMed Central

2016-01-01

Binding free energies of bromodomain inhibitors are calculated with recently formulated approaches, namely ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration with enhanced sampling). A set of compounds is provided by GlaxoSmithKline, which represents a range of chemical functionality and binding affinities. The predicted binding free energies exhibit a good Spearman correlation of 0.78 with the experimental data from the 3-trajectory ESMACS, and an excellent correlation of 0.92 from the TIES approach where applicable. Given access to suitable high end computing resources and a high degree of automation, we can compute individual binding affinities in a few hours with precisions no greater than 0.2 kcal/mol for TIES, and no larger than 0.34 and 1.71 kcal/mol for the 1- and 3-trajectory ESMACS approaches. PMID:28005370

Binding of cyclic carboxylates to octa-acid deep-cavity cavitand

NASA Astrophysics Data System (ADS)

Gibb, Corinne L. D.; Gibb, Bruce C.

2014-04-01

As part of the fourth statistical assessment of modeling of proteins and ligands (sampl.eyesopen.com) prediction challenge, the strength of association of nine guests ( 1- 9) binding to octa-acid host was determined by a combination of 1H NMR and isothermal titration calorimetry. Association constants in sodium tetraborate buffered (pH 9.2) aqueous solution ranged from 5.39 × 102 M-1 in the case of benzoate 1, up to 3.82 × 105 M-1 for trans-4-methylcyclohexanoate 7. Overall, the free energy difference between the free energies of complexation of these weakest and strongest binding guests was ΔΔG° = 3.88 kcal mol-1. Based on a multitude of previous studies, the anticipated order of strength of binding was close to that which was actually obtained. However, the binding of guest 3 (4-ethylbenzoate) was considerably stronger than initially estimated.

A Brownian motor mechanism of translocation and strand separation by hepatitis C virus helicase.

PubMed

Levin, Mikhail K; Gurjar, Madhura; Patel, Smita S

2005-05-01

Helicases translocate along their nucleic acid substrates using the energy of ATP hydrolysis and by changing conformations of their nucleic acid-binding sites. Our goal is to characterize the conformational changes of hepatitis C virus (HCV) helicase at different stages of ATPase cycle and to determine how they lead to translocation. We have reported that ATP binding reduces HCV helicase affinity for nucleic acid. Now we identify the stage of the ATPase cycle responsible for translocation and unwinding. We show that a rapid directional movement occurs upon helicase binding to DNA in the absence of ATP, resulting in opening of several base pairs. We propose that HCV helicase translocates as a Brownian motor with a simple two-stroke cycle. The directional movement step is fueled by single-stranded DNA binding energy while ATP binding allows for a brief period of random movement that prepares the helicase for the next cycle.

Onset of η-meson binding in the He isotopes

NASA Astrophysics Data System (ADS)

Barnea, N.; Friedman, E.; Gal, A.

2017-12-01

The onset of binding η (548) mesons in nuclei is studied in the He isotopes by doing precise ηNNN and ηNNNN few-body stochastic variational method calculations for two semi-realistic NN potentials and two energy dependent ηN potentials derived from coupled-channel models of the N* (1535) nucleon resonance. The energy dependence of the ηN subthreshold input is treated self consistently. It is found that a minimal value of the real part of the ηN scattering length aηN close to 1 fm is required to bind η mesons in 3He, yielding then a few MeV η binding in 4He. The onset of η-meson binding in 4He requires that Re aηN exceeds 0.7 fm approximately. These results compare well with results of recent ηNNN and ηNNNN pionless effective field theory calculations. Related optical-model calculations are also discussed.

Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations

PubMed Central

Chen, Jianzhong; Zhang, Dinglin; Zhang, Yuxin; Li, Guohui

2012-01-01

Inhibition of p53-MDM2/MDMX interaction is considered to be a promising strategy for anticancer drug design to activate wild-type p53 in tumors. We carry out molecular dynamics (MD) simulations to study the binding mechanisms of peptide and non-peptide inhibitors to MDM2/MDMX. The rank of binding free energies calculated by molecular mechanics generalized Born surface area (MM-GBSA) method agrees with one of the experimental values. The results suggest that van der Waals energy drives two kinds of inhibitors to MDM2/MDMX. We also find that the peptide inhibitors can produce more interaction contacts with MDM2/MDMX than the non-peptide inhibitors. Binding mode predictions based on the inhibitor-residue interactions show that the π–π, CH–π and CH–CH interactions dominated by shape complimentarity, govern the binding of the inhibitors in the hydrophobic cleft of MDM2/MDMX. Our studies confirm the residue Tyr99 in MDMX can generate a steric clash with the inhibitors due to energy and structure. This finding may theoretically provide help to develop potent dual-specific or MDMX inhibitors. PMID:22408446

Microsolvation of Fluoromethane.

PubMed

Rosenberg, Robert E

2016-09-29

Fluorinated organic compounds are ubiquitous in the pharmaceutical and agricultural industries. To better discern the mode of action of these compounds, it is critical to understand the potential for and strength of hydrogen bonds involving fluorine. It is known that CH3F forms a hydrogen bond with H2O in the gas phase but does not dissolve in bulk water. This paper examines CH3F surrounded by one to six water molecules. For systems of similar topologies, CH3F formed hydrogen bonds of nearly the same strength as water. Although CH3F can bind to a second water cluster with only a modest loss in binding energy, it must bind to these clusters as a double hydrogen bond acceptor. This means that CH3F cannot form a low-energy cyclic 2D hydrogen bonding network with water molecules, which limits its solubility in bulk water. However, CH3F should be able to bind to the periphery of small hydrogen bonding networks. These conclusions were not appreciably altered by SMD calculations. A more complete consideration of solvation, especially entropic effects, was not undertaken. Data for geometries, population changes, and vibrational frequency shifts were also analyzed and compared to binding energies.

Intrinsic Conformational Preferences and Interactions in α-Synuclein Fibrils: Insights from Molecular Dynamics Simulations.

PubMed

Ilie, Ioana M; Nayar, Divya; den Otter, Wouter K; van der Vegt, Nico F A; Briels, Wim J

2018-06-12

Amyloid formation by the intrinsically disordered α-synuclein protein is the hallmark of Parkinson's disease. We present atomistic Molecular Dynamics simulations of the core of α-synuclein using enhanced sampling techniques to describe the conformational and binding free energy landscapes of fragments implicated in fibril stabilization. The theoretical framework is derived to combine the free energy profiles of the fragments into the reaction free energy of a protein binding to a fibril. Our study shows that individual fragments in solution have a propensity toward attaining non-β conformations, indicating that in a fibril β-strands are stabilized by interactions with other strands. We show that most dimers of hydrogen-bonded fragments are unstable in solution, while hydrogen bonding stabilizes the collective binding of five fragments to the end of a fibril. Hydrophobic effects make further contributions to the stability of fibrils. This study is the first of its kind where structural and binding preferences of the five major fragments of the hydrophobic core of α-synuclein have been investigated. This approach improves sampling of intrinsically disordered proteins, provides information on the binding mechanism between the core sequences of α-synuclein, and enables the parametrization of coarse grained models.

Molecular dynamics and Monte Carlo simulations for protein-ligand binding and inhibitor design.

PubMed

Cole, Daniel J; Tirado-Rives, Julian; Jorgensen, William L

2015-05-01

Non-nucleoside inhibitors of HIV reverse transcriptase are an important component of treatment against HIV infection. Novel inhibitors are sought that increase potency against variants that contain the Tyr181Cys mutation. Molecular dynamics based free energy perturbation simulations have been run to study factors that contribute to protein-ligand binding, and the results are compared with those from previous Monte Carlo based simulations and activity data. Predictions of protein-ligand binding modes are very consistent for the two simulation methods; the accord is attributed to the use of an enhanced sampling protocol. The Tyr181Cys binding pocket supports large, hydrophobic substituents, which is in good agreement with experiment. Although some discrepancies exist between the results of the two simulation methods and experiment, free energy perturbation simulations can be used to rapidly test small molecules for gains in binding affinity. Free energy perturbation methods show promise in providing fast, reliable and accurate data that can be used to complement experiment in lead optimization projects. This article is part of a Special Issue entitled "Recent developments of molecular dynamics". Copyright © 2014 Elsevier B.V. All rights reserved.

Unveiling the molecular mechanism of brassinosteroids: Insights from structure-based molecular modeling studies.

PubMed

Lei, Beilei; Liu, Jiyuan; Yao, Xiaojun

2015-12-01

Brassinosteroid (BR) phytohormones play indispensable roles in plant growth and development. Brassinolide (BL) and 24-epibrassinolide (24-epiBL) are the most active ones among the BRs reported thus far. Unfortunately, the extremely low natural content and intricate synthesis process limit their popularization in agricultural production. Earlier reports to discover alternative compounds have resulted in molecules with nearly same scaffold structure and without diversity in chemical space. In the present study, receptors structure based BRs regulation mechanism was analyzed. First, we examined the detailed binding interactions and their dynamic stability between BL and its receptor BRI1 and co-receptor BAK1. Then, the binding modes and binding free energies for 24-epiBL and a series of representative BRs binding with BRI1 and BRI1-BAK1 were carried out by molecular docking, energy minimization and MM-PBSA free energy calculation. The obtained binding structures and energetic results provided vital insights into the structural factors affecting the activity from both receptors and BRs aspects. Subsequently, the obtained knowledge will serve as valuable guidance to build pharmacophore models for rational screening of new scaffold alternative BRs. Copyright © 2015 Elsevier Inc. All rights reserved.

Subsite binding energies of an exo-polygalacturonase using isothermal titration calorimetry

USDA-ARS?s Scientific Manuscript database

Thermodynamic parameters for binding of a series of galacturonic acid oligomers to an exo-polygalacturonase, RPG16 from Rhizopus oryzae, were determined by isothermal titration calorimetry. Binding of oligomers varying in chain length from two to five galacturonic acid residues is an exothermic proc...

Superhalogens as building blocks of two-dimensional organic-inorganic hybrid perovskites for optoelectronics applications.

PubMed

Yao, Qiushi; Fang, Hong; Deng, Kaiming; Kan, Erjun; Jena, Puru

2016-10-20

Organic-inorganic hybrid perovskites, well known for their potential as the next generation solar cells, have found another niche application in optoelectronics. This was demonstrated in a recent experiment (L. Dou, et al., Science, 2015, 349, 1518) on atomically thin (C 4 H 9 NH 3 ) 2 PbBr 4 , where, due to quantum confinement, the bandgap and the exciton binding energy are enhanced over their corresponding values in the three-dimensional bulk phase. Using density functional theory we show that when halogen atoms (e.g. I) are sequentially replaced with superhalogen molecules (e.g. BH 4 ) the bandgap and exciton binding energy increase monotonically with the superhalogen content with the exciton binding energy of (C 4 H 9 NH 3 ) 2 Pb(BH 4 ) 4 approaching the value in monolayer black phosphorus. Lead-free admixtures (C 4 H 9 NH 3 ) 2 MI 4-x (BH 4 ) x (M = Sn and Ge; x = 0-4) also show a similar trend. Thus, a combination of quantum confinement and compositional change can be used as an effective strategy to tailor the bandgap and the exciton binding energy of two-dimensional hybrid perovskites, making them promising candidates for optoelectronic applications.

Signatures of van der Waals binding: A coupling-constant scaling analysis

NASA Astrophysics Data System (ADS)

Jiao, Yang; Schröder, Elsebeth; Hyldgaard, Per

2018-02-01

The van der Waals (vdW) density functional (vdW-DF) method [Rep. Prog. Phys. 78, 066501 (2015), 10.1088/0034-4885/78/6/066501] describes dispersion or vdW binding by tracking the effects of an electrodynamic coupling among pairs of electrons and their associated exchange-correlation holes. This is done in a nonlocal-correlation energy term Ecnl, which permits density functional theory calculation in the Kohn-Sham scheme. However, to map the nature of vdW forces in a fully interacting materials system, it is necessary to also account for associated kinetic-correlation energy effects. Here, we present a coupling-constant scaling analysis, which permits us to compute the kinetic-correlation energy Tcnl that is specific to the vdW-DF account of nonlocal correlations. We thus provide a more complete spatially resolved analysis of the electrodynamical-coupling nature of nonlocal-correlation binding, including vdW attraction, in both covalently and noncovalently bonded systems. We find that kinetic-correlation energy effects play a significant role in the account of vdW or dispersion interactions among molecules. Furthermore, our mapping shows that the total nonlocal-correlation binding is concentrated to pockets in the sparse electron distribution located between the material fragments.

Binding free energy predictions of farnesoid X receptor (FXR) agonists using a linear interaction energy (LIE) approach with reliability estimation: application to the D3R Grand Challenge 2

NASA Astrophysics Data System (ADS)

Rifai, Eko Aditya; van Dijk, Marc; Vermeulen, Nico P. E.; Geerke, Daan P.

2018-01-01

Computational protein binding affinity prediction can play an important role in drug research but performing efficient and accurate binding free energy calculations is still challenging. In the context of phase 2 of the Drug Design Data Resource (D3R) Grand Challenge 2 we used our automated eTOX ALLIES approach to apply the (iterative) linear interaction energy (LIE) method and we evaluated its performance in predicting binding affinities for farnesoid X receptor (FXR) agonists. Efficiency was obtained by our pre-calibrated LIE models and molecular dynamics (MD) simulations at the nanosecond scale, while predictive accuracy was obtained for a small subset of compounds. Using our recently introduced reliability estimation metrics, we could classify predictions with higher confidence by featuring an applicability domain (AD) analysis in combination with protein-ligand interaction profiling. The outcomes of and agreement between our AD and interaction-profile analyses to distinguish and rationalize the performance of our predictions highlighted the relevance of sufficiently exploring protein-ligand interactions during training and it demonstrated the possibility to quantitatively and efficiently evaluate if this is achieved by using simulation data only.

Beyond the benzene dimer: an investigation of the additivity of pi-pi interactions.

PubMed

Tauer, Tony P; Sherrill, C David

2005-11-24

The benzene dimer is the simplest prototype of pi-pi interactions and has been used to understand the fundamental physics of these interactions as they are observed in more complex systems. In biological systems, however, aromatic rings are rarely found in isolated pairs; thus, it is important to understand whether aromatic pairs remain a good model of pi-pi interactions in clusters. In this study, ab initio methods are used to compute the binding energies of several benzene trimers and tetramers, most of them in 1D stacked configurations. The two-body terms change only slightly relative to the dimer, and except for the cyclic trimer, the three- and four-body terms are negligible. This indicates that aromatic clusters do not feature any large nonadditive effects in their binding energies, and polarization effects in benzene clusters do not greatly change the binding that would be anticipated from unperturbed benzene-benzene interactions, at least for the 1D stacked systems considered. Three-body effects are larger for the cyclic trimer, but for all systems considered, the computed binding energies are within 10% of what would be estimated from benzene dimer energies at the same geometries.

Polarizability and binding energy of a shallow donor in spherical quantum dot-quantum well (QD-QW)

NASA Astrophysics Data System (ADS)

Rahmani, K.; Chrafih, Y.; M’Zred, S.; Janati, S.; Zorkani, I.; Jorio, A.; Mmadi, A.

2018-03-01

The polarizability and the binding energy is estimated for a shallow donor confined to move in inhomogeneous quantum dots (CdS/HgS/CdS). In this work, the Hass variational method within the effective mass approximation in used in the case of an infinitely deep well. The polarizability and the binding energy depend on the inner and the outer radius of the QDQW, also it depends strongly on the donor position. It’s found that the stark effect is more important when the impurity is located at the center of the (QDQW) and becomes less important when the donor moves toward the extremities of the spherical layer. When the electric field increases, the binding energy and the polarizability decreases. Its effects is more pronounced when the impurity is placed on the center of the spherical layer and decrease when the donor move toward extremities of this spherical layer. We have demonstrated the existence of a critical value {≤ft( {{{{R_1}} \\over {{R_2}}}} \\right)cri} which can be used to distinguish the tree dimension confinement from the spherical surface confinement and it’s may be important for the nanofabrication techniques.

Transformation of cooperative free energies between ligation systems of hemoglobin: resolution of the carbon monoxide binding intermediates.

PubMed

Huang, Y; Ackers, G K

1996-01-23

A strategy has been developed for quantitatively "translating" the distributions of cooperative free energy between different oxygenation analogs of hemoglobin (Hb). The method was used to resolve the cooperative free energies of all eight carbon monoxide binding intermediates. These parameters of the FeCOHb system were determined by thermodynamic transformation of corresponding free energies obtained previously for all species of the Co/FeCO system, i.e., where cobalt-substituted hemes comprise the unligated sites [Speros, P. C., et al. (1991) Biochemistry 30, 7254-7262]. Using hybridized combinations of normal and cobalt-substituted Hb, ligation analog systems Co/FeX (X = CO, CN) were constructed and experimentally quantified. Energetics of cobalt-induced structural perturbation were determined for all species of both the "mixed metal" Co/Fe system and also the ligated Co/FeCN system. It was found that major energetic perturbations of the Co/Fe hybrid species originate from a pure cobalt substitution effect on the alpha subunits. These perturbations are transduced to the beta subunit within the same dimeric half-tetramer, resulting in alteration of the free energies for binding at the nonsubstituted (Fe) sites. Using the linkage strategy developed in this study along with the determined energetics of these couplings, the experimental assembly free energies for the Co/FeCO species were transformed into cooperative free energies of the 10 Fe/FeCO species. The resulting values were found to distribute according to predictions of a symmetry rule mechanism proposed previously [Ackers, G. K., et al. (1992) Science 255, 54-63]. Their distribution is consistent with accurate CO binding data of normal Hb [Perrella, M., et al. (1990b) Biophys. Chem. 37, 211-223] and also with accurate O2 binding data obtained under the same conditions [Chu, A. H., et al. (1984) Biochemistry 23, 604-617].

Is there a link between selectivity and binding thermodynamics profiles?

PubMed

Tarcsay, Ákos; Keserű, György M

2015-01-01

Thermodynamics of ligand binding is influenced by the interplay between enthalpy and entropy contributions of the binding event. The impact of these binding free energy components, however, is not limited to the primary target only. Here, we investigate the relationship between binding thermodynamics and selectivity profiles by combining publicly available data from broad off-target assay profiling and the corresponding thermodynamics measurements. Our analysis indicates that compounds binding their primary targets with higher entropy contributions tend to hit more off-targets compared with those ligands that demonstrated enthalpy-driven binding. Copyright © 2014 Elsevier Ltd. All rights reserved.

Determining ERβ Binding Affinity to Singly Mutant ERE Using Dual Polarization Interferometry

NASA Astrophysics Data System (ADS)

Song, Hong Yan; Su, Xiaodi

In a classic mode of estrogen action, estrogen receptors (ERs) bind to estrogen responsive element (ERE) to activate gene transcription. A perfect ERE contains a 13-base pair sequence of a palindromic repeat separated by a three-base spacer, 5‧-GGTCAnnnTGACC-3‧. In addition to the consensus or wild-type ERE (wtERE), naturally occurring EREs often have one or two base pairs’ alternation. Based on the newly constructed Thermodynamic Modeling of ChIP-seq (TherMos) model, binding energy between ERβ and a series of 34-bp mutant EREs (mutERE) was simulated to predict the binding affinity between ERs and EREs with single base pair deviation at different sites of the 13-bp inverted sequence. Experimentally, dual polarization interferometry (DPI) method was developed to measure ERβ-mutEREs binding affinity. On a biotin-NeutrAvidin (NA)-biotin treated DPI chip, wtERE is immobilized. In a direct binding assay, ERβ-wtERE binding affinity is determined. In a competition assay, ERβ was preincubated with mutant EREs before being added for competitive binding to the immobilized wtERE. This competition strategy provided a successful platform to evaluate the binding affinity variation among large number of ERE with different base mutations. The experimental result correlates well with the mathematically predicted binding energy with a Spearman correlation coefficient of 0.97.

Role of Electrostatics in Protein-RNA Binding: The Global vs the Local Energy Landscape.

PubMed

Ghaemi, Zhaleh; Guzman, Irisbel; Gnutt, David; Luthey-Schulten, Zaida; Gruebele, Martin

2017-09-14

U1A protein-stem loop 2 RNA association is a basic step in the assembly of the spliceosomal U1 small nuclear ribonucleoprotein. Long-range electrostatic interactions due to the positive charge of U1A are thought to provide high binding affinity for the negatively charged RNA. Short range interactions, such as hydrogen bonds and contacts between RNA bases and protein side chains, favor a specific binding site. Here, we propose that electrostatic interactions are as important as local contacts in biasing the protein-RNA energy landscape toward a specific binding site. We show by using molecular dynamics simulations that deletion of two long-range electrostatic interactions (K22Q and K50Q) leads to mutant-specific alternative RNA bound states. One of these states preserves short-range interactions with aromatic residues in the original binding site, while the other one does not. We test the computational prediction with experimental temperature-jump kinetics using a tryptophan probe in the U1A-RNA binding site. The two mutants show the distinct predicted kinetic behaviors. Thus, the stem loop 2 RNA has multiple binding sites on a rough RNA-protein binding landscape. We speculate that the rough protein-RNA binding landscape, when biased to different local minima by electrostatics, could be one way that protein-RNA interactions evolve toward new binding sites and novel function.

Dominant Alcohol-Protein Interaction via Hydration-Enabled Enthalpy-Driven Binding Mechanism

PubMed Central

Chong, Yuan; Kleinhammes, Alfred; Tang, Pei; Xu, Yan; Wu, Yue

2015-01-01

Water plays an important role in weak associations of small drug molecules with proteins. Intense focus has been on binding-induced structural changes in the water network surrounding protein binding sites, especially their contributions to binding thermodynamics. However, water is also tightly coupled to protein conformations and dynamics, and so far little is known about the influence of water-protein interactions on ligand binding. Alcohols are a type of low-affinity drugs, and it remains unclear how water affects alcohol-protein interactions. Here, we present alcohol adsorption isotherms under controlled protein hydration using in-situ NMR detection. As functions of hydration level, Gibbs free energy, enthalpy, and entropy of binding were determined from the temperature dependence of isotherms. Two types of alcohol binding were found. The dominant type is low-affinity nonspecific binding, which is strongly dependent on temperature and the level of hydration. At low hydration levels, this nonspecific binding only occurs above a threshold of alcohol vapor pressure. An increased hydration level reduces this threshold, with it finally disappearing at a hydration level of h~0.2 (g water/g protein), gradually shifting alcohol binding from an entropy-driven to an enthalpy-driven process. Water at charged and polar groups on the protein surface was found to be particularly important in enabling this binding. Although further increase in hydration has smaller effects on the changes of binding enthalpy and entropy, it results in significant negative change in Gibbs free energy due to unmatched enthalpy-entropy compensation. These results show the crucial role of water-protein interplay in alcohol binding. PMID:25856773

Insight into the novel inhibition mechanism of apigenin to Pneumolysin by molecular modeling

NASA Astrophysics Data System (ADS)

Niu, Xiaodi; Yang, Yanan; Song, Meng; Wang, Guizhen; Sun, Lin; Gao, Yawen; Wang, Hongsu

2017-11-01

In this study, the mechanism of apigenin inhibition was explored using molecular modelling, binding energy calculation, and mutagenesis assays. Energy decomposition analysis indicated that apigenin binds in the gap between domains 3 and 4 of PLY. Using principal component analysis, we found that binding of apigenin to PLY weakens the motion of domains 3 and 4. Consequently, these domains cannot complete the transition from monomer to oligomer, thereby blocking oligomerisation of PLY and counteracting its haemolytic activity. This inhibitory mechanism was confirmed by haemolysis assays, and these findings will promote the future development of an antimicrobial agent.

Theoretical study of the rhenium–alkane interaction in transition metal–alkane σ-complexes

PubMed Central

Cobar, Erika A.; Khaliullin, Rustam Z.; Bergman, Robert G.; Head-Gordon, Martin

2007-01-01

Metal–alkane binding energies have been calculated for [CpRe(CO)2](alkane) and [(CO)2M(C5H4)CC(C5H4)M(CO)2](alkane), where M = Re or Mn. Calculated binding energies were found to increase with the number of metal–alkane interaction sites. In all cases examined, the manganese–alkane binding energies were predicted to be significantly lower than those for the analogous rhenium–alkane complexes. The metal (Mn or Re)–alkane interaction was predicted to be primarily one of charge transfer, both from the alkane to the metal complex (70–80% of total charge transfer) and from the metal complex to the alkane (20–30% of the total charge transfer). PMID:17442751

Insights into the binding specificity of wild type and mutated wheat germ agglutinin towards Neu5Acα(2-3)Gal: a study by in silico mutations and molecular dynamics simulations.

PubMed

Parasuraman, Ponnusamy; Murugan, Veeramani; Selvin, Jeyasigamani F A; Gromiha, M Michael; Fukui, Kazuhiko; Veluraja, Kasinadar

2014-08-01

Wheat germ agglutinin (WGA) is a plant lectin, which specifically recognizes the sugars NeuNAc and GlcNAc. Mutated WGA with enhanced binding specificity can be used as biomarkers for cancer. In silico mutations are performed at the active site of WGA to enhance the binding specificity towards sialylglycans, and molecular dynamics simulations of 20 ns are carried out for wild type and mutated WGAs (WGA1, WGA2, and WGA3) in complex with sialylgalactose to examine the change in binding specificity. MD simulations reveal the change in binding specificity of wild type and mutated WGAs towards sialylgalactose and bound conformational flexibility of sialylgalactose. The mutated polar amino acid residues Asn114 (S114N), Lys118 (G118K), and Arg118 (G118R) make direct and water mediated hydrogen bonds and hydrophobic interactions with sialylgalactose. An analysis of possible hydrogen bonds, hydrophobic interactions, total pair wise interaction energy between active site residues and sialylgalactose and MM-PBSA free energy calculation reveals the plausible binding modes and the role of water in stabilizing different binding modes. An interesting observation is that the binding specificity of mutated WGAs (cyborg lectin) towards sialylgalactose is found to be higher in double point mutation (WGA3). One of the substituted residues Arg118 plays a crucial role in sugar binding. Based on the interactions and energy calculations, it is concluded that the order of binding specificity of WGAs towards sialylgalactose is WGA3 > WGA1 > WGA2 > WGA. On comparing with the wild type, double point mutated WGA (WGA3) exhibits increased specificity towards sialylgalactose, and thus, it can be effectively used in targeted drug delivery and as biological cell marker in cancer therapeutics. Copyright © 2014 John Wiley & Sons, Ltd.

Quantifying the topography of the intrinsic energy landscape of flexible biomolecular recognition

PubMed Central

Chu, Xiakun; Gan, Linfeng; Wang, Erkang; Wang, Jin

2013-01-01

Biomolecular functions are determined by their interactions with other molecules. Biomolecular recognition is often flexible and associated with large conformational changes involving both binding and folding. However, the global and physical understanding for the process is still challenging. Here, we quantified the intrinsic energy landscapes of flexible biomolecular recognition in terms of binding–folding dynamics for 15 homodimers by exploring the underlying density of states, using a structure-based model both with and without considering energetic roughness. By quantifying three individual effective intrinsic energy landscapes (one for interfacial binding, two for monomeric folding), the association mechanisms for flexible recognition of 15 homodimers can be classified into two-state cooperative “coupled binding–folding” and three-state noncooperative “folding prior to binding” scenarios. We found that the association mechanism of flexible biomolecular recognition relies on the interplay between the underlying effective intrinsic binding and folding energy landscapes. By quantifying the whole global intrinsic binding–folding energy landscapes, we found strong correlations between the landscape topography measure Λ (dimensionless ratio of energy gap versus roughness modulated by the configurational entropy) and the ratio of the thermodynamic stable temperature versus trapping temperature, as well as between Λ and binding kinetics. Therefore, the global energy landscape topography determines the binding–folding thermodynamics and kinetics, crucial for the feasibility and efficiency of realizing biomolecular function. We also found “U-shape” temperature-dependent kinetic behavior and a dynamical cross-over temperature for dividing exponential and nonexponential kinetics for two-state homodimers. Our study provides a unique way to bridge the gap between theory and experiments. PMID:23754431

Insights on the Cuprate High Energy Anomaly Observed in ARPES

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

Moritz, Brian

2011-08-16

Recently, angle-resolved photoemission spectroscopy has been used to highlight an anomalously large band renormalization at high binding energies in cuprate superconductors: the high energy 'waterfall' or high energy anomaly (HEA). The anomaly is present for both hole- and electron-doped cuprates as well as the half-filled parent insulators with different energy scales arising on either side of the phase diagram. While photoemission matrix elements clearly play a role in changing the aesthetic appearance of the band dispersion, i.e. creating a 'waterfall'-like appearance, they provide an inadequate description for the physics that underlies the strong band renormalization giving rise to the HEA.more » Model calculations of the single-band Hubbard Hamiltonian showcase the role played by correlations in the formation of the HEA and uncover significant differences in the HEA energy scale for hole- and electron-doped cuprates. In addition, this approach properly captures the transfer of spectral weight accompanying doping in a correlated material and provides a unifying description of the HEA across both sides of the cuprate phase diagram. We find that the anomaly demarcates a transition, or cross-over, from a quasiparticle band at low binding energies near the Fermi level to valence bands at higher binding energy, assumed to be of strong oxygen character.« less

Statins in therapy: understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies.

PubMed

Fong, Clifford W

2014-10-06

The atomic electrostatic potentials calculated by the CHELPG method have been shown to be sensitive indicators of the gas phase and solution properties of the statins. Solvation free energies in water, n-octanol and n-octane have been determined using the SMD solvent model. The percentage hydrophilicity and hydrophobicity (or lipophilicity) of the statins in solution have been determined using (a) the differences in solvation free energies between n-octanol and n-octane as a measure of hydrophilicity, and the solvation energy in octane as a measure of hydrophobicity (b) the sum of the atomic electrostatic charges on the hydrogen bonding and polar bonding nuclei of the common pharmacophore combined with a solvent measure of hydrophobicity, and (c) using the buried surface areas after statin binding to HMGCR to calculate the hydrophobicity of the bound statins. The data suggests that clinical definitions of statins as either "hydrophilic" or "lipophilic" based on experimental partition coefficients are misleading. An estimate of the binding energy between rosuvastatin and HMGCR has been made using: (a) a coulombic electrostatic interaction model, (b) the calculated desolvation and resolvation of the statin in water, and (c) the first shell transfer solvation energy as a proxy for the restructuring of the water molecules immediately adjacent to the active binding site of HMGCR prior to binding. Desolvation and resolvation of the statins before and after binding to HMGCR are major determinants of the energetics of the binding process. An analysis of the amphiphilic nature of lovastatin anion, acid and lactone and fluvastatin anion and their abilities to cross the blood brain barrier has indicated that this process may be dominated by desolvation and resolvation effects, rather than the statin molecular size or statin-lipid interactions within the bilayer. The ionization energy and electron affinity of the statins are sensitive physical indicators of the ease that the various statins can undergo endogenous oxidative metabolism. The absolute chemical hardness is also an indicator of the stability of the statins, and may be a useful indicator for drug design. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Statistical Analysis on the Performance of Molecular Mechanics Poisson–Boltzmann Surface Area versus Absolute Binding Free Energy Calculations: Bromodomains as a Case Study

PubMed Central

2017-01-01

Binding free energy calculations that make use of alchemical pathways are becoming increasingly feasible thanks to advances in hardware and algorithms. Although relative binding free energy (RBFE) calculations are starting to find widespread use, absolute binding free energy (ABFE) calculations are still being explored mainly in academic settings due to the high computational requirements and still uncertain predictive value. However, in some drug design scenarios, RBFE calculations are not applicable and ABFE calculations could provide an alternative. Computationally cheaper end-point calculations in implicit solvent, such as molecular mechanics Poisson–Boltzmann surface area (MMPBSA) calculations, could too be used if one is primarily interested in a relative ranking of affinities. Here, we compare MMPBSA calculations to previously performed absolute alchemical free energy calculations in their ability to correlate with experimental binding free energies for three sets of bromodomain–inhibitor pairs. Different MMPBSA approaches have been considered, including a standard single-trajectory protocol, a protocol that includes a binding entropy estimate, and protocols that take into account the ligand hydration shell. Despite the improvements observed with the latter two MMPBSA approaches, ABFE calculations were found to be overall superior in obtaining correlation with experimental affinities for the test cases considered. A difference in weighted average Pearson () and Spearman () correlations of 0.25 and 0.31 was observed when using a standard single-trajectory MMPBSA setup ( = 0.64 and = 0.66 for ABFE; = 0.39 and = 0.35 for MMPBSA). The best performing MMPBSA protocols returned weighted average Pearson and Spearman correlations that were about 0.1 inferior to ABFE calculations: = 0.55 and = 0.56 when including an entropy estimate, and = 0.53 and = 0.55 when including explicit water molecules. Overall, the study suggests that ABFE calculations are indeed the more accurate approach, yet there is also value in MMPBSA calculations considering the lower compute requirements, and if agreement to experimental affinities in absolute terms is not of interest. Moreover, for the specific protein–ligand systems considered in this study, we find that including an explicit ligand hydration shell or a binding entropy estimate in the MMPBSA calculations resulted in significant performance improvements at a negligible computational cost. PMID:28786670

Prediction of potency of protease inhibitors using free energy simulations with polarizable quantum mechanics-based ligand charges and a hybrid water model.

PubMed

Das, Debananda; Koh, Yasuhiro; Tojo, Yasushi; Ghosh, Arun K; Mitsuya, Hiroaki

2009-12-01

Reliable and robust prediction of the binding affinity for drug molecules continues to be a daunting challenge. We simulated the binding interactions and free energy of binding of nine protease inhibitors (PIs) with wild-type and various mutant proteases by performing GBSA simulations in which each PI's partial charge was determined by quantum mechanics (QM) and the partial charge accounts for the polarization induced by the protease environment. We employed a hybrid solvation model that retains selected explicit water molecules in the protein with surface-generalized Born (SGB) implicit solvent. We examined the correlation of the free energy with the antiviral potency of PIs with regard to amino acid substitutions in protease. The GBSA free energy thus simulated showed strong correlations (r > 0.75) with antiviral IC(50) values of PIs when amino acid substitutions were present in the protease active site. We also simulated the binding free energy of PIs with P2-bis-tetrahydrofuranylurethane (bis-THF) or related cores, utilizing a bis-THF-containing protease crystal structure as a template. The free energy showed a strong correlation (r = 0.93) with experimentally determined anti-HIV-1 potency. The present data suggest that the presence of selected explicit water in protein and protein polarization-induced quantum charges for the inhibitor, compared to lack of explicit water and a static force-field-based charge model, can serve as an improved lead optimization tool and warrants further exploration.

Small Changes in the Primary Structure of Transportan 10 Alter the Thermodynamics and Kinetics of its Interaction with Phospholipid Vesicles

PubMed Central

2008-01-01

The kinetics and thermodynamics of binding of transportan 10 (tp10) and four of its variants to phospholipid vesicles, and the kinetics of peptide-induced dye efflux, were compared. Tp10 is a 21-residue, amphipathic, cationic, cell-penetrating peptide similar to helical antimicrobial peptides. The tp10 variants examined include amidated and free peptides, and replacements of tyrosine by tryptophan. Carboxy-terminal amidation or substitution of tryptophan for tyrosine enhance binding and activity. The Gibbs energies of peptide binding to membranes determined experimentally and calculated from the interfacial hydrophobicity scale are in good agreement. The Gibbs energy for insertion into the bilayer core was calculated using hydrophobicity scales of residue transfer from water to octanol and to the membrane/water interface. Peptide-induced efflux becomes faster as the Gibbs energies for binding and insertion of the tp10 variants decrease. If anionic lipids are included, binding and efflux rate increase, as expected because all tp10 variants are cationic and an electrostatic component is added. Whether the most important effect of peptide amidation is the change in charge or an enhancement of helical structure, however, still needs to be established. Nevertheless, it is clear that the changes in efflux rate reflect the differences in the thermodynamics of binding and insertion of the free and amidated peptide groups. PMID:18260641

Crystal structure correlations with the intrinsic thermodynamics of human carbonic anhydrase inhibitor binding

PubMed Central

Smirnov, Alexey; Zubrienė, Asta; Manakova, Elena; Gražulis, Saulius

2018-01-01

The structure-thermodynamics correlation analysis was performed for a series of fluorine- and chlorine-substituted benzenesulfonamide inhibitors binding to several human carbonic anhydrase (CA) isoforms. The total of 24 crystal structures of 16 inhibitors bound to isoforms CA I, CA II, CA XII, and CA XIII provided the structural information of selective recognition between a compound and CA isoform. The binding thermodynamics of all structures was determined by the analysis of binding-linked protonation events, yielding the intrinsic parameters, i.e., the enthalpy, entropy, and Gibbs energy of binding. Inhibitor binding was compared within structurally similar pairs that differ by para- or meta-substituents enabling to obtain the contributing energies of ligand fragments. The pairs were divided into two groups. First, similar binders—the pairs that keep the same orientation of the benzene ring exhibited classical hydrophobic effect, a less exothermic enthalpy and a more favorable entropy upon addition of the hydrophobic fragments. Second, dissimilar binders—the pairs of binders that demonstrated altered positions of the benzene rings exhibited the non-classical hydrophobic effect, a more favorable enthalpy and variable entropy contribution. A deeper understanding of the energies contributing to the protein-ligand recognition should lead toward the eventual goal of rational drug design where chemical structures of ligands could be designed based on the target protein structure. PMID:29503769

A theory of adhesion at a bimetallic interface - Overlap effects.

NASA Technical Reports Server (NTRS)

Ferrante, J.; Smith, J. R.

1973-01-01

A preliminary calculation of the chemical bonding adhesive interaction between metal surfaces is provided. In this first theory the Hohenberg and Kohn formalism is used to give the bimetallic adhesive binding energy versus separation. The close-packed planes of Al, Mg, and Zn are considered. The effect of simple overlap of the metal-vacuum distributions is determined. The importance of registry between contact surfaces is ascertained. A minimum in the binding energy curve is exhibited for all combinations. The theoretical predictions agree with trends in bond strengths taken from available experimental data. An insight into the mechanisms involved in metallic transfer is given. The relationship between adhesive energies, cohesive energies, and surface energies is discussed.

Structures and Binding Energies of the Naphthalene Dimer in Its Ground and Excited States.

PubMed

Dubinets, N O; Safonov, A A; Bagaturyants, A A

2016-05-05

Possible structures of the naphthalene dimer corresponding to local energy minima in the ground and excited (excimer) electronic states are comprehensively investigated using DFT-D and TDDFT-D methods with a special accent on the excimer structures. The corresponding binding and electronic transition energies are calculated, and the nature of the electronic states in different structures is analyzed. Several parallel (stacked) and T-shaped structures were found in both the ground and excited (excimer) states in a rather narrow energy range. The T-shaped structure with the lowest energy in the excited state exhibits a marked charge transfer from the upright molecule to the base one.

Site Identification by Ligand Competitive Saturation (SILCS) Simulations for Fragment-Based Drug Design

PubMed Central

Faller, Christina E.; Raman, E. Prabhu; MacKerell, Alexander D.; Guvench, Olgun

2015-01-01

Fragment-based drug design (FBDD) involves screening low molecular weight molecules (“fragments”) that correspond to functional groups found in larger drug-like molecules to determine their binding to target proteins or nucleic acids. Based on the principle of thermodynamic additivity, two fragments that bind non-overlapping nearby sites on the target can be combined to yield a new molecule whose binding free energy is the sum of those of the fragments. Experimental FBDD approaches, like NMR and X-ray crystallography, have proven very useful but can be expensive in terms of time, materials, and labor. Accordingly, a variety of computational FBDD approaches have been developed that provide different levels of detail and accuracy. The Site Identification by Ligand Competitive Saturation (SILCS) method of computational FBDD uses all-atom explicit-solvent molecular dynamics (MD) simulations to identify fragment binding. The target is “soaked” in an aqueous solution with multiple fragments having different identities. The resulting computational competition assay reveals what small molecule types are most likely to bind which regions of the target. From SILCS simulations, 3D probability maps of fragment binding called “FragMaps” can be produced. Based on the probabilities relative to bulk, SILCS FragMaps can be used to determine “Grid Free Energies (GFEs),” which provide per-atom contributions to fragment binding affinities. For essentially no additional computational overhead relative to the production of the FragMaps, GFEs can be used to compute Ligand Grid Free Energies (LGFEs) for arbitrarily complex molecules, and these LGFEs can be used to rank-order the molecules in accordance with binding affinities. PMID:25709034

Structural Reorganization and the Cooperative Binding of Single-stranded Telomere DNA in Sterkiella nova*

PubMed Central

Buczek, Pawel; Horvath, Martin P.

2009-01-01

In Sterkiella nova, α and β telomere proteins bind cooperatively with single-stranded DNA to form a ternary α·β·DNA complex. Association of telomere protein subunits is DNA-dependent, and α-β association enhances DNA affinity. To further understand the molecular basis for binding cooperativity, we characterized several possible stepwise assembly pathways using isothermal titration calorimetry. In one path, α and DNA first form a stable α·DNA complex followed by addition of β in a second step. Binding energy accumulates with nearly equal free energy of association for each of these steps. Heat capacity is nonetheless dramatically different with ΔCp = −305 ± 3 cal mol−1 K−1 for α binding with DNA and ΔCp = −2010 ± 20 cal mol−1 K−1 for addition of β to complete the α·β·DNA complex. By examining alternate routes including titration of single-stranded DNA with a preformed α·β complex, a significant portion of binding energy and heat capacity could be assigned to structural reorganization involving protein-protein interactions and repositioning of the DNA. Structural reorganization probably affords a mechanism to regulate high affinity binding of telomere single-stranded DNA with important implications for telomere biology. Regulation of telomere complex dissociation is thought to involve post-translational modifications in the lysine-rich C-terminal portion of β. We observed no difference in binding energetics or crystal structure when comparing complexes prepared with full-length β or a C-terminally truncated form, supporting interesting parallels between the intrinsically disordered regions of histones and this portion of β. PMID:17082188

Prediction of binding constants of protein ligands: A fast method for the prioritization of hits obtained from de novo design or 3D database search programs

NASA Astrophysics Data System (ADS)

Böhm, Hans-Joachim

1998-07-01

A dataset of 82 protein-ligand complexes of known 3D structure and binding constant Ki was analysed to elucidate the important factors that determine the strength of protein-ligand interactions. The following parameters were investigated: the number and geometry of hydrogen bonds and ionic interactions between the protein and the ligand, the size of the lipophilic contact surface, the flexibility of the ligand, the electrostatic potential in the binding site, water molecules in the binding site, cavities along the protein-ligand interface and specific interactions between aromatic rings. Based on these parameters, a new empirical scoring function is presented that estimates the free energy of binding for a protein-ligand complex of known 3D structure. The function distinguishes between buried and solvent accessible hydrogen bonds. It tolerates deviations in the hydrogen bond geometry of up to 0.25 Å in the length and up to 30 °Cs in the hydrogen bond angle without penalizing the score. The new energy function reproduces the binding constants (ranging from 3.7 × 10-2 M to 1 × 10-14 M, corresponding to binding energies between -8 and -80 kJ/mol) of the dataset with a standard deviation of 7.3 kJ/mol corresponding to 1.3 orders of magnitude in binding affinity. The function can be evaluated very fast and is therefore also suitable for the application in a 3D database search or de novo ligand design program such as LUDI. The physical significance of the individual contributions is discussed.

Robust tunable excitonic features in monolayer transition metal dichalcogenide quantum dots

NASA Astrophysics Data System (ADS)

Fouladi-Oskouei, J.; Shojaei, S.; Liu, Z.

2018-04-01

The effects of quantum confinement on excitons in parabolic quantum dots of monolayer transition metal dichalcogenides (TMDC QDs) are investigated within a massive Dirac fermion model. A giant spin-valley coupling of the TMDC QDs is obtained, larger than that of monolayer TMDC sheets and consistent with recent experimental measurements. The exciton transition energy and the binding energy are calculated, and it is found that the strong quantum confinement results in extremely high exciton binding energies. The enormously large exciton binding energy in TMDC QDs (({{E}{{B2D}}}∼ 500 meV)<{{E}{{BQD}}}~≲ 1800 meV for different kinds of TMDC QDs) ensures that the many body interactions play a significant role in the investigation of the optical properties of these novel nanostructures. The estimated oscillator strength and radiative lifetime of excitons are strongly size-dependent and indicate a giant oscillator strength enhancement and ultrafast radiative annihilation of excitons, varying from a few tens of femtoseconds to a few picoseconds. We found that the spin-dependent band gap, spin-valley coupling, binding energy and excitonic effects can be tuned by quantum confinements, leading to tunable quantum dots in monolayer TMDCs. This finding offers new functionality in engineering the interaction of a 2D material with light and creates promise for the quantum manipulation of spin and valley degrees of freedom in TMDC nanostructures, enabling versatile novel 2D quantum photonic and optoelectronic nanodevices.

Extended fenske-hall calculation of inner-shell binding energies using ( Z + 1)-bazis sets: Sulfur-containing molecules

NASA Astrophysics Data System (ADS)

Zwanziger, Ch.; Zwanziger, H.; Szargan, R.; Reinhold, J.

1981-08-01

It is shown that the S1s and S2p binding energies and their chemical shifts in the molecules H 2S, SO 2, SF 6 and COS obtained with hole-state calculations using an extended Fenske-Hall method are in good agreement with experimental values if mixed ( Z + 1)-basis sets are applied.

A new assay format for NF-kappaB based on a DNA triple helix and a fluorescence resonance energy transfer.

PubMed

Altevogt, Dominik; Hrenn, Andrea; Kern, Claudia; Clima, Lilia; Bannwarth, Willi; Merfort, Irmgard

2009-10-07

Herein we report a feasibility study for a new concept to detect DNA binding protein NF-kappaB based on a DNA triple helix formation in combination with a fluorescence resonance energy transfer (FRET). The new principle avoids expensive antibodies and radioactivity and might have implications for assays of other DNA binding proteins.

Energy profile of nanobody-GFP complex under force.

PubMed

Klamecka, Kamila; Severin, Philip M; Milles, Lukas F; Gaub, Hermann E; Leonhardt, Heinrich

2015-09-10

Nanobodies (Nbs)-the smallest known fully functional and naturally occuring antigen-binding fragments-have attracted a lot of attention throughout the last two decades. Exploring their potential beyond the current use requires more detailed characterization of their binding forces as those cannot be directly derived from the binding affinities. Here we used atomic force microscope to measure rupture force of the Nb-green fluorescent protein (GFP) complex in various pulling geometries and derived the energy profile characterizing the interaction along the direction of the pulling force. We found that-despite identical epitopes-the Nb binds stronger (41-56 pN) to enhanced GFP than to wild-type GFP (28-45 pN). Measured forces make the Nb-GFP pair a potent reference for investigating molecular forces in living systems both in and ex vivo.

Comparative molecular dynamics simulations of histone deacetylase-like protein: binding modes and free energy analysis to hydroxamic acid inhibitors.

PubMed

Yan, Chunli; Xiu, Zhilong; Li, Xiaohui; Li, Shenmin; Hao, Ce; Teng, Hu

2008-10-01

Histone deacetylases (HDACs) play an important role in gene transcription, and inhibitors of HDACs can induce cell differentiation and suppress cell proliferation in tumor cells. Histone deacetylase1 (HDAC1) binds suberanilohydroxamic acid (SAHA) and 7-phenyl-2, 4, 6-hepta-trienoyl hydroxamic acid (CG-1521) with moderately low affinity (DeltaG = -8.6 and -7.8 kcal mol(-1)). The structurally related (E)-2-(3-(3-(hydroxyamino)-3-oxoprop-1-enyl)phenyl)-N(1),N(3)-diphenylmalonamide (SK-683), a Trichostatin A (TSA)-like HDAC1 inhibitor, and TSA are bound to the HDAC1 with -12.3 and -10.3 kcal mol(-1) of DeltaG, higher binding free energies than SAHA and CG-1521. Histone deacetylase-like protein (HDLP), an HDAC homologue, shows a 35.2% sequence identity of HDLP and human HDAC1. Molecular dynamics simulation and the molecular mechanics/generalized-Born surface area (MM-GBSA) free energy calculations were applied to investigate the factors responsible for the relatively activity of these four inhibitors to HDLP. In addition, computational alanine scanning of the binding site residues was carried out to determine the contribution components from van der Waals, electrostatic interaction, nonpolar and polar energy of solvation as well as the effects of backbones and side-chains with the MM-GBSA method. MM-GBSA methods reproduced the experimental relative affinities of the four inhibitors in good agreement (R(2) = 0.996) between experimental and computed binding energies. The MM-GBSA calculations showed that, the number of hydrogen bonds formed between the HDLP and inhibitors, which varied in the system studied, and electrostatic interactions determined the magnitude of the free energies for HDLP-inhibitor interactions. The MM-GBSA calculations revealed that the binding of HDLP to these four hydroxamic acid inhibitors is mainly driven by van der Waals/nonpolar interactions. This study can be a guide for the optimization of HDAC inhibitors and future design of new therapeutic agents for the treatment of cancer.

Insights into regioselective metabolism of mefenamic acid by cytochrome P450 BM3 mutants through crystallography, docking, molecular dynamics, and free energy calculations.

PubMed

Capoferri, Luigi; Leth, Rasmus; ter Haar, Ernst; Mohanty, Arun K; Grootenhuis, Peter D J; Vottero, Eduardo; Commandeur, Jan N M; Vermeulen, Nico P E; Jørgensen, Flemming Steen; Olsen, Lars; Geerke, Daan P

2016-03-01

Cytochrome P450 BM3 (CYP102A1) mutant M11 is able to metabolize a wide range of drugs and drug-like compounds. Among these, M11 was recently found to be able to catalyze formation of human metabolites of mefenamic acid and other nonsteroidal anti-inflammatory drugs (NSAIDs). Interestingly, single active-site mutations such as V87I were reported to invert regioselectivity in NSAID hydroxylation. In this work, we combine crystallography and molecular simulation to study the effect of single mutations on binding and regioselective metabolism of mefenamic acid by M11 mutants. The heme domain of the protein mutant M11 was expressed, purified, and crystallized, and its X-ray structure was used as template for modeling. A multistep approach was used that combines molecular docking, molecular dynamics (MD) simulation, and binding free-energy calculations to address protein flexibility. In this way, preferred binding modes that are consistent with oxidation at the experimentally observed sites of metabolism (SOMs) were identified. Whereas docking could not be used to retrospectively predict experimental trends in regioselectivity, we were able to rank binding modes in line with the preferred SOMs of mefenamic acid by M11 and its mutants by including protein flexibility and dynamics in free-energy computation. In addition, we could obtain structural insights into the change in regioselectivity of mefenamic acid hydroxylation due to single active-site mutations. Our findings confirm that use of MD and binding free-energy calculation is useful for studying biocatalysis in those cases in which enzyme binding is a critical event in determining the selective metabolism of a substrate. © 2016 Wiley Periodicals, Inc.

Search for β2 Adrenergic Receptor Ligands by Virtual Screening via Grid Computing and Investigation of Binding Modes by Docking and Molecular Dynamics Simulations

PubMed Central

Bai, Qifeng; Shao, Yonghua; Pan, Dabo; Zhang, Yang; Liu, Huanxiang; Yao, Xiaojun

2014-01-01

We designed a program called MolGridCal that can be used to screen small molecule database in grid computing on basis of JPPF grid environment. Based on MolGridCal program, we proposed an integrated strategy for virtual screening and binding mode investigation by combining molecular docking, molecular dynamics (MD) simulations and free energy calculations. To test the effectiveness of MolGridCal, we screened potential ligands for β2 adrenergic receptor (β2AR) from a database containing 50,000 small molecules. MolGridCal can not only send tasks to the grid server automatically, but also can distribute tasks using the screensaver function. As for the results of virtual screening, the known agonist BI-167107 of β2AR is ranked among the top 2% of the screened candidates, indicating MolGridCal program can give reasonable results. To further study the binding mode and refine the results of MolGridCal, more accurate docking and scoring methods are used to estimate the binding affinity for the top three molecules (agonist BI-167107, neutral antagonist alprenolol and inverse agonist ICI 118,551). The results indicate agonist BI-167107 has the best binding affinity. MD simulation and free energy calculation are employed to investigate the dynamic interaction mechanism between the ligands and β2AR. The results show that the agonist BI-167107 also has the lowest binding free energy. This study can provide a new way to perform virtual screening effectively through integrating molecular docking based on grid computing, MD simulations and free energy calculations. The source codes of MolGridCal are freely available at http://molgridcal.codeplex.com. PMID:25229694

Calculation of positron binding energies using the generalized any particle propagator theory

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

Romero, Jonathan; Charry, Jorge A.; Flores-Moreno, Roberto

2014-09-21

We recently extended the electron propagator theory to any type of quantum species based in the framework of the Any-Particle Molecular Orbital (APMO) approach [J. Romero, E. Posada, R. Flores-Moreno, and A. Reyes, J. Chem. Phys. 137, 074105 (2012)]. The generalized any particle molecular orbital propagator theory (APMO/PT) was implemented in its quasiparticle second order version in the LOWDIN code and was applied to calculate nuclear quantum effects in electron binding energies and proton binding energies in molecular systems [M. Díaz-Tinoco, J. Romero, J. V. Ortiz, A. Reyes, and R. Flores-Moreno, J. Chem. Phys. 138, 194108 (2013)]. In this work,more » we present the derivation of third order quasiparticle APMO/PT methods and we apply them to calculate positron binding energies (PBEs) of atoms and molecules. We calculated the PBEs of anions and some diatomic molecules using the second order, third order, and renormalized third order quasiparticle APMO/PT approaches and compared our results with those previously calculated employing configuration interaction (CI), explicitly correlated and quantum Montecarlo methodologies. We found that renormalized APMO/PT methods can achieve accuracies of ∼0.35 eV for anionic systems, compared to Full-CI results, and provide a quantitative description of positron binding to anionic and highly polar species. Third order APMO/PT approaches display considerable potential to study positron binding to large molecules because of the fifth power scaling with respect to the number of basis sets. In this regard, we present additional PBE calculations of some small polar organic molecules, amino acids and DNA nucleobases. We complement our numerical assessment with formal and numerical analyses of the treatment of electron-positron correlation within the quasiparticle propagator approach.« less

States of direct and indirect excitons in strained zinc-blende GaN/InGaN asymmetric quantum wells

NASA Astrophysics Data System (ADS)

Rojas-Briseño, J. G.; Martínez-Orozco, J. C.; Mora-Ramos, M. E.

2017-12-01

The total and binding energies of excitons in step-like asymmetric quantum wells made of zincblende GaN/InxlGa(1-xl)N/InxrGa(1-xr)N/GaN are theoretically reported. It is discussed how the asymmetry in the carrier confinement leads to singular behaviors in the exciton binding energy, allowing to observe both direct and indirect exciton states in the heterostructure. The study is carried out with the use of the effective mass approximation. The effects of strain are taken into account and a comparison of the results obtained for both strained and unstrained situations is presented. Exciton energy shows a decreasing behavior when the size of the effective confinement region is augmented. The total exciton energy as well as the binding energy are reported as functions of the indium concentration and quantum well width. In addition, the results of the calculation of the photoluminescence peak are presented. For this latter quantity, our results for the limiting case of a single zinc-blende GaN/InGaN quantum well show very good agreement with published experimental ones.

The Dual Role of Disorder on the Dissociation of Interfacial Charge Transfer Excitons

NASA Astrophysics Data System (ADS)

Shi, Liang; Lee, Chee-Kong; Willard, Adam

In organic-based photovoltaics (OPV), dissociation of neutral photo-excitations (i.e., Frenkel excitons) into free charge carriers requires the excitons to overcome binding energy that can significantly exceed thermal energies. The inability of bound charges to overcome this large binding energy has been implicated as a primary source of efficiency loss in OPVs. Despite the potential impact on the performance of organic solar cells much remains to be understood about the microscopic mechanism of exciton dissociation in OPV materials. Here we explore the role of static molecular disorder in mediating this charge dissociation process. Using a simple lattice model of exciton dynamics we demonstrate that random spatial variations in the energetic landscape can mitigate the effects of the exciton binding energy by lowering the free energy barrier. By considering the competition between this thermodynamic effect and the disorder-induced slowing of dissociation kinetics we demonstrate that exciton dissociation yields are expected to depend non-monotonically on the degree of static disorder. We conclude that a certain amount of molecular-scale disorder is desirable in order to optimize the performance of organic photovoltaic materials.

Determination of the binding energies of the np Rydberg states of H{sub 2}, HD, and D{sub 2} from high-resolution spectroscopic data by multichannel quantum-defect theory

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

Sprecher, Daniel; Merkt, Frédéric, E-mail: frederic.merkt@phys.chem.ethz.ch; Jungen, Christian

2014-03-14

Multichannel quantum-defect theory (MQDT) is used to calculate the electron binding energies of np Rydberg states of H{sub 2}, HD, and D{sub 2} around n = 60 at an accuracy of better than 0.5 MHz. The theory includes the effects of rovibronic channel interactions and the hyperfine structure, and has been extended to the calculation of the asymmetric hyperfine structure of Rydberg states of a heteronuclear diatomic molecule (HD). Starting values for the eigenquantum-defect parameters of MQDT were extracted from ab initio potential-energy functions for the low-lying p Rydberg states of molecular hydrogen and subsequently refined in a global weighted fitmore » to available experimental data on the singlet and triplet Rydberg states of H{sub 2} and D{sub 2}. The electron binding energies of high-np Rydberg states derived in this work represent important quantities for future determinations of the adiabatic ionization energies of H{sub 2}, HD, and D{sub 2} at sub-MHz accuracy.« less

Hydrogen incorporation into BN fullerene-like nanostructures: A first-principles study

NASA Astrophysics Data System (ADS)

Ganji, M. D.; Abbaszadeh, B.; Ahaz, B.

2011-10-01

We performed density functional theory calculations to investigate the possibility of formation of endohedrally H@(BN) n-fullerene ( n: 24, 36, 60) and H@C 60 complexes for potential applications in solid-state quantum-computers. Spin-polarized approach within the generalized gradient approximation with the Perdew-Burke-Ernzerhof functional was used for the total energies and structural relaxation calculations. The calculated binding energies show that H atom being incorporated into B 60N 60 nanocage can form most stable complexes while the B 24N 24 and C 60 nanocages might form unstable complex with positive binding energy. We have also examined the penetration of an H atom into the respective nanocages and the calculated barrier energies indicate that the H atom prefers to penetrate into the B 24N 24 and B 60N 60 nanocages with barrier energy of about 0.47 eV (10.84 kcal/mol). Furthermore the binding characteristic is rationalized by analyzing the electronic structures. Our findings reveal that the B 60N 60 nanocage has fascinating potential application in future solid-state quantum-computers.

Understanding the physical basis of the salt dependence of the electrostatic binding free energy of mutated charged ligand-nucleic acid complexes.

PubMed

Harris, Robert C; Bredenberg, Johan H; Silalahi, Alexander R J; Boschitsch, Alexander H; Fenley, Marcia O

2011-06-01

The predictions of the derivative of the electrostatic binding free energy of a biomolecular complex, ΔG(el), with respect to the logarithm of the 1:1 salt concentration, d(ΔG(el))/d(ln[NaCl]), SK, by the Poisson-Boltzmann equation, PBE, are very similar to those of the simpler Debye-Hückel equation, DHE, because the terms in the PBE's predictions of SK that depend on the details of the dielectric interface are small compared to the contributions from long-range electrostatic interactions. These facts allow one to obtain predictions of SK using a simplified charge model along with the DHE that are highly correlated with both the PBE and experimental binding data. The DHE-based model developed here, which was derived from the generalized Born model, explains the lack of correlation between SK and ΔG(el) in the presence of a dielectric discontinuity, which conflicts with the popular use of this supposed correlation to parse experimental binding free energies into electrostatic and nonelectrostatic components. Moreover, the DHE model also provides a clear justification for the correlations between SK and various empirical quantities, like the number of ion pairs, the ligand charge on the interface, the Coulomb binding free energy, and the product of the charges on the complex's components, but these correlations are weak, questioning their usefulness. Copyright © 2011 Elsevier B.V. All rights reserved.

Free energy landscape of siRNA-polycation complexation: Elucidating the effect of molecular geometry, polymer flexibility, and charge neutralization.

PubMed

Grasso, Gianvito; Deriu, Marco Agostino; Patrulea, Viorica; Borchard, Gerrit; Möller, Michael; Danani, Andrea

2017-01-01

The success of medical threatments with DNA and silencing interference RNA is strongly related to the design of efficient delivery technologies. Cationic polymers represent an attractive strategy to serve as nucleic-acid carriers with the envisioned advantages of efficient complexation, low cost, ease of production, well-defined size, and low polydispersity index. However, the balance between efficacy and toxicity (safety) of these polymers is a challenge and in need of improvement. With the aim of designing more effective polycationic-based gene carriers, many parameters such as carrier morphology, size, molecular weight, surface chemistry, and flexibility/rigidity ratio need to be taken into consideration. In the present work, the binding mechanism of three cationic polymers (polyarginine, polylysine and polyethyleneimine) to a model siRNA target is computationally investigated at the atomistic level. In order to better understand the polycationic carrier-siRNA interactions, replica exchange molecular dynamic simulations were carried out to provide an exhaustive exploration of all the possible binding sites, taking fully into account the siRNA flexibility together with the presence of explicit solvent and ions. Moreover, well-tempered metadynamics simulations were employed to elucidate how molecular geometry, polycation flexibility, and charge neutralization affect the siRNA-polycations free energy landscape in term of low-energy binding modes and unbinding free energy barriers. Significant differences among polymer binding modes have been detected, revealing the advantageous binding properties of polyarginine and polylysine compared to polyethyleneimine.

Free energy landscape of siRNA-polycation complexation: Elucidating the effect of molecular geometry, polymer flexibility, and charge neutralization

PubMed Central

Patrulea, Viorica; Borchard, Gerrit; Möller, Michael; Danani, Andrea

2017-01-01

The success of medical threatments with DNA and silencing interference RNA is strongly related to the design of efficient delivery technologies. Cationic polymers represent an attractive strategy to serve as nucleic-acid carriers with the envisioned advantages of efficient complexation, low cost, ease of production, well-defined size, and low polydispersity index. However, the balance between efficacy and toxicity (safety) of these polymers is a challenge and in need of improvement. With the aim of designing more effective polycationic-based gene carriers, many parameters such as carrier morphology, size, molecular weight, surface chemistry, and flexibility/rigidity ratio need to be taken into consideration. In the present work, the binding mechanism of three cationic polymers (polyarginine, polylysine and polyethyleneimine) to a model siRNA target is computationally investigated at the atomistic level. In order to better understand the polycationic carrier-siRNA interactions, replica exchange molecular dynamic simulations were carried out to provide an exhaustive exploration of all the possible binding sites, taking fully into account the siRNA flexibility together with the presence of explicit solvent and ions. Moreover, well-tempered metadynamics simulations were employed to elucidate how molecular geometry, polycation flexibility, and charge neutralization affect the siRNA-polycations free energy landscape in term of low-energy binding modes and unbinding free energy barriers. Significant differences among polymer binding modes have been detected, revealing the advantageous binding properties of polyarginine and polylysine compared to polyethyleneimine. PMID:29088239

Using the Concept of Transient Complex for Affinity Predictions in CAPRI Rounds 20–27 and Beyond

PubMed Central

Qin, Sanbo; Zhou, Huan-Xiang

2013-01-01

Predictions of protein-protein binders and binding affinities have traditionally focused on features pertaining to the native complexes. In developing a computational method for predicting protein-protein association rate constants, we introduced the concept of transient complex after mapping the interaction energy surface. The transient complex is located at the outer boundary of the bound-state energy well, having near-native separation and relative orientation between the subunits but not yet formed most of the short-range native interactions. We found that the width of the binding funnel and the electrostatic interaction energy of the transient complex are among the features predictive of binders and binding affinities. These ideas were very promising for the five affinity-related targets (T43–45, 55, and 56) of CAPRI rounds 20–27. For T43, we ranked the single crystallographic complex as number 1 and were one of only two groups that clearly identified that complex as a true binder; for T44, we ranked the only design with measurable binding affinity as number 4. For the nine docking targets, continuing on our success in previous CAPRI rounds, we produced 10 medium-quality models for T47 and acceptable models for T48 and T49. We conclude that the interaction energy landscape and the transient complex in particular will complement existing features in leading to better prediction of binding affinities. PMID:23873496

Blockade of Neuronal α7-nAChR by α-Conotoxin ImI Explained by Computational Scanning and Energy Calculations

PubMed Central

Yu, Rilei; Craik, David J.; Kaas, Quentin

2011-01-01

α-Conotoxins potently inhibit isoforms of nicotinic acetylcholine receptors (nAChRs), which are essential for neuronal and neuromuscular transmission. They are also used as neurochemical tools to study nAChR physiology and are being evaluated as drug leads to treat various neuronal disorders. A number of experimental studies have been performed to investigate the structure-activity relationships of conotoxin/nAChR complexes. However, the structural determinants of their binding interactions are still ambiguous in the absence of experimental structures of conotoxin-receptor complexes. In this study, the binding modes of α-conotoxin ImI to the α7-nAChR, currently the best-studied system experimentally, were investigated using comparative modeling and molecular dynamics simulations. The structures of more than 30 single point mutants of either the conotoxin or the receptor were modeled and analyzed. The models were used to explain qualitatively the change of affinities measured experimentally, including some nAChR positions located outside the binding site. Mutational energies were calculated using different methods that combine a conformational refinement procedure (minimization with a distance dependent dielectric constant or explicit water, or molecular dynamics using five restraint strategies) and a binding energy function (MM-GB/SA or MM-PB/SA). The protocol using explicit water energy minimization and MM-GB/SA gave the best correlations with experimental binding affinities, with an R2 value of 0.74. The van der Waals and non-polar desolvation components were found to be the main driving force for binding of the conotoxin to the nAChR. The electrostatic component was responsible for the selectivity of the various ImI mutants. Overall, this study provides novel insights into the binding mechanism of α-conotoxins to nAChRs and the methodological developments reported here open avenues for computational scanning studies of a rapidly expanding range of wild-type and chemically modified α-conotoxins. PMID:21390272

Drug-binding energetics of human α-1-acid glycoprotein assessed by isothermal titration calorimetry and molecular docking simulations

PubMed Central

Huang, Johnny X.; Cooper, Matthew A.; Baker, Mark A.; Azad, Mohammad A.K.; Nation, Roger L.; Li, Jian; Velkov, Tony

2012-01-01

This study utilizes sensitive, modern isothermal titration calorimetric (ITC) methods to characterize the microscopic thermodynamic parameters that drive the binding of basic drugs to α-1-acid glycoprotein (AGP) and thereby rationalize the thermodynamic data in relation to docking models and crystallographic structures of the drug-AGP complexes. The binding of basic compounds from the tricyclic antidepressant series, together with miaserine, chlorpromazine, disopyramide and cimetidine all displayed an exothermically driven binding interaction with AGP. The impact of protonation/deprotonation events, ionic strength, temperature and the individual selectivity of the A and F1*S AGP variants on drug-binding thermodynamics were characterized. A correlation plot of the thermodynamic parameters for all of the test compounds revealed enthalpy-entropy compensation is in effect. The exothermic binding energetics of the test compounds were driven by a combination of favorable (negative) enthalpic (ΔH°) and favorable (positive) entropic (ΔS°) contributions to the Gibbs free energy (ΔG°). Collectively, the data imply that the free energies that drive drug binding to AGP and its relationship to drug-serum residency evolve from the complex interplay of enthalpic and entropic forces from interactions with explicit combinations of hydrophobic and polar side-chain sub-domains within the multi-lobed AGP ligand binding cavity. PMID:23192962

Core Binding Site of a Thioflavin-T-Derived Imaging Probe on Amyloid β Fibrils Predicted by Computational Methods.

PubMed

Kawai, Ryoko; Araki, Mitsugu; Yoshimura, Masashi; Kamiya, Narutoshi; Ono, Masahiro; Saji, Hideo; Okuno, Yasushi

2018-05-16

Development of new diagnostic imaging probes for Alzheimer's disease, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) probes, has been strongly desired. In this study, we investigated the most accessible amyloid β (Aβ) binding site of [ 123 I]IMPY, a Thioflavin-T-derived SPECT probe, using experimental and computational methods. First, we performed a competitive inhibition assay with Orange-G, which recognizes the KLVFFA region in Aβ fibrils, suggesting that IMPY and Orange-G bind to different sites in Aβ fibrils. Next, we precisely predicted the IMPY binding site on a multiple-protofilament Aβ fibril model using computational approaches, consisting of molecular dynamics and docking simulations. We generated possible IMPY-binding structures using docking simulations to identify candidates for probe-binding sites. The binding free energy of IMPY with the Aβ fibril was calculated by a free energy simulation method, MP-CAFEE. These computational results suggest that IMPY preferentially binds to an interfacial pocket located between two protofilaments and is stabilized mainly through hydrophobic interactions. Finally, our computational approach was validated by comparing it with the experimental results. The present study demonstrates the possibility of computational approaches to screen new PET/SPECT probes for Aβ imaging.

New Method for Measuring the Anchoring Energy of Strongly-Bound Membrane-Associated Proteins [Method for measuring the anchoring energy of strongly-bound membrane-associated proteins].

DOE PAGES

Kent, Michael S.; La Bauve, Elisa; Vernon, Briana C.; ...

2016-02-01

Here, we describe a new method to measure the activation energy required to remove a strongly-bound membrane-associated protein from a lipid membrane (anchoring energy). It is based on measuring the rate of release of a liposome-bound protein during centrifugation on a sucrose gradient as a function of time and temperature. The method was used to determine anchoring energy for the soluble dengue virus envelope protein (sE) strongly bound to 80:20 POPC:POPG liposomes at pH 5.5. We also measured the binding energy of sE at the same pH for the initial, predominantly reversible, phase of binding to a 70:30 PC:PG lipidmore » bilayer. The anchoring energy (37 +/- 1.7 kcal/mol, 20% PG) was found to be much larger than the binding energy (7.8 +/- 0.3 kcal/mol for 30% PG, or est. 7.0 kcal/mol for 20% PG). This is consistent with data showing that free sE is a monomer at pH 5.5, but assembles into trimers after associating with membranes. But, trimerization alone is insufficient to account for the observed difference in energies, and we conclude that some energy dissipation occurs during the release process. This new method to determine anchoring energy should be useful to understand the complex interactions of integral monotopic proteins and strongly-bound peripheral membrane proteins with lipid membranes.« less

New Method for Measuring the Anchoring Energy of Strongly-Bound Membrane-Associated Proteins [Method for measuring the anchoring energy of strongly-bound membrane-associated proteins].

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

Kent, Michael S.; La Bauve, Elisa; Vernon, Briana C.

Here, we describe a new method to measure the activation energy required to remove a strongly-bound membrane-associated protein from a lipid membrane (anchoring energy). It is based on measuring the rate of release of a liposome-bound protein during centrifugation on a sucrose gradient as a function of time and temperature. The method was used to determine anchoring energy for the soluble dengue virus envelope protein (sE) strongly bound to 80:20 POPC:POPG liposomes at pH 5.5. We also measured the binding energy of sE at the same pH for the initial, predominantly reversible, phase of binding to a 70:30 PC:PG lipidmore » bilayer. The anchoring energy (37 +/- 1.7 kcal/mol, 20% PG) was found to be much larger than the binding energy (7.8 +/- 0.3 kcal/mol for 30% PG, or est. 7.0 kcal/mol for 20% PG). This is consistent with data showing that free sE is a monomer at pH 5.5, but assembles into trimers after associating with membranes. But, trimerization alone is insufficient to account for the observed difference in energies, and we conclude that some energy dissipation occurs during the release process. This new method to determine anchoring energy should be useful to understand the complex interactions of integral monotopic proteins and strongly-bound peripheral membrane proteins with lipid membranes.« less

Gas Adsorption and Selectivity in Zeolitic Imidazolate Frameworks from First Principles Calculations

NASA Astrophysics Data System (ADS)

Ray, Keith; Olmsted, David; He, Ning; Houndonougbo, Yao; Laird, Brian; Asta, Mark

2012-02-01

Zeolitic Imidazolate Framework (ZIFs) are excellent candidate materials for carbon capture and gas separation. Here we employ the van der Waals density functional (vdW-DF) [1] in an analysis of the binding energetics for CO2, CH4 and N2 molecules in a set of ZIFs featuring different chemical functionalizations. We investigate multiple low-energy binding sites, which differ in their positions relative to functional groups on the imidazole linkers. In all cases an accurate treatment of van der Waals forces appears essential to provide reasonable binding energy magnitudes. We report results obtained from different parameterizations of the vdW-DF, providing comparisons between calculations and experimental values of the heat of adsorption [2]. This research is supported by the Energy Frontier Research Center ``Molecularly Engineered Energy Materials,'' funded by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Award Number DE-SC0001342. [1] M. Dion, H. Rydberg, E. Schroder, D. C. Langreth, B. I. Lundqvist, Phys. Rev. Let. 92, 246401 (2004) [2] W. Morris, B. Leung, H. Furukawa, O. K. Yaghi, N. He, H. Hayashi, Y. Houndonougbo, M. Asta, B. B. Laird, O. M. Yaghi, J. AM. CHEM. SOC. 2010, 132, 11006-11008

Coupled-cluster and explicitly correlated perturbation-theory calculations of the uracil anion.

PubMed

Bachorz, Rafał A; Klopper, Wim; Gutowski, Maciej

2007-02-28

A valence-type anion of the canonical tautomer of uracil has been characterized using explicitly correlated second-order Moller-Plesset perturbation theory (RI-MP2-R12) in conjunction with conventional coupled-cluster theory with single, double, and perturbative triple excitations. At this level of electron-correlation treatment and after inclusion of a zero-point vibrational energy correction, determined in the harmonic approximation at the RI-MP2 level of theory, the valence anion is adiabatically stable with respect to the neutral molecule by 40 meV. The anion is characterized by a vertical detachment energy of 0.60 eV. To obtain accurate estimates of the vertical and adiabatic electron binding energies, a scheme was applied in which electronic energy contributions from various levels of theory were added, each of them extrapolated to the corresponding basis-set limit. The MP2 basis-set limits were also evaluated using an explicitly correlated approach, and the results of these calculations are in agreement with the extrapolated values. A remarkable feature of the valence anionic state is that the adiabatic electron binding energy is positive but smaller than the adiabatic electron binding energy of the dipole-bound state.

Precise determination of neutron binding energy of 64Cu

NASA Astrophysics Data System (ADS)

Telezhnikov, S. A.; Granja, C.; Honzatko, J.; Pospisil, S.; Tomandl, I.

2016-05-01

The neutron binding energy in 64Cu has been accurately measured in thermal neutron capture. A composite target of natural Cu and NaCl was used on a high flux neutron beam using a large measuring time. The γ-ray spectrum emitted in the ( n, γ) reaction was measured with a HPGe detector in large statistics (up to 106 events per channel). Intrinsic limitations of HPGe detectors, which restrict the accuracy of energy calibration, were determined. The value B n of 64Cu was determined as 7915.867(24) keV.

Characterization of p-Type CdTe Electrodes in Acetonitrile/Electrolyte Solutions. Nearly Ideal Behavior from Reductive Surface Pretreatments.

DTIC Science & Technology

1983-06-30

using Ag conductive palnt and the entire assembly was mounted in glass tubing with ordinary epoxy leaving only the front crystal face, ...energy set, several eV higher than either Te2- or Teo (as measured for sputtered CdTe and Te, respectively) is assigned to TeO2 , the lowest stable...binding energy reported for TeO2 (575.9 eV). 33 The lower binding energy set of bands, lying midway between Teo and Te2 - , results from both Teo and

Computational study of the binding mechanism between farnesoid X receptor α and antagonist N-benzyl-N-(3-(tertbutyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) benzamide.

PubMed

Du, Juan; Qiu, Miaoxue; Guo, Lizhong; Yao, Xiaojun

2018-05-02

Farnesoid X receptor α (FXRα) is a bile acid-activated transcription factor, which plays important roles in the regulation of multiple metabolic processes. Development of FXR antagonist has revealed great potential for the treatment of metabolic disorders. The compound N-Benzyl-N-(3-(tertbutyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino). Benzamide (NDB) was recently determined as a selective antagonist of FXRα, while the detailed interaction mechanism is not well understood. In this study, the combined computational methods including molecular dynamics simulations, binding free energy calculation, and principal component analysis were utilized to investigate the effect of NDB on the dynamics behaviors and dimerization of FXRα The binding free energy calculation indicated that the protein dimerization increases NDB affinity and the binding of NDB also stabilizes the interaction between two subunits of FXRα. Further decomposition of the overall binding free energies into individual residues identifies several residues significant for NDB binding, including Leu291, Met294, Ala295, His298, Met332, Ser336, Ala452, and Leu455. It also suggests that the interactions of L289(A)-W458(B), W458(A)-L289(B), R459(A)-N461(B), and N461(A)-R459(B) are important for the dimer stabilization. This study provides a molecular basis for the understanding of binding mechanism between antagonist NDB and FXRα and valuable information for the novel FXR modulators design for the treatment of metabolic syndrome.

Exploring the selectivity of auto-inducer complex with LuxR using molecular docking, mutational studies and molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Rajamanikandan, Sundaraj; Srinivasan, Pappu

2017-03-01

Bacteria communicate with one another using extracellular signaling molecules called auto-inducers (AHLs), a process termed as quorum sensing. The quorum sensing process allows bacteria to regulate various physiological activities. In this regard, quorum sensing master regulator LuxR from Vibrio harveyi represents an attractive therapeutic target for the development of novel anti-quorum sensing agents. Eventhough the binding of AHL complex with LuxR is evidenced in earlier reports, but their mode of binding is not clearly determined. Therefore, in the present work, molecular docking, in silico mutational studies, molecular dynamics simulations and free energy calculations were performed to understand the selectivity of AHL into the binding site of LuxR. The results revealed that Asn133 and Gln137 residues play a crucial role in recognizing AHL more effectively into the binding site of LuxR with good binding free energy. In addition to that, the carbonyl group presents in the lactone ring and amide group of AHL plays a vital role in the formation of hydrogen bond interactions with the protein. Further, structure based virtual screening was performed using ChemBridge database to screen potent lead molecules against LuxR. 4-benzyl-2-pyrrolidinone and N-[2(1-cyclohexen-1-yl) enthyl]-N'(2-ethoxyphenyl) were selected based on dock score, binding affinity and mode of interactions with the receptor. Furthermore, binding free energy, density functional theory and ADME prediction were performed to rank the lead molecules. Thus, the identified lead molecules can be used for the development of anti-quorum sensing drugs.

Enzyme architecture: deconstruction of the enzyme-activating phosphodianion interactions of orotidine 5'-monophosphate decarboxylase.

PubMed

Goldman, Lawrence M; Amyes, Tina L; Goryanova, Bogdana; Gerlt, John A; Richard, John P

2014-07-16

The mechanism for activation of orotidine 5'-monophosphate decarboxylase (OMPDC) by interactions of side chains from Gln215 and Try217 at a gripper loop and R235, adjacent to this loop, with the phosphodianion of OMP was probed by determining the kinetic parameters k(cat) and K(m) for all combinations of single, double, and triple Q215A, Y217F, and R235A mutations. The 12 kcal/mol intrinsic binding energy of the phosphodianion is shown to be equal to the sum of the binding energies of the side chains of R235 (6 kcal/mol), Q215 (2 kcal/mol), Y217 (2 kcal/mol), and hydrogen bonds to the G234 and R235 backbone amides (2 kcal/mol). Analysis of a triple mutant cube shows small (ca. 1 kcal/mol) interactions between phosphodianion gripper side chains, which are consistent with steric crowding of the side chains around the phosphodianion at wild-type OMPDC. These mutations result in the same change in the activation barrier to the OMPDC-catalyzed reactions of the whole substrate OMP and the substrate pieces (1-β-D-erythrofuranosyl)orotic acid (EO) and phosphite dianion. This shows that the transition states for these reactions are stabilized by similar interactions with the protein catalyst. The 12 kcal/mol intrinsic phosphodianion binding energy of OMP is divided between the 8 kcal/mol of binding energy, which is utilized to drive a thermodynamically unfavorable conformational change of the free enzyme, resulting in an increase in (k(cat))(obs) for OMPDC-catalyzed decarboxylation of OMP, and the 4 kcal/mol of binding energy, which is utilized to stabilize the Michaelis complex, resulting in a decrease in (K(m))(obs).

Molecular dynamics simulation and binding free energy studies of novel leads belonging to the benzofuran class inhibitors of Mycobacterium tuberculosis Polyketide Synthase 13.

PubMed

Cruz, Jorddy N; Costa, José F S; Khayat, André S; Kuca, Kamil; Barros, Carlos A L; Neto, A M J C

2018-05-04

In this work, the binding mechanism of new Polyketide Synthase 13 (Pks13) inhibitors has been studied through molecular dynamics simulation and free energy calculations. The drug Tam1 and its analogs, belonging to the benzofuran class, were submitted to 100 ns simulations, and according to the results obtained for root mean square deviation, all the simulations converged from approximately 30 ns. For the analysis of backbone flotation, the root mean square fluctuations were plotted for the Cα atoms; analysis revealed that the greatest fluctuation occurred in the residues that are part of the protein lid domain. The binding free energy value (ΔG bind ) obtained for the Tam16 lead molecule was of -51.43 kcal/mol. When comparing this result with the ΔG bind values for the remaining analogs, the drug Tam16 was found to be the highest ranked: this result is in agreement with the experimental results obtained by Aggarwal and collaborators, where it was verified that the IC 50 for Tam16 is the smallest necessary to inhibit the Pks13 (IC 50  = 0.19 μM). The energy decomposition analysis suggested that the residues which most interact with inhibitors are: Ser1636, Tyr1637, Asn1640, Ala1667, Phe1670, and Tyr1674, from which the greatest energy contribution to Phe1670 was particularly notable. For the lead molecule Tam16, a hydrogen bond with the hydroxyl of the phenol not observed in the other analogs induced a more stable molecular structure. Aggarwal and colleagues reported this hydrogen bonding as being responsible for the stability of the molecule, optimizing its physic-chemical, toxicological, and pharmacokinetic properties.

Cooperative Binding of Cyclodextrin Dimers to Isoflavone Analogues Elucidated by Free Energy Calculations.

PubMed

Zhang, Haiyang; Tan, Tianwei; Hetényi, Csaba; Lv, Yongqin; van der Spoel, David

2014-04-03

Dimerization of cyclodextrin (CD) molecules is an elementary step in the construction of CD-based nanostructured materials. Cooperative binding of CD cavities to guest molecules facilitates the dimerization process and, consequently, the overall stability and assembly of CD nanostructures. In the present study, all three dimerization modes (head-to-head, head-to-tail, and tail-to-tail) of β-CD molecules and their binding to three isoflavone drug analogues (puerarin, daidzin, and daidzein) were investigated in explicit water surrounding using molecular dynamics simulations. Total and individual contributions from the binding partners and solvent environment to the thermodynamics of these binding reactions are quantified in detail using free energy calculations. Cooperative drug binding to two CD cavities gives an enhanced binding strength for daidzin and daidzein, whereas for puerarin no obvious enhancement is observed. Head-to-head dimerization yields the most stable complexes for inclusion of the tested isoflavones (templates) and may be a promising building block for construction of template-stabilized CD nanostructures. Compared to the case of CD monomers, the desolvation of CD dimers and entropy changes upon complexation prove to be influential factors of cooperative binding. Our results shed light on key points of the design of CD-based supramolecular assemblies. We also show that structure-based calculation of binding thermodynamics can quantify stabilization caused by cooperative effects in building blocks of nanostructured materials.

Exploring the binding mechanism of Heteroaryldihydropyrimidines and Hepatitis B Virus capsid combined 3D-QSAR and molecular dynamics.

PubMed

Tu, Jing; Li, Jiao Jiao; Shan, Zhi Jie; Zhai, Hong Lin

2017-01-01

The non-nucleoside drugs have been developed to treat HBV infection owing to their increased efficacy and lesser side effects, in which heteroaryldihydropyrimidines (HAPs) have been identified as effective inhibitors of HBV capsid. In this paper, the binding mechanism of HAPs targeting on HBV capsid protein was explored through three-dimensional quantitative structure-activity relationship, molecular dynamics and binding free energy decompositions. The obtained models of comparative molecular field analysis and comparative molecular similarity indices analysis enable the sufficient interpretation of structure-activity relationship of HAPs-HBV. The binding free energy analysis correlates with the experimental data. The computational results disclose that the non-polar contribution is the major driving force and Y132A mutation enhances the binding affinity for inhibitor 2 bound to HBV. The hydrogen bond interactions between the inhibitors and Trp102 help to stabilize the conformation of HAPs-HBV. The study provides insight into the binding mechanism of HAPs-HBV and would be useful for the rational design and modification of new lead compounds of HAP drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

Fluoxetine (Prozac) Binding to Serotonin Transporter Is Modulated by Chloride and Conformational Changes

PubMed Central

Tavoulari, Sotiria; Forrest, Lucy R.; Rudnick, Gary

2010-01-01

Serotonin transporter (SERT) is the main target for widely used antidepressant agents. Several of these drugs, including imipramine, citalopram, sertraline, and fluoxetine (Prozac), bound more avidly to SERT in the presence of Cl–. In contrast, Cl– did not enhance cocaine or paroxetine binding. A Cl– binding site recently identified in SERT, and shown to be important for Cl– dependent transport, was also critical for the Cl– dependence of antidepressant affinity. Mutation of the residues contributing to this site eliminated the Cl–-mediated affinity increase for imipramine and fluoxetine. Analysis of ligand docking to a single state of SERT indicated only small differences in the energy of interaction between bound ligands and Cl–. These differences in interaction energy cannot account for the affinity differences observed for Cl– dependence. However, fluoxetine binding led to a conformational change, detected by cysteine accessibility experiments, that was qualitatively different from that induced by cocaine or other ligands. Given the known Cl– requirement for serotonin-induced conformational changes, we propose that Cl– binding facilitates conformational changes required for optimal binding of fluoxetine and other antidepressant drugs. PMID:19641126

Small Au clusters on a defective MgO(1 0 0) surface

NASA Astrophysics Data System (ADS)

Barcaro, Giovanni; Fortunelli, Alessandro

2008-05-01

The lowest energy structures of small T]>rndm where rndm is a random number (Metropolis criterion), the new configuration is accepted, otherwise the old configuration is kept, and the process is iterated. For each size we performed 3-5 BH runs, each one composed of 20-25 Monte Carlo steps, using a value of 0.5 eV as kT in the Metropolis criterion. Previous experience [13-15] shows that this is sufficient to single out the global minimum for adsorbed clusters of this size, and that the BH approach is more efficient as a global optimization algorithm than other techniques such as simulated annealing [18]. The MgO support was described via an (Mg 12O 12) cluster embedded in an array of ±2.0 a.u. point charges and repulsive pseudopotentials on the positive charges in direct contact with the cluster (see Ref. [15] for more details on the method). The atoms of the oxide cluster and the point charges were located at the lattice positions of the MgO rock-salt bulk structure using the experimental lattice constant of 4.208 Å. At variance with the ), evaluated by subtracting the energy of the oxide surface and of the metal cluster, both frozen in their interacting configuration, from the value of the total energy of the system, and by taking the absolute value; (ii) the binding energy of the metal cluster (E), evaluated by subtracting the energy of the isolated metal atoms from the total energy of the metal cluster in its interacting configuration, and by taking the absolute value; (iii) the metal cluster distortion energy (E), which corresponds to the difference between the energy of the metal cluster in the configuration interacting with the surface minus the energy of the cluster in its lowest-energy gas-phase configuration (a positive quantity); (iv) the oxide distortion energy (ΔE), evaluated subtracting the energy of the relaxed isolated defected oxide from the energy of the isolated defected oxide in the interacting configuration; and (v) the total binding energy (E), which is the sum of the binding energy of the metal cluster, the adhesion energy and the oxide distortion energy (E=E+E-ΔE). Note that the total binding energy of gas-phase clusters in their global minima can be obtained by summing E+E.

Binding of an adatom to a simple metal surface

NASA Technical Reports Server (NTRS)

Huntington, H. B.; Turk, L. A.; White, W. W., III

1975-01-01

The density functional formalism of Hohenberg and Kohn is used to investigate the energies, charge densities and forces which hold an adatom on the surface of a simple metal. The valence wavefunction of the adatom is fitted to the Herman-Skillman solutions at large distance and is simplified somewhat in the core region. The field of the ion is represented by the Ashcroft pseudopotential. For the metal the jellium model is used. Detailed calculations are carried out for a sodium adatom on a sodium surface. Simply juxtaposing adatom and surface gives a binding energy of about 1/3 eV. This value is approximately twice the surface energy per atom in the close-packed plane. Charge redistributions as determined variationally increase the binding energy by about 10%. The equilibrium distance for the adatom turns out to be 1.66 A from the surface, as compared with 1.52 A, the observed value for one-half the distance between the close-packed planes.

Alignment of RNA molecules: Binding energy and statistical properties of random sequences

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

Valba, O. V., E-mail: valbaolga@gmail.com; Nechaev, S. K., E-mail: sergei.nechaev@gmail.com; Tamm, M. V., E-mail: thumm.m@gmail.com

2012-02-15

A new statistical approach to the problem of pairwise alignment of RNA sequences is proposed. The problem is analyzed for a pair of interacting polymers forming an RNA-like hierarchical cloverleaf structures. An alignment is characterized by the numbers of matches, mismatches, and gaps. A weight function is assigned to each alignment; this function is interpreted as a free energy taking into account both direct monomer-monomer interactions and a combinatorial contribution due to formation of various cloverleaf secondary structures. The binding free energy is determined for a pair of RNA molecules. Statistical properties are discussed, including fluctuations of the binding energymore » between a pair of RNA molecules and loop length distribution in a complex. Based on an analysis of the free energy per nucleotide pair complexes of random RNAs as a function of the number of nucleotide types c, a hypothesis is put forward about the exclusivity of the alphabet c = 4 used by nature.« less

Free Energy Wells and Barriers to Ion Transport Across Membranes

NASA Astrophysics Data System (ADS)

Rempe, Susan

2014-03-01

The flow of ions across cellular membranes is essential to many biological processes. Ion transport is also important in synthetic materials used as battery electrolytes. Transport often involves specific ions and fast conduction. To achieve those properties, ion conduction pathways must solvate specific ions by just the ``right amount.'' The right amount of solvation avoids ion traps due to deep free energy wells, and avoids ion block due to high free energy barriers. Ion channel proteins in cellular membranes demonstrate this subtle balance in solvation of specific ions. Using ab initio molecular simulations, we have interrogated the link between binding site structure and ion solvation free energies in biological ion binding sites. Our results emphasize the surprisingly important role of the environment that surrounds ion-binding sites for fast transport of specific ions. We acknowledge support from Sandia's LDRD program. Sandia National Labs is a multi-program laboratory operated by Sandia Corp., a wholly owned subsidiary of Lockheed Martin Corp., for the US DOE's NNSA under contract DE-AC04-94AL85000.

Calculation of protein-ligand binding affinities.

PubMed

Gilson, Michael K; Zhou, Huan-Xiang

2007-01-01

Accurate methods of computing the affinity of a small molecule with a protein are needed to speed the discovery of new medications and biological probes. This paper reviews physics-based models of binding, beginning with a summary of the changes in potential energy, solvation energy, and configurational entropy that influence affinity, and a theoretical overview to frame the discussion of specific computational approaches. Important advances are reported in modeling protein-ligand energetics, such as the incorporation of electronic polarization and the use of quantum mechanical methods. Recent calculations suggest that changes in configurational entropy strongly oppose binding and must be included if accurate affinities are to be obtained. The linear interaction energy (LIE) and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) methods are analyzed, as are free energy pathway methods, which show promise and may be ready for more extensive testing. Ultimately, major improvements in modeling accuracy will likely require advances on multiple fronts, as well as continued validation against experiment.

Sirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins

PubMed Central

Kang, Hyeog; Oka, Shinichi; Lee, Duck-Yeon; Park, Junhong; Aponte, Angel M.; Jung, Young-Sang; Bitterman, Jacob; Zhai, Peiyong; He, Yi; Kooshapur, Hamed; Ghirlando, Rodolfo; Tjandra, Nico; Lee, Sean B.; Kim, Myung K.; Sadoshima, Junichi; Chung, Jay H.

2017-01-01

Sirt1 is an NAD+-dependent protein deacetylase that regulates many physiological functions, including stress resistance, adipogenesis, cell senescence and energy production. Sirt1 can be activated by energy deprivation, but the mechanism is poorly understood. Here, we report that Sirt1 is negatively regulated by ATP, which binds to the C-terminal domain (CTD) of Sirt1. ATP suppresses Sirt1 activity by impairing the CTD's ability to bind to the deacetylase domain as well as its ability to function as the substrate recruitment site. ATP, but not NAD+, causes a conformational shift to a less compact structure. Mutations that prevent ATP binding increase Sirt1's ability to promote stress resistance and inhibit adipogenesis under high-ATP conditions. Interestingly, the CTD can be attached to other proteins, thereby converting them into energy-regulated proteins. These discoveries provide insight into how extreme energy deprivation can impact Sirt1 activity and underscore the complex nature of Sirt1 structure and regulation. PMID:28504272

Free energy surfaces for the interaction of D-glucose with planar aromatic groups in aqueous solution

NASA Astrophysics Data System (ADS)

Wohlert, Jakob; Schnupf, Udo; Brady, John W.

2010-10-01

Multidimensional potentials of mean force for the interactions in aqueous solution of both anomers of D-glucopyranose with two planar aromatic molecules, indole and para-methyl-phenol, have been calculated using molecular dynamics simulations with umbrella sampling and were subsequently used to estimate binding free energies. Indole and para-methyl-phenol serve as models for the side chains of the amino acids tryptophan and tyrosine, respectively. In all cases, a weak affinity between the glucose molecules and the flat aromatic surfaces was found. The global minimum for these interactions was found to be for the case when the pseudoplanar face of β-D-glucopyranose is stacked against the planar surfaces of the aromatic residues. The calculated binding free energies are in good agreement with both experiment and previous simulations. The multidimensional free energy maps suggest a mechanism that could lend kinetic stability to the complexes formed by sugars bound to sugar-binding proteins.

Interpretation of the silver L X-ray spectrum

NASA Technical Reports Server (NTRS)

Chen, M. H.; Crasemann, B.; Aoyagi, M.; Mark, H.

1977-01-01

Silver L X-ray energies were calculated using theoretical binding energies from relaxed orbital relativistic Hartree-Fock-Slater calculations. Theoretical X-ray energies are compared with experimental results.

Design, synthesis and antimalarial screening of some hybrid 4-aminoquinoline-triazine derivatives against pf-DHFR-TS.

PubMed

Sahu, Supriya; Ghosh, Surajit Kumar; Kalita, Junmoni; Dutta, Mayurakhi; Bhat, Hans Raj

2016-04-01

Existing antifolate antimalarial drugs have shown resistance due to the mutations at some amino acid positions of Plasmodium falciparum DHFR-TS. In the present study, to overcome this resistance, a new series of hybrid 4-aminoquinoline-triazine derivatives were designed and docked into the active site of Pf-DHFR-TS (PDB i.d. 1J3K) using validated CDOCKER protocol. Binding energy was calculated by applying CHARMm forcefield. Binding energy and the pattern of interaction of the docked compounds were analysed. Fifteen compounds were selected for synthesis based on their binding energy values and docking poses. Synthesized compounds were characterised by FTIR, (1)H NMR, (13)C NMR, mass spectroscopy and were screened for antimalarial activity against 3D7 strain of Plasmodium falciparum. Copyright © 2016 Elsevier Inc. All rights reserved.

Total-energy Assisted Tight-binding Method Based on Local Density Approximation of Density Functional Theory

NASA Astrophysics Data System (ADS)

Fujiwara, Takeo; Nishino, Shinya; Yamamoto, Susumu; Suzuki, Takashi; Ikeda, Minoru; Ohtani, Yasuaki

2018-06-01

A novel tight-binding method is developed, based on the extended Hückel approximation and charge self-consistency, with referring the band structure and the total energy of the local density approximation of the density functional theory. The parameters are so adjusted by computer that the result reproduces the band structure and the total energy, and the algorithm for determining parameters is established. The set of determined parameters is applicable to a variety of crystalline compounds and change of lattice constants, and, in other words, it is transferable. Examples are demonstrated for Si crystals of several crystalline structures varying lattice constants. Since the set of parameters is transferable, the present tight-binding method may be applicable also to molecular dynamics simulations of large-scale systems and long-time dynamical processes.

Comparison of molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) and molecular mechanics-three-dimensional reference interaction site model (MM-3D-RISM) method to calculate the binding free energy of protein-ligand complexes: Effect of metal ion and advance statistical test

NASA Astrophysics Data System (ADS)

Pandey, Preeti; Srivastava, Rakesh; Bandyopadhyay, Pradipta

2018-03-01

The relative performance of MM-PBSA and MM-3D-RISM methods to estimate the binding free energy of protein-ligand complexes is investigated by applying these to three proteins (Dihydrofolate Reductase, Catechol-O-methyltransferase, and Stromelysin-1) differing in the number of metal ions they contain. None of the computational methods could distinguish all the ligands based on their calculated binding free energies (as compared to experimental values). The difference between the two comes from both polar and non-polar part of solvation. For charged ligand case, MM-PBSA and MM-3D-RISM give a qualitatively different result for the polar part of solvation.

DFTB3: Extension of the self-consistent-charge density-functional tight-binding method (SCC-DFTB).

PubMed

Gaus, Michael; Cui, Qiang; Elstner, Marcus

2012-04-10

The self-consistent-charge density-functional tight-binding method (SCC-DFTB) is an approximate quantum chemical method derived from density functional theory (DFT) based on a second-order expansion of the DFT total energy around a reference density. In the present study we combine earlier extensions and improve them consistently with, first, an improved Coulomb interaction between atomic partial charges, and second, the complete third-order expansion of the DFT total energy. These modifications lead us to the next generation of the DFTB methodology called DFTB3, which substantially improves the description of charged systems containing elements C, H, N, O, and P, especially regarding hydrogen binding energies and proton affinities. As a result, DFTB3 is particularly applicable to biomolecular systems. Remaining challenges and possible solutions are also briefly discussed.

Role of polyols (erythritol, xylitol and sorbitol) on the structural stabilization of collagen

NASA Astrophysics Data System (ADS)

Usha, R.; Raman, S. Sundar; Subramanian, V.; Ramasami, T.

2006-10-01

The effect of erythritol, xylitol and sorbitol on monomeric collagen solution was evaluated with melting temperature, fluorescence studies, conformational stability and binding energy. The emission intensity and the melting temperature increase as the chain length of polyols increases. Circular dichroism (CD) results indicate the possibility of aggregation of collagen in the presence of polyols. The interaction between collagen and polyols were calculated using binding energy, RMS deviation with collagen like models. Molecular mechanics calculations suggest that polyols bind well with collagen models, that have serine in the X position. The stability of collagen decreases as the number of carbon atoms present in the polyols increases.

The nature of cation-pi binding: interactions between tetramethylammonium ion and benzene in aqueous solution.

PubMed Central

Gao, J; Chou, L W; Auerbach, A

1993-01-01

A combined quantum mechanical and molecular mechanical Monte Carlo simulation method was used to determine the free energy of binding between tetramethylammonium ion (TMA+) and benzene in water. The computed free energy as a function of distance (the potential of mean force) has two minima that represent contact and solvent-separated complexes. These species are separated by a broad barrier of about 3 kJ/mol. The results are in good accord with experimental data and suggest that TMA+ binds to benzene more favorably than to chloride ion, with an association constant of about 0.8 M-1. Images FIGURE 2 PMID:8369448

Navigating ligand protein binding free energy landscapes: universality and diversity of protein folding and molecular recognition mechanisms

NASA Astrophysics Data System (ADS)

Verkhivker, Gennady M.; Rejto, Paul A.; Bouzida, Djamal; Arthurs, Sandra; Colson, Anthony B.; Freer, Stephan T.; Gehlhaar, Daniel K.; Larson, Veda; Luty, Brock A.; Marrone, Tami; Rose, Peter W.

2001-03-01

Thermodynamic and kinetic aspects of ligand-protein binding are studied for the methotrexate-dihydrofolate reductase system from the binding free energy profile constructed as a function of the order parameter. Thermodynamic stability of the native complex and a cooperative transition to the unique native structure suggest the nucleation kinetic mechanism at the equilibrium transition temperature. Structural properties of the transition state ensemble and the ensemble of nucleation conformations are determined by kinetic simulations of the transmission coefficient and ligand-protein association pathways. Structural analysis of the transition states and the nucleation conformations reconciles different views on the nucleation mechanism in protein folding.

Carbohydrate binding specificity of pea lectin studied by NMR spectroscopy and molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Cheong, Youngjoo; Shim, Gyuchang; Kang, Dongil; Kim, Yangmee

1999-02-01

The conformational details of Man( α1,6)Man( α)OMe are investigated through NMR spectroscopy in conjunction with molecular modeling. The lowest energy structure (M1) in the adiabatic energy map calculated with a dielectric constant of 50 has glycosidic dihedral angles of φ=-60°, ψ=180° and ω=180°. The other low energy structure (M2) has glycosidic dihedral angles of φ=-60°, ψ=180° and ω=-60°. Molecular dynamics simulations and NMR experiments prove that Man( α1,6)Man( α)OMe in the free form exists with conformational averaging of M1 and M2 conformers predominantly. Molecular dynamics simulations of the pea lectin-carbohydrate complex with explicit water molecules starting from the X-ray crystallographic structure of pea lectin show that the protein-carbohydrate interaction centers mainly on the hydrogen bonds and van der Waals interactions between protein and carbohydrate. From the molecular dynamics simulation, it is found that the M1 structure can bind to pea lectin better than the M2 structure. The origin of this selectivity is the water- mediated hydrogen bond interactions between the remote mannose and the binding site of pea lectin as well as the direct hydrogen bond interaction between the terminal mannose and pea lectin. Extensive networks of interactions in the carbohydrate binding site and the metal binding site are important in maintaining the carbohydrate binding properties of pea lectin. Especially, the predominant factors of mannose binding specificity of pea lectin are the hydrogen bond interactions between the 4th hydroxyl groups of the terminal sugar ring and the side chains of Asp-81 and Asn-125 in the carbohydrate binding site, and the additional interactions between these side chains of Asp-81 and Asn-125 and the calcium ion in the metal binding site of pea lectin.

Energetic basis for the molecular-scale organization of bone

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

Tao, Jinhui; Battle, Keith C.; Pan, Haihua

2014-12-24

The remarkable properties of bone derive from a highly organized arrangement of co-aligned nm-scale apatite platelets within a fibrillar collagen matrix. The origin of this arrangement is poorly understood and the crystal structures of hydroxyapatite (HAP) and the non-mineralized collagen fibrils alone do not provide an explanation. Moreover, little is known about collagen-apatite interaction energies, which should strongly influence both the molecular-scale organization and the resulting mechanical properties of the composite. We investigated collagen-mineral interactions by combining dynamic force spectroscopy (DFS) measurements of binding energies with molecular dynamics (MD) simulations of binding and AFM observations of collagen adsorption on singlemore » crystals of calcium phosphate for four mineral phases of potential importance in bone formation. In all cases, we observe a strong preferential orientation of collagen binding, but comparison between the observed orientations and TEM analyses native tissues shows only calcium-deficient apatite (CDAP) provides an interface with collagen that is consistent with both. MD simulations predict preferred collagen orientations that agree with observations and results from both MD and DFS reveal large values for the binding energy due to multiple binding sites. These findings reconcile apparent contradictions inherent in a hydroxyapatite or carbonated apatite (CAP) model of bone mineral and provide an energetic rationale for the molecular scale organization of bone.« less

Molecular modeling and molecular dynamics simulation studies on the interactions of hydroxylated polychlorinated biphenyls with estrogen receptor-β.

PubMed

Li, Xiaolin; Ye, Li; Wang, Xiaoxiang; Shi, Wei; Qian, XiangPing; Zhu, YongLiang; Yu, HongXia

2013-10-01

Endocrine-disrupting chemicals have attracted great concern. As major metabolites of polychlorinated biphenyls (PCBs), hydroxylated polychlorinated biphenyls (HO-PCBs) may disrupt estrogen hormone status because of their structural similarity to estrogen endogenous compounds. However, interactions between HO-PCBs and estrogen receptors (ERs) are not fully understood. In the present work, a molecular modeling study combining molecular docking, molecular dynamics simulations, and binding free energy calculations was performed to characterize the interactions of three HO-PCBs (4'-HO-PCB50, 2'-HO-PCB65, and 4'-HO-PCB69) having much different estrogenic activities with ERβ. Docking results showed that binding between ligands and ERβ was stabilized by hydrogen bond and hydrophobic interactions. The binding free energies of three ligands with ERβ were calculated, and further binding free energy decomposition analysis indicated that the dominating driving force of the binding between the ligands and ERβ was the van der Waals interaction. Some key residues, such as Leu298, Phe356, Gly472, His475, and Leu476, played important roles in ligand-receptor interactions by forming hydrophobic and hydrogen bond interactions with ligands. The results may be beneficial to increase understanding of the interactions between HO-PCBs and ERβ.

Graphane versus graphene: a computational investigation of the interaction of nucleobases, aminoacids, heterocycles, small molecules (CO2, H2O, NH3, CH4, H2), metal ions and onium ions.

PubMed

Umadevi, Deivasigamani; Narahari Sastry, G

2015-11-11

Graphane has emerged as a two-dimensional hydrocarbon with interesting physical properties and potential applications. Understanding the interaction of graphane with various molecules and ions is crucial to appreciate its potential applications. We investigated the interaction of nucleobases, aminoacids, saturated and unsaturated heterocycles, small molecules, metal ions and onium ions with graphane by using density functional theory calculations. The preferred orientations of these molecules and ions on the graphane surface have been analysed. The binding energies of graphane with these molecules have been compared with the corresponding binding energies of graphene. Our results reveal that graphane forms stable complexes with all the molecules and ions yet showing lesser binding affinity when compared to graphene. As an exemption, the preferential strong binding of H2O with graphane than graphene reveals the fact that graphane is more hydrophilic than graphene. Charge transfer between graphane and the molecules and ions have been found to be an important factor in determining the binding strength of the complexes. The effect of the interaction of these molecules and ions on the HOMO-LUMO energy gap of graphane has also been investigated.

Energetic basis for the molecular-scale organization of bone

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

Tao, Jinhui; Battle, Keith C.; Pan, Haihua

The remarkable properties of bone derive from a highly organized arrangement of co-aligned nm-scale apatite platelets within a fibrillar collagen matrix. The origin of this arrangement is poorly understood and the crystal structures of hydroxyapatite (HAP) and the non-mineralized collagen fibrils alone do not provide an explanation. Moreover, little is known about collagen-apatite interaction energies, which should strongly influence both the molecular-scale organization and the resulting mechanical properties of the composite. We investigated collagen-mineral interactions by combining dynamic force spectroscopy (DFS) measurements of binding energies with molecular dynamics (MD) simulations of binding and AFM observations of collagen adsorption on singlemore » crystals of calcium phosphate for four mineral phases of potential importance in bone formation. In all cases, we observe a strong preferential orientation of collagen binding, but comparison between the observed orientations and TEM analyses native tissues shows only calcium-deficient apatite (CDAP) provides an interface with collagen that is consistent with both. MD simulations predict preferred collagen orientations that agree with observations and results from both MD and DFS reveal large values for the binding energy due to multiple binding sites. These findings reconcile apparent contradictions inherent in a hydroxyapatite or carbonated apatite (CAP) model of bone mineral and provide an energetic rationale for the molecular scale organization of bone.« less

Systematic optimization model and algorithm for binding sequence selection in computational enzyme design

PubMed Central

Huang, Xiaoqiang; Han, Kehang; Zhu, Yushan

2013-01-01

A systematic optimization model for binding sequence selection in computational enzyme design was developed based on the transition state theory of enzyme catalysis and graph-theoretical modeling. The saddle point on the free energy surface of the reaction system was represented by catalytic geometrical constraints, and the binding energy between the active site and transition state was minimized to reduce the activation energy barrier. The resulting hyperscale combinatorial optimization problem was tackled using a novel heuristic global optimization algorithm, which was inspired and tested by the protein core sequence selection problem. The sequence recapitulation tests on native active sites for two enzyme catalyzed hydrolytic reactions were applied to evaluate the predictive power of the design methodology. The results of the calculation show that most of the native binding sites can be successfully identified if the catalytic geometrical constraints and the structural motifs of the substrate are taken into account. Reliably predicting active site sequences may have significant implications for the creation of novel enzymes that are capable of catalyzing targeted chemical reactions. PMID:23649589

Binding analysis for interaction of diacetylcurcumin with β-casein nanoparticles by using fluorescence spectroscopy and molecular docking calculations

NASA Astrophysics Data System (ADS)

Mehranfar, Fahimeh; Bordbar, Abdol-Khalegh; Fani, Najme; Keyhanfar, Mehrnaz

2013-11-01

The interaction of diacetylcurcumin (DAC), as a novel synthetic derivative of curcumin, with bovine β-casein (an abundant milk protein that is highly amphiphilic and self assembles into stable micellar nanoparticles in aqueous solution) was investigated using fluorescence quenching experiments, Forster energy transfer measurements and molecular docking calculations. The fluorescence quenching measurements revealed the presence of a single binding site on β-casein for DAC with the binding constant value equals to (4.40 ± 0.03) × 104 M-1. Forster energy transfer measurements suggested that the distance between bound DAC and Trp143 residue is higher than the respective critical distance, hence, the static quenching is more likely responsible for fluorescence quenching other than the mechanism of non-radiative energy transfer. Our results from molecular docking calculations indicated that binding of DAC to β-casein predominantly occurred through hydrophobic contacts in the hydrophobic core of protein. Additionally, in vitro investigation of the cytotoxicity of free DAC and DAC-β-casein complex in human breast cancer cell line MCF7 revealed the higher cytotoxic effect of DAC-β-casein complex.

Bacterial protease uses distinct thermodynamic signatures for substrate recognition.

PubMed

Bezerra, Gustavo Arruda; Ohara-Nemoto, Yuko; Cornaciu, Irina; Fedosyuk, Sofiya; Hoffmann, Guillaume; Round, Adam; Márquez, José A; Nemoto, Takayuki K; Djinović-Carugo, Kristina

2017-06-06

Porphyromonas gingivalis and Porphyromonas endodontalis are important bacteria related to periodontitis, the most common chronic inflammatory disease in humans worldwide. Its comorbidity with systemic diseases, such as type 2 diabetes, oral cancers and cardiovascular diseases, continues to generate considerable interest. Surprisingly, these two microorganisms do not ferment carbohydrates; rather they use proteinaceous substrates as carbon and energy sources. However, the underlying biochemical mechanisms of their energy metabolism remain unknown. Here, we show that dipeptidyl peptidase 11 (DPP11), a central metabolic enzyme in these bacteria, undergoes a conformational change upon peptide binding to distinguish substrates from end products. It binds substrates through an entropy-driven process and end products in an enthalpy-driven fashion. We show that increase in protein conformational entropy is the main-driving force for substrate binding via the unfolding of specific regions of the enzyme ("entropy reservoirs"). The relationship between our structural and thermodynamics data yields a distinct model for protein-protein interactions where protein conformational entropy modulates the binding free-energy. Further, our findings provide a framework for the structure-based design of specific DPP11 inhibitors.

Enantiospecific adsorption of propranolol enantiomers on naturally chiral copper surface: A molecular dynamics simulation investigation

NASA Astrophysics Data System (ADS)

Sedghamiz, Tahereh; Bahrami, Maryam; Ghatee, Mohammad Hadi

2017-04-01

Adsorption of propranolol enantiomers on naturally chiral copper (Cu(3,1,17)S) and achiral copper (Cu(100)) surfaces were studied by molecular dynamics simulation to unravel the features of adsorbate-adsorbent enantioselectivity. Adsorption of S- and R-propranolol on Cu(3,1,17)S terraces (with 100 plane) leads mainly to endo- and exo-conformers, respectively. Simulated pair correlation function (g(r)) and mean square displacement (MSD) were analyzed to identify adsorption sites of enantiomers on Cu(3,1,17)S substrate surface, and their simulated binding energies were used to access the adsorption strength. According to (g(r)), R-propranolol adsorbs via naphtyl group while S-propranolol mainly adsorbs through chain group. R-enantiomer binds more tightly to the chiral substrate surface than S-enantiomer as indicated by a higher simulated binding energy by 2.74 kJ mol-1 per molecule. The difference in binding energies of propranolol enantiomers on naturally chiral Cu(3,1,17)S is almost six times larger than on the achiral Cu(100) surface, which substantiates the appreciably strong specific enantioselective adsorption on the former surface.

Donor states in a semimagnetic Cd1 -xinMnxin Te /Cd1 -xoutMnxout Te Double Quantum Well

NASA Astrophysics Data System (ADS)

Kalpana, Panneer Selvam; Nithiananthi, Perumal; Jayakumar, Kalyanasundaram

2017-02-01

The theoretical investigation has been carried out on the binding energy of donor associated with the electrons confined in a Cd1 -xinMnxin Te /Cd1 -xoutMnxout Te Double Quantum Well (DQW) as a function of central barrier width for various well dimensions and impurity locations in the barrier and the well. The magnetic field can act as a tool to continuously change the interwell coupling inside this DQW systems and its effect on donor binding has also been studied. Moreover, the polaronic corrections, which is due to the strong exchange interaction between the magnetic moment of Mn2+ ion and the spin of the confined carrier, to the binding energy of the hydrogenic donor impurity has also been estimated with and without the application of magnetic field. The binding energy of the donor impurity is determined by solving the Schrodinger equation variationally in the effective mass approximation and the effect due to Bound Magnetic Polaron (BMP) is included using mean field theory with the modified Brillouin function. The results are reported and discussed.

Nuclear binding energy using semi empirical mass formula

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

Ankita,, E-mail: ankitagoyal@gmail.com; Suthar, B.

2016-05-06

In the present communication, semi empirical mass formula using the liquid drop model has been presented. Nuclear binding energies are calculated using semi empirical mass formula with various constants given by different researchers. We also compare these calculated values with experimental data and comparative study for finding suitable constants is added using the error plot. The study is extended to find the more suitable constant to reduce the error.

Short-range correlations in carbon-12, oxygen-16, and neon-20: Intrinsic properties

NASA Technical Reports Server (NTRS)

Braley, R. C.; Ford, W. F.; Becker, R. L.; Patterson, M. R.

1972-01-01

The Brueckner-Hartree-Fock (BHF) method has been applied to nuclei whose intrinsic structure is nonspherical. Reaction matrix elements were calculated as functions of starting energy for the Hamada-Johnston interaction using the Pauli operator appropriate to O-16 and a shifted oscillator spectrum for virtual excited states. Binding energies, single particle energies, radii, and shape deformations of the intrinsic state, in ordinary as well as renormalized BHF, are discussed and compared with previous HF studies and with experiment when possible. Results are presented for C-12, 0-16 and Ne-20. It is found that the binding energies and radii are too small, but that separation energies are well reproduced when the renormalized theory is used.

Tuning exciton energy and fine-structure splitting in single InAs quantum dots by applying uniaxial stress

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

Su, Dan; Dou, Xiuming; Wu, Xuefei

2016-04-15

Exciton and biexciton emission energies as well as excitonic fine-structure splitting (FSS) in single InAs/GaAs quantum dots (QDs) have been continuously tuned in situ in an optical cryostat using a developed uniaxial stress device. With increasing tensile stress, the red shift of excitonic emission is up to 5 nm; FSS decreases firstly and then increases monotonically, reaching a minimum value of approximately 10 μeV; biexciton binding energy decreases from 460 to 106 μeV. This technique provides a simple and convenient means to tune QD structural symmetry, exciton energy and biexciton binding energy and can be used for generating entangled andmore » indistinguishable photons.« less

KLK14 interactions with HAI-1 and HAI-2 serine protease inhibitors: A molecular dynamics and relative free-energy calculations study.

PubMed

Solís-Calero, Christian; Carvalho, Hernandes F

2017-11-01

Kallikrein 14 (KLK14) is a serine protease linked to several pathologies including prostate cancer and positively correlates with Gleason score. Though KLK14 functioning in cancer is poorly understood, it has been implicated in HGF/Met signaling, given that KLK14 proteolytically inhibits HGF activator-inhibitor 1 (HAI-1), which strongly inhibits pro-HGF activators, thereby contributing to tumor progression. In this work, KLK14 binding to either hepatocyte growth factor activator inhibitor type-1 (HAI-1) or type-2 (HAI-2) was essayed using homology modeling, molecular dynamic simulations and free-energy calculations through MM/PBSA and MM/GBSA. KLK14 was successfully modeled. Calculated free energies suggested higher binding affinity for the KLK14/HAI-1 interaction than for KLK14/HAI-2. This difference in binding affinity is largely explained by the higher stability of the hydrogen-bond networks in KLK14/HAI-1 along the simulation trajectory. A key arginine residue in both HAI-1 and HAI-2 is responsible for their interaction with the S1 pocket in KLK14. Additionally, MM/GBSA free-energy decomposition postulates that KLK14 Asp174 and Trp196 are hotspots for binding HAI-1 and HAI-2. © 2017 International Federation for Cell Biology.

Understanding the impact of Fc glycosylation on its conformational changes by molecular dynamics simulations and bioinformatics.

PubMed

Zhang, Yubo

2015-12-01

N-linked glycosylation of Fc at N297 plays an important role in its effector function, aberrance of which would cause disease pathogenesis. Here, we performed all-atom molecular dynamics simulations to explore the effects of Fc glycosylation on its dynamics behaviors. Firstly, equilibrium simulations suggested that Fc deglycosylation was able to induce residual flexibility in its CH2 domain. Besides, the free energy landscape revealed three minimum energy wells in deglycosylated Fc, representing its "open", "semi-closed" and "closed" states. However, we could only observe the "open" state of glycosylated Fc. Supportively, principal component analysis emphasized the prominent motion of delyclosylated Fc and dynamically depicted how it changed from the "open" state to its "closed" state. Secondly, we studied the recognition mechanism of the Fc binding to its partners. Energy decomposition analysis identified key residues of Fc to recognize its two partners P13 and P34. Evidently, electrostatic potential surfaces showed that electrostatic attraction helped to stabilize the interaction between Fc and its partners. Also, relative binding free energies explained different binding affinities in Fc-P13 and Fc-P34. Collectively, these results together provided the structural basis for understanding conformational changes of deglycosylated Fc and the recognition mechanism of the Fc binding to its partners.

Reducing exciton binding energy by increasing thin film permittivity: an effective approach to enhance exciton separation efficiency in organic solar cells.

PubMed

Leblebici, Sibel Y; Chen, Teresa L; Olalde-Velasco, Paul; Yang, Wanli; Ma, Biwu

2013-10-23

Photocurrent generation in organic solar cells requires that excitons, which are formed upon light absorption, dissociate into free carriers at the interface of electron acceptor and donor materials. The high exciton binding energy, arising from the low permittivity of organic semiconductor films, generally causes low exciton separation efficiency and subsequently low power conversion efficiency. We demonstrate here, for the first time, that the exciton binding energy in B,O-chelated azadipyrromethene (BO-ADPM) donor films is reduced by increasing the film permittivity by blending the BO-ADPM donor with a high dielectric constant small molecule, camphoric anhydride (CA). Various spectroscopic techniques, including impedance spectroscopy, photon absorption and emission spectroscopies, as well as X-ray spectroscopies, are applied to characterize the thin film electronic and photophysical properties. Planar heterojunction solar cells are fabricated with a BO-ADPM:CA film as the electron donor and C60 as the acceptor. With an increase in the dielectric constant of the donor film from ∼4.5 to ∼11, the exciton binding energy is reduced and the internal quantum efficiency of the photovoltaic cells improves across the entire spectrum, with an ∼30% improvement in the BO-ADPM photoactive region.

Hydrogen adsorption in HKUST-1: a combined inelastic neutron scattering and first-principles study.

PubMed

Brown, Craig M; Liu, Yun; Yildirim, Taner; Peterson, Vanessa K; Kepert, Cameron J

2009-05-20

Hydrogen adsorption in high surface area nanoporous coordination polymers has attracted a great deal of interest in recent years due to the potential applications in energy storage. Here we present combined inelastic neutron scattering measurements and detailed first-principles calculations aimed at unraveling the nature of hydrogen adsorption in HKUST-1 (Cu3(1,3,5-benzenetricarboxylate)2), a metal-organic framework (MOF) with unsaturated metal centers. We reveal that, in this system, the major contribution to the overall binding comes from the classical Coulomb interaction which is not screened due to the open metal site; this explains the relatively high binding energies and short H2-metal distances observed in MOFs with exposed metal sites as compared to traditional ones. Despite the short distances, there is no indication of an elongation of the H-H bond for the bound H2 molecule at the metal site. We find that both the phonon and rotational energy levels of the hydrogen molecule are closely similar, making the interpretation of the inelastic neutron scattering data difficult. Finally, we show that the orientation of H2 has a surprisingly large effect on the binding potential, reducing the classical binding energy by almost 30%. The implication of these results for the development of MOF materials for better hydrogen storage is discussed.

Hydrogen adsorption in HKUST-1: a combined inelastic neutron scattering and first-principles study

NASA Astrophysics Data System (ADS)

Brown, Craig M.; Liu, Yun; Yildirim, Taner; Peterson, Vanessa K.; Kepert, Cameron J.

2009-05-01

Hydrogen adsorption in high surface area nanoporous coordination polymers has attracted a great deal of interest in recent years due to the potential applications in energy storage. Here we present combined inelastic neutron scattering measurements and detailed first-principles calculations aimed at unraveling the nature of hydrogen adsorption in HKUST-1 (Cu3(1,3,5-benzenetricarboxylate)2), a metal-organic framework (MOF) with unsaturated metal centers. We reveal that, in this system, the major contribution to the overall binding comes from the classical Coulomb interaction which is not screened due to the open metal site; this explains the relatively high binding energies and short H2-metal distances observed in MOFs with exposed metal sites as compared to traditional ones. Despite the short distances, there is no indication of an elongation of the H-H bond for the bound H2 molecule at the metal site. We find that both the phonon and rotational energy levels of the hydrogen molecule are closely similar, making the interpretation of the inelastic neutron scattering data difficult. Finally, we show that the orientation of H2 has a surprisingly large effect on the binding potential, reducing the classical binding energy by almost 30%. The implication of these results for the development of MOF materials for better hydrogen storage is discussed.

Crystal molecular dynamics simulations to speed up MM/PB(GB)SA evaluation of binding free energies of di-mannose deoxy analogs with P51G-m4-Cyanovirin-N.

PubMed

Vorontsov, Ivan I; Miyashita, Osamu

2011-04-30

Complexes of two Cyanovirin-N (CVN) mutants, m4-CVN and P51G-m4-CVN, with deoxy di-mannose analogs were employed as models to generate conformational ensembles using explicit water Molecular Dynamics (MD) simulations in solution and in crystal environment. The results were utilized for evaluation of binding free energies with the molecular mechanics Poisson-Boltzmann (or Generalized Born) surface area, MM/PB(GB)SA, methods. The calculations provided the ranking of deoxy di-mannose ligands affinity in agreement with available qualitative experimental evidences. This confirms the importance of the hydrogen-bond network between di-mannose 3'- and 4'-hydroxyl groups and the protein binding site B(M) as a basis of the CVN activity as an effective HIV fusion inhibitor. Comparison of binding free energies averaged over snapshots from the solution and crystal simulations showed high promises in the use of the crystal matrix for acceleration of the conformational ensemble generation, the most time consuming step in MM/PB(GB)SA approach. Correlation between energy values based on solution versus crystal ensembles is 0.95 for both MM/PBSA and MM/GBSA methods. Copyright © 2010 Wiley Periodicals, 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.

Enhanced Ligand Sampling for Relative Protein–Ligand Binding Free Energy Calculations

PubMed Central

2016-01-01

Free energy calculations are used to study how strongly potential drug molecules interact with their target receptors. The accuracy of these calculations depends on the accuracy of the molecular dynamics (MD) force field as well as proper sampling of the major conformations of each molecule. However, proper sampling of ligand conformations can be difficult when there are large barriers separating the major ligand conformations. An example of this is for ligands with an asymmetrically substituted phenyl ring, where the presence of protein loops hinders the proper sampling of the different ring conformations. These ring conformations become more difficult to sample when the size of the functional groups attached to the ring increases. The Adaptive Integration Method (AIM) has been developed, which adaptively changes the alchemical coupling parameter λ during the MD simulation so that conformations sampled at one λ can aid sampling at the other λ values. The Accelerated Adaptive Integration Method (AcclAIM) builds on AIM by lowering potential barriers for specific degrees of freedom at intermediate λ values. However, these methods may not work when there are very large barriers separating the major ligand conformations. In this work, we describe a modification to AIM that improves sampling of the different ring conformations, even when there is a very large barrier between them. This method combines AIM with conformational Monte Carlo sampling, giving improved convergence of ring populations and the resulting free energy. This method, called AIM/MC, is applied to study the relative binding free energy for a pair of ligands that bind to thrombin and a different pair of ligands that bind to aspartyl protease β-APP cleaving enzyme 1 (BACE1). These protein–ligand binding free energy calculations illustrate the improvements in conformational sampling and the convergence of the free energy compared to both AIM and AcclAIM. PMID:25906170

Pnicogen bonds between X═PH3 (X = O, S, NH, CH2) and phosphorus and nitrogen bases.

PubMed

Alkorta, Ibon; Sánchez-Sanz, Goar; Elguero, José; Del Bene, Janet E

2014-02-27

Ab initio MP2/aug'-cc-pVTZ calculations have been carried out to investigate the pnicogen bonded complexes formed between the acids O═PH3, S═PH3, HN═PH3, and H2C═PH3 and the bases NH3, NCH, N2, PH3, and PCH. All nitrogen and phosphorus bases form complexes in which the bases are lone pair electron donors. The binding energies of complexes involving the stronger bases NH3, NCH, and PH3 differentiate among the acids, but the binding energies of complexes with the weaker bases do not. These complexes are stabilized by charge transfer from the lone pair orbital of N or P to the σ*P═A orbital of X═PH3, where A is the atom of X directly bonded to P. PCH also forms complexes with the X═PH3 acids as a π electron donor to the σ*P═A orbital. The binding energies and the charge-transfer energies of the π complexes are greater than those of the complexes in which PCH is a lone pair donor. Whether the positive charge on P increases, decreases, or remains the same upon complex formation, the chemical shieldings of (31)P decrease in the complexes relative to the corresponding monomers. (1p)J(P-N) and (1p)J(P-P) values correlate best with the corresponding P-N and P-P distances as a function of the nature of the base. (1)J(P-A) values do not correlate with P-A distances. Rather, the absolute values of (1)J(P-O), (1)J(P-S), and (1)J(P-N) decrease upon complexation. Decreasing (1)J(P-A) values correlate linearly with increasing complex binding energies. In contrast, (1)J(P-C) values increase upon complexation and correlate linearly with increasing binding energies.

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes via Nonequilibrium Candidate Monte Carlo.

PubMed

Gill, Samuel C; Lim, Nathan M; Grinaway, Patrick B; Rustenburg, Ariën S; Fass, Josh; Ross, Gregory A; Chodera, John D; Mobley, David L

2018-05-31

Accurately predicting protein-ligand binding affinities and binding modes is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation time scales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes. In this technique, the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over 2 orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step toward applying this methodology to pharmaceutically relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding modes of ligands using enhanced sampling (BLUES) package which is freely available on GitHub.

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.

Designing molecular complexes using free-energy derivatives from liquid-state integral equation theory

NASA Astrophysics Data System (ADS)

Mrugalla, Florian; Kast, Stefan M.

2016-09-01

Complex formation between molecules in solution is the key process by which molecular interactions are translated into functional systems. These processes are governed by the binding or free energy of association which depends on both direct molecular interactions and the solvation contribution. A design goal frequently addressed in pharmaceutical sciences is the optimization of chemical properties of the complex partners in the sense of minimizing their binding free energy with respect to a change in chemical structure. Here, we demonstrate that liquid-state theory in the form of the solute-solute equation of the reference interaction site model provides all necessary information for such a task with high efficiency. In particular, computing derivatives of the potential of mean force (PMF), which defines the free-energy surface of complex formation, with respect to potential parameters can be viewed as a means to define a direction in chemical space toward better binders. We illustrate the methodology in the benchmark case of alkali ion binding to the crown ether 18-crown-6 in aqueous solution. In order to examine the validity of the underlying solute-solute theory, we first compare PMFs computed by different approaches, including explicit free-energy molecular dynamics simulations as a reference. Predictions of an optimally binding ion radius based on free-energy derivatives are then shown to yield consistent results for different ion parameter sets and to compare well with earlier, orders-of-magnitude more costly explicit simulation results. This proof-of-principle study, therefore, demonstrates the potential of liquid-state theory for molecular design problems.

Investigation on the individual contributions of N-H...O=C and C-H...O=C interactions to the binding energies of beta-sheet models.

PubMed

Wang, Chang-Sheng; Sun, Chang-Liang

2010-04-15

In this article, the binding energies of 16 antiparallel and parallel beta-sheet models are estimated using the analytic potential energy function we proposed recently and the results are compared with those obtained from MP2, AMBER99, OPLSAA/L, and CHARMM27 calculations. The comparisons indicate that the analytic potential energy function can produce reasonable binding energies for beta-sheet models. Further comparisons suggest that the binding energy of the beta-sheet models might come mainly from dipole-dipole attractive and repulsive interactions and VDW interactions between the two strands. The dipole-dipole attractive and repulsive interactions are further obtained in this article. The total of N-H...H-N and C=O...O=C dipole-dipole repulsive interaction (the secondary electrostatic repulsive interaction) in the small ring of the antiparallel beta-sheet models is estimated to be about 6.0 kcal/mol. The individual N-H...O=C dipole-dipole attractive interaction is predicted to be -6.2 +/- 0.2 kcal/mol in the antiparallel beta-sheet models and -5.2 +/- 0.6 kcal/mol in the parallel beta-sheet models. The individual C(alpha)-H...O=C attractive interaction is -1.2 +/- 0.2 kcal/mol in the antiparallel beta-sheet models and -1.5 +/- 0.2 kcal/mol in the parallel beta-sheet models. These values are important in understanding the interactions at protein-protein interfaces and developing a more accurate force field for peptides and proteins. 2009 Wiley Periodicals, Inc.

Designing molecular complexes using free-energy derivatives from liquid-state integral equation theory.

PubMed

Mrugalla, Florian; Kast, Stefan M

2016-09-01

Complex formation between molecules in solution is the key process by which molecular interactions are translated into functional systems. These processes are governed by the binding or free energy of association which depends on both direct molecular interactions and the solvation contribution. A design goal frequently addressed in pharmaceutical sciences is the optimization of chemical properties of the complex partners in the sense of minimizing their binding free energy with respect to a change in chemical structure. Here, we demonstrate that liquid-state theory in the form of the solute-solute equation of the reference interaction site model provides all necessary information for such a task with high efficiency. In particular, computing derivatives of the potential of mean force (PMF), which defines the free-energy surface of complex formation, with respect to potential parameters can be viewed as a means to define a direction in chemical space toward better binders. We illustrate the methodology in the benchmark case of alkali ion binding to the crown ether 18-crown-6 in aqueous solution. In order to examine the validity of the underlying solute-solute theory, we first compare PMFs computed by different approaches, including explicit free-energy molecular dynamics simulations as a reference. Predictions of an optimally binding ion radius based on free-energy derivatives are then shown to yield consistent results for different ion parameter sets and to compare well with earlier, orders-of-magnitude more costly explicit simulation results. This proof-of-principle study, therefore, demonstrates the potential of liquid-state theory for molecular design problems.

Structure-based design of ligands for protein basic domains: Application to the HIV-1 Tat protein

NASA Astrophysics Data System (ADS)

Filikov, Anton V.; James, Thomas L.

1998-05-01

A methodology has been developed for designing ligands to bind a flexible basic protein domain where the structure of the domain is essentially known. It is based on an empirical binding free energy function developed for highly charged complexes and on Monte Carlo simulations in internal coordinates with both the ligand and the receptor being flexible. HIV-1 encodes a transactivating regulatory protein called Tat. Binding of the basic domain of Tat to TAR RNA is required for efficient transcription of the viral genome. The structure of a biologically active peptide containing the Tat basic RNA-binding domain is available from NMR studies. The goal of the current project is to design a ligand which will bind to that basic domain and potentially inhibit the TAR-Tat interaction. The basic domain contains six arginine and two lysine residues. Our strategy was to design a ligand for arginine first and then a superligand for the basic domain by joining arginine ligands with a linker. Several possible arginine ligands were obtained by searching the Available Chemicals Directory with DOCK 3.5 software. Phytic acid, which can potentially bind multiple arginines, was chosen as a building block for the superligand. Calorimetric binding studies of several compounds to methylguanidine and Arg-/Lys-containing peptides were performed. The data were used to develop an empirical binding free energy function for prediction of affinity of the ligands for the Tat basic domain. Modeling of the conformations of the complexes with both the superligand and the basic domain being flexible has been carried out via Biased Probability Monte Carlo (BPMC) simulations in internal coordinates (ICM 2.6 suite of programs). The simulations used parameters to ensure correct folding, i.e., consistent with the experimental NMR structure of a 25-residue Tat peptide, from a random starting conformation. Superligands for the basic domain were designed by joining together two molecules of phytic acid with peptidic and peptidomimetic linkers. The linkers were refined by varying the length and side chains of the linking residues, carrying out BPMC simulations, and evaluation of the binding free energy for the best energy conformation. The dissociation constant of the best ligand designed is estimated to be in the low- to mid-nanomolar range.

Developing a molecular picture of soil organic matter–mineral interactions by quantifying organo–mineral binding

DOE PAGES

Newcomb, C. J.; Qafoku, N. P.; Grate, J. W.; ...

2017-08-30

Long residence times of soil organic matter have been attributed to reactive mineral surface sites that sorb organic species and cause inaccessibility due to isolation and chemical stabilization at the organic-mineral interface. Instrumentation for probing this interface is limited. As a result, much of the micron- and molecular-scale knowledge about organic-mineral interactions remains largely qualitative. We report the use of force spectroscopy to directly measure the binding between organic ligands with known chemical functionalities to soil minerals in aqueous environments. By systematically studying the role of organic functional group chemistry with model minerals, we demonstrate that the chemistry of bothmore » the organic ligand and mineral contribute to values of binding free energy and that changes in pH and ionic strength produce significant differences in binding energies. These direct measurements of molecular binding provide mechanistic insights into organo-mineral interactions, which could potentially inform land-carbon models that explicitly include mineral-bound C pools.« less

Rearrangements under confinement lead to increased binding energy of Synaptotagmin-1 with anionic membranes in Mg2+ and Ca2.

PubMed

Gruget, Clémence; Coleman, Jeff; Bello, Oscar; Krishnakumar, Shyam S; Perez, Eric; Rothman, James E; Pincet, Frederic; Donaldson, Stephen H

2018-05-01

Synaptotagmin-1 (Syt1) is the primary calcium sensor (Ca 2+ ) that mediates neurotransmitter release at the synapse. The tandem C2 domains (C2A and C2B) of Syt1 exhibit functionally critical, Ca 2+ -dependent interactions with the plasma membrane. With the surface forces apparatus, we directly measure the binding energy of membrane-anchored Syt1 to an anionic membrane and find that Syt1 binds with ~6 k B T in EGTA, ~10 k B T in Mg 2+ and ~18 k B T in Ca 2+ . Molecular rearrangements measured during confinement are more prevalent in Ca 2+ and Mg 2+ and suggest that Syt1 initially binds through C2B, then reorients the C2 domains into the preferred binding configuration. These results provide energetic and mechanistic details of the Syt1 Ca 2+ -activation process in synaptic transmission. © 2018 Federation of European Biochemical Societies.

Investigation of flavonoids bearing different substituents on ring C and their cu2+ complex binding with bovine serum albumin: structure-affinity relationship aspects.

PubMed

Shi, Shuyun; Zhang, Yuping; Chen, Xiaoqin; Peng, Mijun

2011-10-12

The effects of 1:1 flavonoid-Cu(2+) complexes of four flavonoids with different C-ring substituents, quercetin (QU), luteolin (LU), taxifolin (TA), and (+)-catechin (CA), on bovine serum albumin (BSA) were investigated and compared with corresponding free flavonoids by spectroscopic analysis in an attempt to characterize the chemical association taking place. The results indicated that all of the quenching mechanisms were based on static quenching combined with nonradiative energy transfer. Cu(2+) chelation changed the binding constants for BSA depending on the structures of flavonoids and the detected concentrations. The reduced hydroxyl groups, increased steric hindrance, and hydrophilicity of Cu(2+) chelation may be the main reasons for the reduced binding constants, whereas the formation of stable flavonoid-Cu(2+) complexes and synergistic action could increase the binding constants. The changed trends of critical energy transfer distance (R(0)) for Cu(2+) chelation were contrary to those of binding constants.

Methyl Transfer by Substrate Signaling from a Knotted Protein Fold

PubMed Central

Christian, Thomas; Sakaguchi, Reiko; Perlinska, Agata P.; Lahoud, Georges; Ito, Takuhiro; Taylor, Erika A.; Yokoyama, Shigeyuki; Sulkowska, Joanna I.; Hou, Ya-Ming

2017-01-01

Proteins with knotted configurations are restricted in conformational space relative to unknotted proteins. Little is known if knotted proteins have sufficient dynamics to communicate between spatially separated substrate-binding sites. In bacteria, TrmD is a methyl transferase that uses a knotted protein fold to catalyze methyl transfer from S-adenosyl methionine (AdoMet) to G37-tRNA. The product m1G37-tRNA is essential for life as a determinant to maintain protein synthesis reading-frame. Using an integrated approach of structure, kinetic, and computational analysis, we show here that the structurally constrained TrmD knot is required for its catalytic activity. Unexpectedly, the TrmD knot has complex internal movements that respond to AdoMet binding and signaling. Most of the signaling propagates the free energy of AdoMet binding to stabilize tRNA binding and to assemble the active site. This work demonstrates new principles of knots as an organized structure that captures the free energies of substrate binding to facilitate catalysis. PMID:27571175

Developing a molecular picture of soil organic matter–mineral interactions by quantifying organo–mineral binding

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

Newcomb, C. J.; Qafoku, N. P.; Grate, J. W.

Long residence times of soil organic matter have been attributed to reactive mineral surface sites that sorb organic species and cause inaccessibility due to isolation and chemical stabilization at the organic-mineral interface. Instrumentation for probing this interface is limited. As a result, much of the micron- and molecular-scale knowledge about organic-mineral interactions remains largely qualitative. We report the use of force spectroscopy to directly measure the binding between organic ligands with known chemical functionalities to soil minerals in aqueous environments. By systematically studying the role of organic functional group chemistry with model minerals, we demonstrate that the chemistry of bothmore » the organic ligand and mineral contribute to values of binding free energy and that changes in pH and ionic strength produce significant differences in binding energies. These direct measurements of molecular binding provide mechanistic insights into organo-mineral interactions, which could potentially inform land-carbon models that explicitly include mineral-bound C pools.« less

Validation of tautomeric and protomeric binding modes by free energy calculations. A case study for the structure based optimization of D-amino acid oxidase inhibitors.

PubMed

Orgován, Zoltán; Ferenczy, György G; Steinbrecher, Thomas; Szilágyi, Bence; Bajusz, Dávid; Keserű, György M

2018-02-01

Optimization of fragment size D-amino acid oxidase (DAAO) inhibitors was investigated using a combination of computational and experimental methods. Retrospective free energy perturbation (FEP) calculations were performed for benzo[d]isoxazole derivatives, a series of known inhibitors with two potential binding modes derived from X-ray structures of other DAAO inhibitors. The good agreement between experimental and computed binding free energies in only one of the hypothesized binding modes strongly support this bioactive conformation. Then, a series of 1-H-indazol-3-ol derivatives formerly not described as DAAO inhibitors was investigated. Binding geometries could be reliably identified by structural similarity to benzo[d]isoxazole and other well characterized series and FEP calculations were performed for several tautomers of the deprotonated and protonated compounds since all these forms are potentially present owing to the experimental pKa values of representative compounds in the series. Deprotonated compounds are proposed to be the most important bound species owing to the significantly better agreement between their calculated and measured affinities compared to the protonated forms. FEP calculations were also used for the prediction of the affinities of compounds not previously tested as DAAO inhibitors and for a comparative structure-activity relationship study of the benzo[d]isoxazole and indazole series. Selected indazole derivatives were synthesized and their measured binding affinity towards DAAO was in good agreement with FEP predictions.

Validation of tautomeric and protomeric binding modes by free energy calculations. A case study for the structure based optimization of d-amino acid oxidase inhibitors

NASA Astrophysics Data System (ADS)

Orgován, Zoltán; Ferenczy, György G.; Steinbrecher, Thomas; Szilágyi, Bence; Bajusz, Dávid; Keserű, György M.

2018-02-01

Optimization of fragment size d-amino acid oxidase (DAAO) inhibitors was investigated using a combination of computational and experimental methods. Retrospective free energy perturbation (FEP) calculations were performed for benzo[d]isoxazole derivatives, a series of known inhibitors with two potential binding modes derived from X-ray structures of other DAAO inhibitors. The good agreement between experimental and computed binding free energies in only one of the hypothesized binding modes strongly support this bioactive conformation. Then, a series of 1-H-indazol-3-ol derivatives formerly not described as DAAO inhibitors was investigated. Binding geometries could be reliably identified by structural similarity to benzo[d]isoxazole and other well characterized series and FEP calculations were performed for several tautomers of the deprotonated and protonated compounds since all these forms are potentially present owing to the experimental pKa values of representative compounds in the series. Deprotonated compounds are proposed to be the most important bound species owing to the significantly better agreement between their calculated and measured affinities compared to the protonated forms. FEP calculations were also used for the prediction of the affinities of compounds not previously tested as DAAO inhibitors and for a comparative structure-activity relationship study of the benzo[d]isoxazole and indazole series. Selected indazole derivatives were synthesized and their measured binding affinity towards DAAO was in good agreement with FEP predictions.

Paul D. Boyer, Adenosine Triphosphate (ATP), and the Binding Change

Science.gov Websites

-- October 1975, DOE Technical Report, 1975 A Perspective of the Binding Change Mechanism for ATP Synthesis Reports, Vol. 18, No. 3, 1998 ATP Synthesis and the Binding Change Mechanism: The Work of Paul D. Boyer Mechanism of ATP Synthesis Additional Web Pages: Adenosine Triphosphate: The Energy Currency of Life Paul D

Thermodynamic Exploration of Eosin-Lysozyme Binding: A Physical Chemistry and Biochemistry Laboratory Experiment

ERIC Educational Resources Information Center

Huisman, Andrew J.; Hartsell, Lydia R.; Krueger, Brent P.; Pikaart, Michael J.

2010-01-01

We developed a modular pair of experiments for use in the undergraduate physical chemistry and biochemistry laboratories. Both experiments examine the thermodynamics of the binding of a small molecule, eosin Y, to the protein lysozyme. The assay for binding is the quenching of lysozyme fluorescence by eosin through resonant energy transfer. In…

Convergence and Sampling in Determining Free Energy Landscapes for Membrane Protein Association

PubMed Central

2016-01-01

Potential of mean force (PMF) calculations are used to characterize the free energy landscape of protein–lipid and protein–protein association within membranes. Coarse-grained simulations allow binding free energies to be determined with reasonable statistical error. This accuracy relies on defining a good collective variable to describe the binding and unbinding transitions, and upon criteria for assessing the convergence of the simulation toward representative equilibrium sampling. As examples, we calculate protein–lipid binding PMFs for ANT/cardiolipin and Kir2.2/PIP2, using umbrella sampling on a distance coordinate. These highlight the importance of replica exchange between windows for convergence. The use of two independent sets of simulations, initiated from bound and unbound states, provide strong evidence for simulation convergence. For a model protein–protein interaction within a membrane, center-of-mass distance is shown to be a poor collective variable for describing transmembrane helix–helix dimerization. Instead, we employ an alternative intermolecular distance matrix RMS (DRMS) coordinate to obtain converged PMFs for the association of the glycophorin transmembrane domain. While the coarse-grained force field gives a reasonable Kd for dimerization, the majority of the bound population is revealed to be in a near-native conformation. Thus, the combination of a refined reaction coordinate with improved sampling reveals previously unnoticed complexities of the dimerization free energy landscape. We propose the use of replica-exchange umbrella sampling starting from different initial conditions as a robust approach for calculation of the binding energies in membrane simulations. PMID:27807980

Thermodynamic Characterization of Hydration Sites from Integral Equation-Derived Free Energy Densities: Application to Protein Binding Sites and Ligand Series.

PubMed

Güssregen, Stefan; Matter, Hans; Hessler, Gerhard; Lionta, Evanthia; Heil, Jochen; Kast, Stefan M

2017-07-24

Water molecules play an essential role for mediating interactions between ligands and protein binding sites. Displacement of specific water molecules can favorably modulate the free energy of binding of protein-ligand complexes. Here, the nature of water interactions in protein binding sites is investigated by 3D RISM (three-dimensional reference interaction site model) integral equation theory to understand and exploit local thermodynamic features of water molecules by ranking their possible displacement in structure-based design. Unlike molecular dynamics-based approaches, 3D RISM theory allows for fast and noise-free calculations using the same detailed level of solute-solvent interaction description. Here we correlate molecular water entities instead of mere site density maxima with local contributions to the solvation free energy using novel algorithms. Distinct water molecules and hydration sites are investigated in multiple protein-ligand X-ray structures, namely streptavidin, factor Xa, and factor VIIa, based on 3D RISM-derived free energy density fields. Our approach allows the semiquantitative assessment of whether a given structural water molecule can potentially be targeted for replacement in structure-based design. Finally, PLS-based regression models from free energy density fields used within a 3D-QSAR approach (CARMa - comparative analysis of 3D RISM Maps) are shown to be able to extract relevant information for the interpretation of structure-activity relationship (SAR) trends, as demonstrated for a series of serine protease inhibitors.

Nucleotide-dependent conformational states of actin

PubMed Central

Pfaendtner, Jim; Branduardi, Davide; Parrinello, Michele; Pollard, Thomas D.; Voth, Gregory A.

2009-01-01

The influence of the state of the bound nucleotide (ATP, ADP-Pi, or ADP) on the conformational free-energy landscape of actin is investigated. Nucleotide-dependent folding of the DNase-I binding (DB) loop in monomeric actin and the actin trimer is carried out using all-atom molecular dynamics (MD) calculations accelerated with a multiscale implementation of the metadynamics algorithm. Additionally, an investigation of the opening and closing of the actin nucleotide binding cleft is performed. Nucleotide-dependent free-energy profiles for all of these conformational changes are calculated within the framework of metadynamics. We find that in ADP-bound monomer, the folded and unfolded states of the DB loop have similar relative free-energy. This result helps explain the experimental difficulty in obtaining an ordered crystal structure for this region of monomeric actin. However, we find that in the ADP-bound actin trimer, the folded DB loop is stable and in a free-energy minimum. It is also demonstrated that the nucleotide binding cleft favors a closed conformation for the bound nucleotide in the ATP and ADP-Pi states, whereas the ADP state favors an open confirmation, both in the monomer and trimer. These results suggest a mechanism of allosteric interactions between the nucleotide binding cleft and the DB loop. This behavior is confirmed by an additional simulation that shows the folding free-energy as a function of the nucleotide cleft width, which demonstrates that the barrier for folding changes significantly depending on the value of the cleft width. PMID:19620726

The molecular mechanism studies of chirality effect of PHA-739358 on Aurora kinase A by molecular dynamics simulation and free energy calculations

NASA Astrophysics Data System (ADS)

Cheng, Yuanhua; Cui, Wei; Chen, Quan; Tung, Chen-Ho; Ji, Mingjuan; Zhang, Fushi

2011-02-01

Aurora kinase family is one of the emerging targets in oncology drug discovery and several small molecules targeting aurora kinases have been discovered and evaluated under early phase I/II trials. Among them, PHA-739358 (compound 1r) is a 3-aminopyrazole derivative with strong activity against Aurora A under early phase II trial. Inhibitory potency of compound 1r (the benzylic substituent at the pro-R position) is 30 times over that of compound 1s (the benzylic substituent at the pro-S position). In present study, the mechanism of how different configurations influence the binding affinity was investigated using molecular dynamics (MD) simulations, free energy calculations and free energy decomposition analysis. The predicted binding free energies of these two complexes are consistent with the experimental data. The analysis of the individual energy terms indicates that although the van der Waals contribution is important for distinguishing the binding affinities of these two inhibitors, the electrostatic contribution plays a more crucial role in that. Moreover, it is observed that different configurations of the benzylic substituent could form different binding patterns with protein, thus leading to variant inhibitory potency of compounds 1r and 1s. The combination of different molecular modeling techniques is an efficient way to interpret the chirality effects of inhibitors and our work gives valuable information for the chiral drug design in the near future.

Convergence and Sampling in Determining Free Energy Landscapes for Membrane Protein Association.

PubMed

Domański, Jan; Hedger, George; Best, Robert B; Stansfeld, Phillip J; Sansom, Mark S P

2017-04-20

Potential of mean force (PMF) calculations are used to characterize the free energy landscape of protein-lipid and protein-protein association within membranes. Coarse-grained simulations allow binding free energies to be determined with reasonable statistical error. This accuracy relies on defining a good collective variable to describe the binding and unbinding transitions, and upon criteria for assessing the convergence of the simulation toward representative equilibrium sampling. As examples, we calculate protein-lipid binding PMFs for ANT/cardiolipin and Kir2.2/PIP 2 , using umbrella sampling on a distance coordinate. These highlight the importance of replica exchange between windows for convergence. The use of two independent sets of simulations, initiated from bound and unbound states, provide strong evidence for simulation convergence. For a model protein-protein interaction within a membrane, center-of-mass distance is shown to be a poor collective variable for describing transmembrane helix-helix dimerization. Instead, we employ an alternative intermolecular distance matrix RMS (D RMS ) coordinate to obtain converged PMFs for the association of the glycophorin transmembrane domain. While the coarse-grained force field gives a reasonable K d for dimerization, the majority of the bound population is revealed to be in a near-native conformation. Thus, the combination of a refined reaction coordinate with improved sampling reveals previously unnoticed complexities of the dimerization free energy landscape. We propose the use of replica-exchange umbrella sampling starting from different initial conditions as a robust approach for calculation of the binding energies in membrane simulations.

Full-potential KKR calculations for vacancies in Al : Screening effect and many-body interactions

NASA Astrophysics Data System (ADS)

Hoshino, T.; Asato, M.; Zeller, R.; Dederichs, P. H.

2004-09-01

We give ab initio calculations for vacancies in Al . The calculations are based on the generalized-gradient approximation in the density-functional theory and employ the all-electron full-potential Korringa-Kohn-Rostoker Green’s function method for point defects, which guarantees the correct embedding of the cluster of point defects in an otherwise perfect crystal. First, we confirm the recent calculated results of Carling [Phys. Rev. Lett. 85, 3862 (2000)], i.e., repulsion of the first-nearest-neighbor (1NN) divacancy in Al , and elucidate quantitatively the micromechanism of repulsion. Using the calculated results for vacancy formation energies and divacancy binding energies in Na , Mg , Al , and Si of face-centered-cubic, we show that the single vacancy in nearly free-electron systems becomes very stable with increasing free-electron density, due to the screening effect, and that the formation of divacancy destroys the stable electron distribution around the single vacancy, resulting in a repulsion of two vacancies on 1NN sites, so that the 1NN divacancy is unstable. Second, we show that the cluster expansion converges rapidly for the binding energies of vacancy agglomerates in Al . The binding energy of 13 vacancies consisting of a central vacancy and its 12 nearest neighbors, is reproduced within the error of 0.002eV per vacancy, if many-body interaction energies up to the four-body terms are taken into account in the cluster expansion, being compared with the average error (>0.1eV) of the glue models which are very often used to provide interatomic potentials for computer simulations. For the cluster expansion of the binding energies of impurities, we get the same convergence as that obtained for vacancies. Thus, the present cluster-expansion approach for the binding energies of agglomerates of vacancies and impurities in Al may provide accurate data to construct the interaction-parameter model for computer simulations which are strongly requested to study the dynamical process in the initial stage of the formation of the so-called Guinier-Preston zones of low-concentrated Al -based alloys such as Al1-cXc ( X=Cu , Zn ; c<0.05 ).

Statistical Analysis on the Performance of Molecular Mechanics Poisson-Boltzmann Surface Area versus Absolute Binding Free Energy Calculations: Bromodomains as a Case Study.

PubMed

Aldeghi, Matteo; Bodkin, Michael J; Knapp, Stefan; Biggin, Philip C

2017-09-25

Binding free energy calculations that make use of alchemical pathways are becoming increasingly feasible thanks to advances in hardware and algorithms. Although relative binding free energy (RBFE) calculations are starting to find widespread use, absolute binding free energy (ABFE) calculations are still being explored mainly in academic settings due to the high computational requirements and still uncertain predictive value. However, in some drug design scenarios, RBFE calculations are not applicable and ABFE calculations could provide an alternative. Computationally cheaper end-point calculations in implicit solvent, such as molecular mechanics Poisson-Boltzmann surface area (MMPBSA) calculations, could too be used if one is primarily interested in a relative ranking of affinities. Here, we compare MMPBSA calculations to previously performed absolute alchemical free energy calculations in their ability to correlate with experimental binding free energies for three sets of bromodomain-inhibitor pairs. Different MMPBSA approaches have been considered, including a standard single-trajectory protocol, a protocol that includes a binding entropy estimate, and protocols that take into account the ligand hydration shell. Despite the improvements observed with the latter two MMPBSA approaches, ABFE calculations were found to be overall superior in obtaining correlation with experimental affinities for the test cases considered. A difference in weighted average Pearson ([Formula: see text]) and Spearman ([Formula: see text]) correlations of 0.25 and 0.31 was observed when using a standard single-trajectory MMPBSA setup ([Formula: see text] = 0.64 and [Formula: see text] = 0.66 for ABFE; [Formula: see text] = 0.39 and [Formula: see text] = 0.35 for MMPBSA). The best performing MMPBSA protocols returned weighted average Pearson and Spearman correlations that were about 0.1 inferior to ABFE calculations: [Formula: see text] = 0.55 and [Formula: see text] = 0.56 when including an entropy estimate, and [Formula: see text] = 0.53 and [Formula: see text] = 0.55 when including explicit water molecules. Overall, the study suggests that ABFE calculations are indeed the more accurate approach, yet there is also value in MMPBSA calculations considering the lower compute requirements, and if agreement to experimental affinities in absolute terms is not of interest. Moreover, for the specific protein-ligand systems considered in this study, we find that including an explicit ligand hydration shell or a binding entropy estimate in the MMPBSA calculations resulted in significant performance improvements at a negligible computational cost.

Atomic and molecular adsorption on Fe(110)

DOE PAGES

Xu, Lang; Kirvassilis, Demetrios; Bai, Yunhai; ...

2017-09-12

Iron is the principal catalyst for the ammonia synthesis process and the Fischer–Tropsch process, as well as many other heterogeneously catalyzed reactions. It is thus of fundamental importance to understand the interactions between the iron surface and various reaction intermediates. Here in this paper, we present a systematic study of atomic and molecular adsorption behavior over Fe(110) using periodic, self-consistent density functional theory (DFT-GGA) calculations. The preferred binding sites, binding energies, and the corresponding surface deformation energies of five atomic species (H, C, N, O, and S), six molecular species (NH 3, CH 4, N 2, CO, HCN, and NO),more » and eleven molecular fragments (CH, CH 2, CH 3, NH, NH 2, OH, CN, COH, HCO, NOH, and HNO) were determined on the Fe(110) surface at a coverage of 0.25 monolayer. The binding strengths calculated using the PW91 functional decreased in the following order: C> CH > N > O > S > NH > COH > CN > CH2 > NOH > OH > HNO > HCO > NH2 > H > NO > HCN > CH 3 > CO > N 2 > NH 3. No stable binding structures were observed for CH 4. The estimated diffusion barriers and pathways, as well as the adsorbate-surface and intramolecular vibrational modes of all the adsorbates at their preferred binding sites, were identified. Using the calculated adsorption energetics, we constructed the potential energy surfaces for a few surface reactions including the decomposition of methane, ammonia, dinitrogen, carbon monoxide, and nitric oxide. These potential energy surfaces provide valuable insight into the ability of Fe(110) to catalyze common elementary steps.« less

A molecular modeling based method to predict elution behavior and binding patches of proteins in multimodal chromatography.

PubMed

Banerjee, Suvrajit; Parimal, Siddharth; Cramer, Steven M

2017-08-18

Multimodal (MM) chromatography provides a powerful means to enhance the selectivity of protein separations by taking advantage of multiple weak interactions that include electrostatic, hydrophobic and van der Waals interactions. In order to increase our understanding of such phenomena, a computationally efficient approach was developed that combines short molecular dynamics simulations and continuum solvent based coarse-grained free energy calculations in order to study the binding of proteins to Self Assembled Monolayers (SAM) presenting MM ligands. Using this method, the free energies of protein-MM SAM binding over a range of incident orientations of the protein can be determined. The resulting free energies were then examined to identify the more "strongly bound" orientations of different proteins with two multimodal surfaces. The overall free energy of protein-MM surface binding was then determined and correlated to retention factors from isocratic chromatography. This correlation, combined with analytical expressions from the literature, was then employed to predict protein gradient elution salt concentrations as well as selectivity reversals with different MM resin systems. Patches on protein surfaces that interacted strongly with MM surfaces were also identified by determining the frequency of heavy atom contacts with the atoms of the MM SAMs. A comparison of these patches to Electrostatic Potential and hydrophobicity maps indicated that while all of these patches contained significant positive charge, only the highest frequency sites also possessed hydrophobicity. The ability to identify key binding patches on proteins may have significant impact on process development for the separation of bioproduct related impurities. Copyright © 2017 Elsevier B.V. All rights reserved.

Wobbled electronic properties of lithium clusters: Deterministic approach through first principles

NASA Astrophysics Data System (ADS)

Kushwaha, Anoop Kumar; Nayak, Saroj Kumar

2018-03-01

The innate tendency to form dendritic growth promoted through cluster formation leading to the failure of a Li-ion battery system have drawn significant attention of the researchers towards the effective destabilization of the cluster growth through selective implementation of electrolytic media such as acetonitrile (MeCN). In the present work, using first principles density functional theory and continuum dielectric model, we have investigated the origin of oscillatory nature of binding energy per atom of Lin (n ≤ 8) under the influence of MeCN. In the gas phase, we found that static mean polarizability is strongly correlated with binding energy and shows oscillatory nature with cluster size due to the open shell of Lin cluster. However, in acetonitrile medium, the binding energy has been correlated with electrostatic Lin -MeCN interaction and it has been found that both of them possess wobbled behavior characterized by the cluster size.

Advances in free-energy-based simulations of protein folding and ligand binding.

PubMed

Perez, Alberto; Morrone, Joseph A; Simmerling, Carlos; Dill, Ken A

2016-02-01

Free-energy-based simulations are increasingly providing the narratives about the structures, dynamics and biological mechanisms that constitute the fabric of protein science. Here, we review two recent successes. It is becoming practical: first, to fold small proteins with free-energy methods without knowing substructures and second, to compute ligand-protein binding affinities, not just their binding poses. Over the past 40 years, the timescales that can be simulated by atomistic MD are doubling every 1.3 years--which is faster than Moore's law. Thus, these advances are not simply due to the availability of faster computers. Force fields, solvation models and simulation methodology have kept pace with computing advancements, and are now quite good. At the tip of the spear recently are GPU-based computing, improved fast-solvation methods, continued advances in force fields, and conformational sampling methods that harness external information. Copyright © 2015 Elsevier Ltd. All rights reserved.

Genuine binding energy of the hydrated electron

PubMed Central

Luckhaus, David; Yamamoto, Yo-ichi; Suzuki, Toshinori; Signorell, Ruth

2017-01-01

The unknown influence of inelastic and elastic scattering of slow electrons in water has made it difficult to clarify the role of the solvated electron in radiation chemistry and biology. We combine accurate scattering simulations with experimental photoemission spectroscopy of the hydrated electron in a liquid water microjet, with the aim of resolving ambiguities regarding the influence of electron scattering on binding energy spectra, photoelectron angular distributions, and probing depths. The scattering parameters used in the simulations are retrieved from independent photoemission experiments of water droplets. For the ground-state hydrated electron, we report genuine values devoid of scattering contributions for the vertical binding energy and the anisotropy parameter of 3.7 ± 0.1 eV and 0.6 ± 0.2, respectively. Our probing depths suggest that even vacuum ultraviolet probing is not particularly surface-selective. Our work demonstrates the importance of quantitative scattering simulations for a detailed analysis of key properties of the hydrated electron. PMID:28508051

The tightly bound nuclei in the liquid drop model

NASA Astrophysics Data System (ADS)

Sree Harsha, N. R.

2018-05-01

In this paper, we shall maximise the binding energy per nucleon function in the semi-empirical mass formula of the liquid drop model of the atomic nuclei to analytically prove that the mean binding energy per nucleon curve has local extrema at A ≈ 58.6960, Z ≈ 26.3908 and at A ≈ 62.0178, Z ≈ 27.7506. The Lagrange method of multipliers is used to arrive at these results, while we have let the values of A and Z take continuous fractional values. The shell model that shows why 62Ni is the most tightly bound nucleus is outlined. A brief account on stellar nucleosynthesis is presented to show why 56Fe is more abundant than 62Ni and 58Fe. We believe that the analytical proof presented in this paper can be a useful tool to the instructors to introduce the nucleus with the highest mean binding energy per nucleon.

Binding energies of the ground triplet state a{sup 3}Σ{sub u}{sup +} of Rb{sub 2} and Cs{sub 2} in terms of the generalized Le Roy–Bernstein near-dissociation expansion

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

Sovkov, V. B.; Ivanov, V. S.

Formulae of Le Roy–Bernstein near-dissociation theory are derived in a general isotope–invariant form, applicable to any term in the rotational expansion of a diatomic ro-vibrational term value. It is proposed to use the generalized Le Roy–Bernstein expansion to describe the binding energies (ro-vibrational term values) of the ground triplet state a{sup 3}Σ{sub u}{sup +} of alkali metal dimers. The parameters of this description are determined for Rb{sub 2} and Cs{sub 2} molecules. This approach gives a recipe to calculate the whole variety of the binding energies with characteristic accuracies from ∼1 × 10{sup −3} to 1 × 10{sup −2} cm{supmore » −1} using a relatively simple algebraic equation.« less

Theoretical study of metal noble-gas positive ions

NASA Technical Reports Server (NTRS)

Bauschlicher, Charles W., Jr.; Partridge, Harry; Langhoff, Stephen R.

1989-01-01

Theoretical calculations have been performed to determine the spectroscopic constant for the ground and selected low-lying electronic states of the transition-metal noble-gas ions Var(+), FeAr(+), CoAr(+), CuHe(+), CuAr(+), and CuKr(+). Analogous calculations have been performed for the ground states of the alkali noble-gas ions LiAr(+), LiKr(+), NaAr(+), and KAr(+) and the alkaline-earth noble-gas ion MgAr(+) to contrast the difference in binding energies between the simple and transition-metal noble-gas ions. The binding energies increase with increasing polarizability of the noble-gas ions, as expected for a charge-induced dipole bonding mechanism. It is found that the spectroscopic constants of the X 1Sigma(+) states of the alkali noble-gas ions are well described at the self-consistent field level. In contrast, the binding energies of the transition-metal noble-gas ions are substantially increased by electron correlation.

Complexes of dipolar excitons in layered quasi-two-dimensional nanostructures

NASA Astrophysics Data System (ADS)

Bondarev, Igor V.; Vladimirova, Maria R.

2018-04-01

We discuss neutral and charged complexes (biexcitons and trions) formed by indirect excitons in layered quasi-two-dimensional semiconductor heterostructures. Indirect excitons—long-lived neutral Coulomb-bound pairs of electrons and holes of different layers—have been known for semiconductor coupled quantum wells and have recently been reported for van der Waals heterostructures such as double bilayer graphene and transition-metal dichalcogenides. Using the configuration space approach, we derive the analytical expressions for the trion and biexciton binding energies as a function of interlayer distance. The method captures essential kinematics of complex formation to reveal significant binding energies, up to a few tens of meV for typical interlayer distances ˜3 -5 Å , with the trion binding energy always being greater than that of the biexciton. Our results can contribute to the understanding of more complex many-body phenomena such as exciton Bose-Einstein condensation and Wigner-like electron-hole crystallization in layered semiconductor heterostructures.

Bose polaron problem: Effect of mass imbalance on binding energy

NASA Astrophysics Data System (ADS)

Ardila, L. A. Peña; Giorgini, S.

2016-12-01

By means of quantum Monte Carlo methods we calculate the binding energy of an impurity immersed in a Bose-Einstein condensate at T =0 . The focus is on the attractive branch of the Bose polaron and on the role played by the mass imbalance between the impurity and the surrounding particles. For an impurity resonantly coupled to the bath, we investigate the dependence of the binding energy on the mass ratio and on the interaction strength within the medium. In particular, we determine the equation of state in the case of a static (infinite mass) impurity, where three-body correlations are irrelevant and the result is expected to be a universal function of the gas parameter. For the mass ratio corresponding to 40K impurities in a gas of 87Rb atoms, we provide an explicit comparison with the experimental findings of a recent study carried out at JILA.

Binding energy of donor impurity states and optical absorption in the Tietz-Hua quantum well under an applied electric field

NASA Astrophysics Data System (ADS)

Al, E. B.; Kasapoglu, E.; Sakiroglu, S.; Duque, C. A.; Sökmen, I.

2018-04-01

For a quantum well which has the Tietz-Hua potential, the ground and some excited donor impurity binding energies and the total absorption coefficients, including linear and third order nonlinear terms for the transitions between the related impurity states with respect to the structure parameters and the impurity position as well as the electric field strength are investigated. The binding energies were obtained using the effective-mass approximation within a variational scheme and the optical transitions between any two impurity states were calculated by using the density matrix formalism and the perturbation expansion method. Our results show that the effects of the electric field and the structure parameters on the optical transitions are more pronounced. So we can adjust the red or blue shift in the peak position of the absorption coefficient by changing the strength of the electric field as well as the structure parameters.

Comparison of the bonding between ML(+) and ML2(+) (M = metal, L = noble gas)

NASA Technical Reports Server (NTRS)

Bauschlicher, Charles W., Jr.; Partridge, Harry; Langhoff, Stephen R.

1990-01-01

Ab initio calculations are reported of the spectroscopic constants for the low-lying states of the molecular ions ML2(+), where M = Li, Na, Mg, V, Fe, Co, Ni and Cu, and where L is usually Ar. Comparison with existing analogous calculations on the ML(+) ions shows how the bonding and binding energy change with the addition of a second noble gas atom. The second binding energy is predicted to be essentially the same as the first for the Li, Na, Mg, and V ions, but larger for the Fe, Co, Ni and Cu ions. The binding energies of the transition metal noble gas ions are not accurately predicted at the SCF level, because correlation is required to describe their M(0)Ln(+) character. All trends can be explained in terms of promotion and hybridization on the metal ion.

Perfect transmission at oblique incidence by trigonal warping in graphene P-N junctions

NASA Astrophysics Data System (ADS)

Zhang, Shu-Hui; Yang, Wen

2018-01-01

We develop an analytical mode-matching technique for the tight-binding model to describe electron transport across graphene P-N junctions. This method shares the simplicity of the conventional mode-matching technique for the low-energy continuum model and the accuracy of the tight-binding model over a wide range of energies. It further reveals an interesting phenomenon on a sharp P-N junction: the disappearance of the well-known Klein tunneling (i.e., perfect transmission) at normal incidence and the appearance of perfect transmission at oblique incidence due to trigonal warping at energies beyond the linear Dirac regime. We show that this phenomenon arises from the conservation of a generalized pseudospin in the tight-binding model. We expect this effect to be experimentally observable in graphene and other Dirac fermions systems, such as the surface of three-dimensional topological insulators.

Electrostatic redesign of the [myoglobin, cytochrome b5] interface to create a well-defined docked complex with rapid interprotein electron transfer.

PubMed

Xiong, Peng; Nocek, Judith M; Griffin, Amanda K K; Wang, Jingyun; Hoffman, Brian M

2009-05-27

Cyt b(5) is the electron-carrier "repair" protein that reduces met-Mb and met-Hb to their O(2)-carrying ferroheme forms. Studies of electron transfer (ET) between Mb and cyt b(5) revealed that they react on a "Dynamic Docking" (DD) energy landscape on which binding and reactivity are uncoupled: binding is weak and involves an ensemble of nearly isoenergetic configurations, only a few of which are reactive; those few contribute negligibly to binding. We set the task of redesigning the surface of Mb so that its reaction with cyt b(5) instead would occur on a conventional "simple docking" (SD) energy landscape, on which a complex exhibits a well-defined (set of) reactive binding configuration(s), with binding and reactivity thus no longer being decoupled. We prepared a myoglobin (Mb) triple mutant (D44K/D60K/E85K; Mb(+6)) substituted with Zn-deuteroporphyrin and monitored cytochrome b(5) (cyt b(5)) binding and electron transfer (ET) quenching of the (3)ZnMb(+6) triplet state. In contrast, to Mb(WT), the three charge reversals around the "front-face" heme edge of Mb(+6) have directed cyt b(5) to a surface area of Mb adjacent to its heme, created a well-defined, most-stable structure that supports good ET pathways, and apparently coupled binding and ET: both K(a) and k(et) are increased by the same factor of approximately 2 x 10(2), creating a complex that exhibits a large ET rate constant, k(et) = 10(6 1) s(-1), and is in slow exchange (k(off) < k(et)). In short, these mutations indeed appear to have created the sought-for conversion from DD to simple docking (SD) energy landscapes.

Energetics of drug-DNA interactions.

PubMed

Chaires, J B

1997-01-01

Understanding the thermodynamics of drug binding to DNA is of both practical and fundamental interest. The practical interest lies in the contribution that thermodynamics can make to the rational design process for the development of new DNA targeted drugs. Thermodynamics offer key insights into the molecular forces that drive complex formation that cannot be obtained by structural or computational studies alone. The fundamental interest in these interactions lies in what they can reveal about the general problems of parsing and predicting ligand binding free energies. For these problems, drug-DNA interactions offer several distinct advantages, among them being that the structures of many drug-DNA complexes are known at high resolution and that such structures reveal that in many cases the drug acts as a rigid body, with little conformational change upon binding. Complete thermodynamic profiles (delta G, delta H, delta S, delta Cp) for numerous drug-DNA interactions have been obtained, with the help of high-sensitivity microcalorimetry. The purpose of this article is to offer a perspective on the interpretation of these thermodynamics parameters, and in particular how they might be correlated with known structural features. Obligatory conformational changes in the DNA to accommodate intercalators and the loss of translational and rotational freedom upon complex formation both present unfavorable free energy barriers for binding. Such barriers must be overcome by favorable free energy contributions from the hydrophobic transfer of ligand from solution into the binding site, polyelectrolyte contributions from coupled ion release, and molecular interactions (hydrogen and ionic bonds, van der Waals interactions) that form within the binding site. Theoretical and semiempirical tools that allow estimates of these contributions to be made will be discussed, and their use in dissecting experimental data illustrated. This process, even at the current level of approximation, can shed considerable light on the drug-DNA binding process.

Twisting a β-Carotene, an Adaptive Trick from Nature for Dissipating Energy during Photoprotection*

PubMed Central

Sobotka, Roman; Kish, Elizabeth; Shukla, Mahendra Kumar; Pascal, Andrew A.; Polívka, Tomáš; Robert, Bruno

2017-01-01

Cyanobacteria possess a family of one-helix high light-inducible proteins (Hlips) that are homologous to light-harvesting antenna of plants and algae. An Hlip protein, high light-inducible protein D (HliD) purified as a small complex with the Ycf39 protein is evaluated using resonance Raman spectroscopy. We show that the HliD binds two different β-carotenes, each present in two non-equivalent binding pockets with different conformations, having their (0,0) absorption maxima at 489 and 522 nm, respectively. Both populations of β-carotene molecules were in all-trans configuration and the absorption position of the farthest blue-shifted β-carotene was attributed entirely to the polarizability of the environment in its binding pocket. In contrast, the absorption maximum of the red-shifted β-carotene was attributed to two different factors: the polarizability of the environment in its binding pocket and, more importantly, to the conformation of its β-rings. This second β-carotene has highly twisted β-rings adopting a flat conformation, which implies that the effective conjugation length N is extended up to 10.5 modifying the energetic levels. This increase in N will also result in a lower S1 energy state, which may provide a permanent energy dissipation channel. Analysis of the carbonyl stretching region for chlorophyll a excitations indicates that the HliD binds six chlorophyll a molecules in five non-equivalent binding sites, with at least one chlorophyll a presenting a slight distortion to its macrocycle. The binding modes and conformations of HliD-bound pigments are discussed with respect to the known structures of LHCII and CP29. PMID:27994060

Understanding the effects on constitutive activation and drug binding of a D130N mutation in the β2 adrenergic receptor via molecular dynamics simulation.

PubMed

Zhu, Yanyan; Yuan, Yuan; Xiao, Xiuchan; Zhang, Liyun; Guo, Yanzhi; Pu, Xuemei

2014-11-01

G-protein-coupled receptors (GPCRs) are currently one of the largest families of drug targets. The constitutive activation induced by mutation of key GPCR residues is associated closely with various diseases. However, the structural basis underlying such activation and its role in drug binding has remained unclear. Herein, we used all-atom molecular dynamics simulations and free energy calculations to study the effects of a D130N mutation on the structure of β2 adrenergic receptor (β2AR) and its binding of the agonist salbutamol. The results indicate that the mutation caused significant changes in some key helices. In particular, the mutation leads to the departure of transmembrane 3 (TM3) from transmembrane 6 (TM6) and marked changes in the NPxxY region as well as the complete disruption of a key ionic lock, all of which contribute to the observed constitutive activation. In addition, the D130N mutation weakens some important H-bonds, leading to structural changes in these regions. Binding free energy calculations indicate that van der Waals and electrostatic interactions are the main driving forces in binding salbutamol; however, binding strength in the mutant β2AR is significantly enhanced mainly through modifying electrostatic interactions. Further analysis revealed that the increase in binding energy upon mutation stems mainly from the H-bonds formed between the hydroxyl group of salbutamol and the serine residues of TM5. This observation suggests that modifications of the H-bond groups of this drug could significantly influence drug efficacy in the treatment of diseases associated with this mutation.

Target Z dependence of Xe L x-ray emission in heavy ion-atom collision near the Bohr velocity: influence of level matching

NASA Astrophysics Data System (ADS)

Ren, Jieru; Zhao, Yongtao; Zhou, Xianming; Cheng, Rui; Lei, Yu; Sun, Yuanbo; Wang, Xing; Xu, Ge; Wang, Yuyu; Liu, Shidong; Yu, Yang; Li, Yongfeng; Zhang, Xiaoan; Xu, Zhongfeng; Xiao, Guoqing

2013-09-01

X-ray yields for the projectile L-shell have been measured for collisions between Xe20+ and thick solid targets throughout the periodic table with incident energies near the Bohr velocity. The yields show a very pronounced cyclic dependence on the target atomic number. This result indicates that Xe L x-ray emission intensity is greatly enhanced either in near-symmetric collisions or if the binding energy of the Xe M-shell matches the L- or N-shell binding energy of the target.

Synthesis, characterization, and binding assessment with human serum albumin of three bipyridine lanthanide(III) complexes.

PubMed

Aramesh-Boroujeni, Zahra; Bordbar, Abdol-Khalegh; Khorasani-Motlagh, Mozhgan; Sattarinezhad, Elham; Fani, Najme; Noroozifar, Meissam

2018-05-18

In this work, the terbium(III), dysprosium(III), and ytterbium(III) complexes containing 2, 2'-bipyridine (bpy) ligand have been synthesized and characterized using CHN elemental analysis, FT-IR, UV-Vis and 1 H-NMR techniques and their binding behavior with human serum albumin (HSA) was studied by UV-Vis, fluorescence and molecular docking examinations. The experimental data indicated that all three lanthanide complexes have high binding affinity to HSA with effective quenching of HSA fluorescence via static mechanism. The binding parameters, the type of interaction, the value of resonance energy transfer, and the binding distance between complexes and HSA were estimated from the analysis of fluorescence measurements and Förster theory. The thermodynamic parameters suggested that van der Waals interactions and hydrogen bonds play an important role in the binding mechanism. While, the energy transfer from HSA molecules to all these complexes occurs with high probability, the order of binding constants (BpyTb > BpyDy > BpyYb) represents the importance of radius of Ln 3+ ion in the complex-HSA interaction. The results of molecular docking calculation and competitive experiments assessed site 3 of HSA, located in subdomain IB, as the most probable binding site for these ligands and also indicated the microenvironment residues around the bound mentioned complexes. The computational results kept in good agreement with experimental data.

Discovery of new sites for drug binding to the hypertension-related renin-angiotensinogen complex.

PubMed

Brás, Natércia F; Fernandes, Pedro A; Ramos, Maria J

2014-04-01

Renin (REN) is a key drug target to stop the hypertension cascade, but thus far only one direct inhibitor has been made commercially available. In this study, we assess an innovative REN inhibition strategy, by targeting the interface of the renin:angiotensinogen (REN:ANG) complex. We characterized the energetic role of interfacial residues of REN:ANG and identified the ones responsible for protein:protein binding, which can serve as drug targets for disruption of the REN:ANG association. For this purpose, we applied a computational alanine scanning mutagenesis protocol, which measures the contribution of each side chain for the protein:protein binding free energy with an accuracy of ≈ 1 kcal/mol. As a result, in REN and ANG, six and eight residues were found to be critical for binding, respectively. The leading force behind REN:ANG complexation was found to be the hydrophobic effect. The binding free energy per residue was found to be proportional to the buried area. Residues responsible for binding were occluded from water at the complex, which promotes an efficient pairing between the two proteins. Two druggable pockets involving critical residues for binding were found on the surface of REN, where small druglike molecules can bind and disrupt the ANG:REN association that may provide an efficient way to achieve REN inhibition and control hypertension.

Investigation of glucose binding sites on insulin.

PubMed

Zoete, Vincent; Meuwly, Markus; Karplus, Martin

2004-05-15

Possible insulin binding sites for D-glucose have been investigated theoretically by docking and molecular dynamics (MD) simulations. Two different docking programs for small molecules were used; Multiple Copy Simultaneous Search (MCSS) and Solvation Energy for Exhaustive Docking (SEED) programs. The configurations resulting from the MCSS search were evaluated with a scoring function developed to estimate the binding free energy. SEED calculations were performed using various values for the dielectric constant of the solute. It is found that scores emphasizing non-polar interactions gave a preferential binding site in agreement with that inferred from recent fluorescence and NMR NOESY experiments. The calculated binding affinity of -1.4 to -3.5 kcal/mol is within the measured range of -2.0 +/- 0.5 kcal/mol. The validity of the binding site is suggested by the dynamical stability of the bound glucose when examined with MD simulations with explicit solvent. Alternative binding sites were found in the simulations and their relative stabilities were estimated. The motions of the bound glucose during molecular dynamics simulations are correlated with the motions of the insulin side chains that are in contact with it and with larger scale insulin motions. These results raise the question of whether glucose binding to insulin could play a role in its activity. The results establish the complementarity of molecular dynamics simulations and normal mode analyses with the search for binding sites proposed with small molecule docking programs. Copyright 2004 Wiley-Liss, Inc.

Forces and Dynamics of Glucose and Inhibitor Binding to Sodium Glucose Co-transporter SGLT1 Studied by Single Molecule Force Spectroscopy*

PubMed Central

Neundlinger, Isabel; Puntheeranurak, Theeraporn; Wildling, Linda; Rankl, Christian; Wang, Lai-Xi; Gruber, Hermann J.; Kinne, Rolf K. H.; Hinterdorfer, Peter

2014-01-01

Single molecule force spectroscopy was employed to investigate the dynamics of the sodium glucose co-transporter (SGLT1) upon substrate and inhibitor binding on the single molecule level. CHO cells stably expressing rbSGLT1 were probed by using atomic force microscopy tips carrying either thioglucose, 2′-aminoethyl β-d-glucopyranoside, or aminophlorizin. Poly(ethylene glycol) (PEG) chains of different length and varying end groups were used as tether. Experiments were performed at 10, 25 and 37 °C to address different conformational states of SGLT1. Unbinding forces between ligands and SGLT1 were recorded at different loading rates by changing the retraction velocity, yielding binding probability, width of energy barrier of the binding pocket, and the kinetic off rate constant of the binding reaction. With increasing temperature, width of energy barrier and average life time increased for the interaction of SGLT1 with thioglucose (coupled via acrylamide to a long PEG) but decreased for aminophlorizin binding. The former indicates that in the membrane-bound SGLT1 the pathway to sugar translocation involves several steps with different temperature sensitivity. The latter suggests that also the aglucon binding sites for transport inhibitors have specific, temperature-sensitive conformations. PMID:24962566

Stability of surface and subsurface hydrogen on and in Au/Ni near-surface alloys

DOE PAGES

Celik, Fuat E.; Mavrikakis, Manos

2015-01-12

Periodic, self-consistent DFT-GGA (PW91) calculations were used to study the interaction of hydrogen atoms with the (111) surfaces of substitutional near-surface alloys (NSAs) of Au and Ni with different surface layer compositions and different arrangements of Au atoms in the surface layer. The effect of hydrogen adsorption on the surface and in the first and second subsurface layers of the NSAs was studied. Increasing the Au content in the surface layer weakens hydrogen binding on the surface, but strengthens subsurface binding, suggesting that the distribution of surface and subsurface hydrogen will be different than that on pure Ni(111). While themore » metal composition of the surface layer has an effect on the binding energy of hydrogen on NSA surfaces, the local composition of the binding site has a stronger effect. For example, fcc hollow sites consisting of three Ni atoms bind H nearly as strongly as on Ni(111), and fcc sites consisting of three Au atoms bind H nearly as weakly as on Au(111). Sites with one or two Au atoms show intermediate binding energies. The preference of hydrogen for three-fold Ni hollow sites alters the relative stabilities of different surface metal atom arrangements, and may provide a driving force for adsorbate-induced surface rearrangement.« less

Stability of Surface and Subsurface Hydrogen on and in Au/Ni Near-Surface Alloys

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

Celik, Fuat E.; Mavrikakis, Manos

2015-10-01

Periodic, self-consistent DFT-GGA (PW91) calculations were used to study the interaction of hydrogen atoms with the (111) surfaces of substitutional near-surface alloys (NSAs) of Au and Ni with different surface layer compositions and different arrangements of Au atoms in the surface layer. The effect of hydrogen adsorption on the surface and in the first and second subsurface layers of the NSAs was studied. Increasing the Au content in the surface layer weakens hydrogen binding on the surface, but strengthens subsurface binding, suggesting that the distribution of surface and subsurface hydrogen will be different than that on pure Ni(111). While themore » metal composition of the surface layer has an effect on the binding energy of hydrogen on NSA surfaces, the local composition of the binding site has a stronger effect. For example, fcc hollow sites consisting of three Ni atoms bind H nearly as strongly as on Ni(111), and fcc sites consisting of three Au atoms bind H nearly as weakly as on Au(111). Sites with one or two Au atoms show intermediate binding energies. The preference of hydrogen for three-fold Ni hollow sites alters the relative stabilities of different surface metal atom arrangements, and may provide a driving force for adsorbate-induced surface rearrangement.« less

Stability of surface and subsurface hydrogen on and in Au/Ni near-surface alloys

NASA Astrophysics Data System (ADS)

Celik, Fuat E.; Mavrikakis, Manos

2015-10-01

Periodic, self-consistent DFT-GGA (PW91) calculations were used to study the interaction of hydrogen atoms with the (111) surfaces of substitutional near-surface alloys (NSAs) of Au and Ni with different surface layer compositions and different arrangements of Au atoms in the surface layer. The effect of hydrogen adsorption on the surface and in the first and second subsurface layers of the NSAs was studied. Increasing the Au content in the surface layer weakens hydrogen binding on the surface, but strengthens subsurface binding, suggesting that the distribution of surface and subsurface hydrogen will be different than that on pure Ni(111). While the metal composition of the surface layer has an effect on the binding energy of hydrogen on NSA surfaces, the local composition of the binding site has a stronger effect. For example, fcc hollow sites consisting of three Ni atoms bind H nearly as strongly as on Ni(111), and fcc sites consisting of three Au atoms bind H nearly as weakly as on Au(111). Sites with one or two Au atoms show intermediate binding energies. The preference of hydrogen for three-fold Ni hollow sites alters the relative stabilities of different surface metal atom arrangements, and may provide a driving force for adsorbate-induced surface rearrangement.

Binding site feature description of 2-substituted benzothiazoles as potential AcrAB-TolC efflux pump inhibitors in E. coli.

PubMed

Yilmaz, S; Altinkanat-Gelmez, G; Bolelli, K; Guneser-Merdan, D; Ufuk Over-Hasdemir, M; Aki-Yalcin, E; Yalcin, I

2015-01-01

The resistance-nodulation-division (RND) family efflux pumps are important in the antibiotic resistance of Gram-negative bacteria. However, although a number of bacterial RND efflux pump inhibitors have been developed, there has been no clinically available RND efflux pump inhibitor to date. A set of BSN-coded 2-substituted benzothiazoles were tested alone and in combinations with ciprofloxacin (CIP) against the AcrAB-TolC overexpressor Escherichia coli AG102 clinical strain. The results indicated that the BSN compounds did not show intrinsic antimicrobial activity when tested alone. However, when used in combinations with CIP, a reversal in the antibacterial activity of CIP with up to 10-fold better MIC values was observed. In order to describe the binding site features of these BSN compounds with AcrB, docking studies were performed using the CDocker method. The performed docking poses and the calculated binding energy scores revealed that the tested compounds BSN-006, BSN-023, and BSN-004 showed significant binding interactions with the phenylalanine-rich region in the distal binding site of the AcrB binding monomer. Moreover, the tested compounds BSN-006 and BSN-023 possessed stronger binding energies than CIP, verifying that BSN compounds are acting as the putative substrates of AcrB.

Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors

PubMed Central

2016-01-01

Available crystal structures of opioid receptors provide a high-resolution picture of ligand binding at the primary (“orthosteric”) site, that is, the site targeted by endogenous ligands. Recently, positive allosteric modulators of opioid receptors have also been discovered, but their modes of binding and action remain unknown. Here, we use a metadynamics-based strategy to efficiently sample the binding process of a recently discovered positive allosteric modulator of the δ-opioid receptor, BMS-986187, in the presence of the orthosteric agonist SNC-80, and with the receptor embedded in an explicit lipid–water environment. The dynamics of BMS-986187 were enhanced by biasing the potential acting on the ligand–receptor distance and ligand–receptor interaction contacts. Representative lowest-energy structures from the reconstructed free-energy landscape revealed two alternative ligand binding poses at an allosteric site delineated by transmembrane (TM) helices TM1, TM2, and TM7, with some participation of TM6. Mutations of amino acid residues at these proposed allosteric sites were found to either affect the binding of BMS-986187 or its ability to modulate the affinity and/or efficacy of SNC-80. Taken together, these combined experimental and computational studies provide the first atomic-level insight into the modulation of opioid receptor binding and signaling by allosteric modulators. PMID:26841170

Photoabsorption of acridine yellow and proflavin bound to human serum albumin studied by means of quantum mechanics/molecular dynamics.

PubMed

Aidas, Kęstutis; Olsen, Jógvan Magnus H; Kongsted, Jacob; Ågren, Hans

2013-02-21

Attempting to unravel mechanisms in optical probing of proteins, we have performed pilot calculations of two cationic chromophores-acridine yellow and proflavin-located at different binding sites within human serum albumin, including the two primary drug binding sites as well as a heme binding site. The computational scheme adopted involves classical molecular dynamics simulations of the ligands bound to the protein and subsequent linear response polarizable embedding density functional theory calculations of the excitation energies. A polarizable embedding potential consisting of point charges fitted to reproduce the electrostatic potential and isotropic atomic polarizabilities computed individually for every residue of the protein was used in the linear response calculations. Comparing the calculated aqueous solution-to-protein shifts of maximum absorption energies to available experimental data, we concluded that the cationic proflavin chromophore is likely not to bind albumin at its drug binding site 1 nor at its heme binding site. Although agreement with experimental data could only be obtained in qualitative terms, our results clearly indicate that the difference in optical response of the two probes is due to deprotonation, and not, as earlier suggested, to different binding sites. The ramifications of this finding for design of molecular probes targeting albumin or other proteins is briefly discussed.

A simulation investigation on interaction mechanism between Ebola nucleoprotein and VP35 peptide.

PubMed

Ding, Jing-Na; Zhang, Yan-Jun; Zhong, Hui; Ao, Cheng-Cheng; Han, Ju-Guang

2018-03-01

Ebola viruses (EBOV) will induce acute hemorrhagic fever, which is fatal to humans and nonhuman primates. The combination of EBOV VP35 peptide with nucleoprotein N-terminal (NPNTD) is proposed based on static crystal structures in recent studies, but VP35 binding mechanism and conformational dynamics are still unclear. This investigation, using Molecular Dynamic (MD) simulation and Molecular Mechanics Generalized Born Surface Area (MM-GB/SA) energy calculation, more convincingly proves the greater roles of the protein binding mechanisms than do hints from the static crystal structure observations. Conformational analysis of the systems demonstrate that combination with VP35 may lead to the conformational transition of NPNTD from "open" to "closed" state. According to the analyses of binding free energies and their decomposition, VP35 residue R37 plays a crucial role in wild type as well as mutant systems. Mutations of I29 and L33 to aspartate as well as M34 to proline affect binding affinity mainly through influencing electrostatic interaction, which is closely related to H-bonds formation. In addition, mutations mainly affect β-hairpin and loop regions, among which, M34P may have the greatest influence to the binding. This study may provide specific binding mechanisms between VP35 peptide and NPNTD, especially some important residues concerning binding.

Discover binding pathways using the sliding binding-box docking approach: application to binding pathways of oseltamivir to avian influenza H5N1 neuraminidase

NASA Astrophysics Data System (ADS)

Tran, Diem-Trang T.; Le, Ly T.; Truong, Thanh N.

2013-08-01

Drug binding and unbinding are transient processes which are hardly observed by experiment and difficult to analyze by computational techniques. In this paper, we employed a cost-effective method called "pathway docking" in which molecular docking was used to screen ligand-receptor binding free energy surface to reveal possible paths of ligand approaching protein binding pocket. A case study was applied on oseltamivir, the key drug against influenza a virus. The equilibrium pathways identified by this method are found to be similar to those identified in prior studies using highly expensive computational approaches.

A kinetic and thermodynamic framework for the Azoarcus group I ribozyme reaction

PubMed Central

Gleitsman, Kristin R.

2014-01-01

Determination of quantitative thermodynamic and kinetic frameworks for ribozymes derived from the Azoarcus group I intron and comparisons to their well-studied analogs from the Tetrahymena group I intron reveal similarities and differences between these RNAs. The guanosine (G) substrate binds to the Azoarcus and Tetrahymena ribozymes with similar equilibrium binding constants and similar very slow association rate constants. These and additional literature observations support a model in which the free ribozyme is not conformationally competent to bind G and in which the probability of assuming the binding-competent state is determined by tertiary interactions of peripheral elements. As proposed previously, the slow binding of guanosine may play a role in the specificity of group I intron self-splicing, and slow binding may be used analogously in other biological processes. The internal equilibrium between ribozyme-bound substrates and products is similar for these ribozymes, but the Azoarcus ribozyme does not display the coupling in the binding of substrates that is observed with the Tetrahymena ribozyme, suggesting that local preorganization of the active site and rearrangements within the active site upon substrate binding are different for these ribozymes. Our results also confirm the much greater tertiary binding energy of the 5′-splice site analog with the Azoarcus ribozyme, binding energy that presumably compensates for the fewer base-pairing interactions to allow the 5′-exon intermediate in self splicing to remain bound subsequent to 5′-exon cleavage and prior to exon ligation. Most generally, these frameworks provide a foundation for design and interpretation of experiments investigating fundamental properties of these and other structured RNAs. PMID:25246656

Probing the interaction of anticancer drug temsirolimus with human serum albumin: molecular docking and spectroscopic insight.

PubMed

Shamsi, Anas; Ahmed, Azaj; Bano, Bilqees

2018-05-01

The binding interaction between temsirolimus, an important antirenal cancer drug, and HSA, an important carrier protein was scrutinized making use of UV and fluorescence spectroscopy. Hyper chromaticity observed in UV spectroscopy in the presence of temsirolimus as compared to free HSA suggests the formation of complex between HSA and temsirolimus. Fluorescence quenching experiments clearly showed quenching in the fluorescence of HSA in the presence of temsirolimus confirming the complex formation and also confirmed that static mode of interaction is operative for this binding process. Binding constant values obtained through UV and fluorescence spectroscopy reveal strong interaction; temsirolimus binds to HSA at 298 K with a binding constant of 2.9 × 10 4  M -1 implying the strength of interaction. The negative Gibbs free energy obtained through Isothermal titration calorimetry as well as quenching experiments suggests that binding process is spontaneous. Molecular docking further provides an insight of various residues that are involved in this binding process; showing the binding energy to be -12.9 kcal/mol. CD spectroscopy was retorted to analyze changes in secondary structure of HSA; increased intensity in presence of temsirolimus showing changes in secondary structure of HSA induced by temsirolimus. This study is of importance as it provides an insight into the binding mechanism of an important antirenal cancer drug with an important carrier protein. Once temsirolimus binds to HSA, it changes conformation of HSA which in turn can alter the functionality of this important carrier protein and this altered functionality of HSA can be highlighted in variety of diseases.

Investigating the binding behaviour of two avidin-based testosterone binders using molecular recognition force spectroscopy.

PubMed

Rangl, Martina; Leitner, Michael; Riihimäki, Tiina; Lehtonen, Soili; Hytönen, Vesa P; Gruber, Hermann J; Kulomaa, Markku; Hinterdorfer, Peter; Ebner, Andreas

2014-02-01

Molecular recognition force spectroscopy, a biosensing atomic force microscopy technique allows to characterise the dissociation of ligand-receptor complexes at the molecular level. Here, we used molecular recognition force spectroscopy to study the binding capability of recently developed testosterone binders. The two avidin-based proteins called sbAvd-1 and sbAvd-2 are expected to bind both testosterone and biotin but differ in their binding behaviour towards these ligands. To explore the ligand binding and dissociation energy landscape of these proteins, we tethered biotin or testosterone to the atomic force microscopy probe while the testosterone-binding protein was immobilized on the surface. Repeated formation and rupture of the ligand-receptor complex at different pulling velocities allowed determination of the loading rate dependence of the complex-rupturing force. In this way, we obtained the molecular dissociation rate (k(off)) and energy landscape distances (x(β)) of the four possible complexes: sbAvd-1-biotin, sbAvd-1-testosterone, sbAvd-2-biotin and sbAvd-2-testosterone. It was found that the kinetic off-rates for both proteins and both ligands are similar. In contrast, the x(β) values, as well as the probability of complex formations, varied considerably. In addition, competitive binding experiments with biotin and testosterone in solution differ significantly for the two testosterone-binding proteins, implying a decreased cross-reactivity of sbAvd-2. Unravelling the binding behaviour of the investigated testosterone-binding proteins is expected to improve their usability for possible sensing applications. Copyright © 2014 John Wiley & Sons, Ltd.

Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations.

PubMed

Ithuralde, Raúl Esteban; Roitberg, Adrián Enrique; Turjanski, Adrián Gustavo

2016-07-20

Intrinsically disordered proteins (IDPs) are a set of proteins that lack a definite secondary structure in solution. IDPs can acquire tertiary structure when bound to their partners; therefore, the recognition process must also involve protein folding. The nature of the transition state (TS), structured or unstructured, determines the binding mechanism. The characterization of the TS has become a major challenge for experimental techniques and molecular simulations approaches since diffusion, recognition, and binding is coupled to folding. In this work we present atomistic molecular dynamics (MD) simulations that sample the free energy surface of the coupled folding and binding of the transcription factor c-myb to the cotranscription factor CREB binding protein (CBP). This process has been recently studied and became a model to study IDPs. Despite the plethora of available information, we still do not know how c-myb binds to CBP. We performed a set of atomistic biased MD simulations running a total of 15.6 μs. Our results show that c-myb folds very fast upon binding to CBP with no unique pathway for binding. The process can proceed through both structured or unstructured TS's with similar probabilities. This finding reconciles previous seemingly different experimental results. We also performed Go-type coarse-grained MD of several structured and unstructured models that indicate that coupled folding and binding follows a native contact mechanism. To the best of our knowledge, this is the first atomistic MD simulation that samples the free energy surface of the coupled folding and binding processes of IDPs.

Electromagnetic Nature of Nuclear Energy

NASA Astrophysics Data System (ADS)

Schaeffer, Bernard

2014-09-01

As it is known since two millenaries, there is an attraction between an electric charge and a neutral object. Coulomb found the fundamental laws of electricity two centuries ago. After one century of nuclear physics, the fundamental laws of the strong force are still ignored. It has been found that electric and magnetic Coulomb's laws alone, without any hypothetical centrifugal force, are able to predict the binding energy of the simplest bound nucleus, the deuteron 2 H with a precision of 4 % . The nuclear potential is given by the formula: Uem2 H / A =e2/4 πɛ0 (1/rnp + a - 1/rnp - a ) + μ0 |μnμp |/4 π rnp3. This potential shows a horizontal inflection point where the electric and magnetic forces are equilibrated, coinciding with the experimental deuteron binding energy. Similar results have been obtained for the α particle 4 He where the electric attractive potential is four times larger than that of 2 H while the magnetic repulsion is only 1 . 5 times larger and the 4 HE binding energy six times larger than that of the deuteron. These results, prove the electromagnetic nature of the nuclear energy without the usual assumptions.

Impact of domain knowledge on blinded predictions of binding energies by alchemical free energy calculations

NASA Astrophysics Data System (ADS)

Mey, Antonia S. J. S.; Jiménez, Jordi Juárez; Michel, Julien

2018-01-01

The Drug Design Data Resource (D3R) consortium organises blinded challenges to address the latest advances in computational methods for ligand pose prediction, affinity ranking, and free energy calculations. Within the context of the second D3R Grand Challenge several blinded binding free energies predictions were made for two congeneric series of Farsenoid X Receptor (FXR) inhibitors with a semi-automated alchemical free energy calculation workflow featuring FESetup and SOMD software tools. Reasonable performance was observed in retrospective analyses of literature datasets. Nevertheless, blinded predictions on the full D3R datasets were poor due to difficulties encountered with the ranking of compounds that vary in their net-charge. Performance increased for predictions that were restricted to subsets of compounds carrying the same net-charge. Disclosure of X-ray crystallography derived binding modes maintained or improved the correlation with experiment in a subsequent rounds of predictions. The best performing protocols on D3R set1 and set2 were comparable or superior to predictions made on the basis of analysis of literature structure activity relationships (SAR)s only, and comparable or slightly inferior, to the best submissions from other groups.