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.

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 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.

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

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).

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.

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

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

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.

Theoretical study on electronic structure of bathocuproine: Renormalization of the band gap in the crystalline state and the large exciton binding energy

NASA Astrophysics Data System (ADS)

Yanagisawa, Susumu; Hatada, Shin-No-Suke; Morikawa, Yoshitada

Bathocuproine (BCP) is a promising organic material of a hole blocking layer in organic light-emitting diodes or an electron buffer layer in organic photovoltaic cells. The nature of the unoccupied electronic states is a key characteristic of the material, which play vital roles in the electron transport. To elucidate the electronic properties of the molecular or crystalline BCP, we use the GW approximation for calculation of the fundamental gap, and the long-range corrected density functional theory for the molecular optical absorption. It is found that the band gap of the BCP single crystal is 4.39 eV, and it is in agreement with the recent low-energy inverse photoemission spectroscopy measurement. The polarization energy is estimated to be larger than 1 eV, demonstrating the large polarization effects induced by the electronic clouds surrounding the injected charge. The theoretical optical absorption energy is 3.68 eV, and the exciton binding energy is estimated to be 0.71 eV, implying the large binding in the eletron-hole pair distributed around the small part of the molecular region. This work was supported by the Grants-in-Aid for Young Scientists (B) (No. 26810009), and for Scientific Research on Innovative Areas ``3D Active-Site Science'' (No. 26105011) from Japan Society for the Promotion of Science.

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.

Two-Photon Rabi Splitting in a Coupled System of a Nanocavity and Exciton Complexes.

PubMed

Qian, Chenjiang; Wu, Shiyao; Song, Feilong; Peng, Kai; Xie, Xin; Yang, Jingnan; Xiao, Shan; Steer, Matthew J; Thayne, Iain G; Tang, Chengchun; Zuo, Zhanchun; Jin, Kuijuan; Gu, Changzhi; Xu, Xiulai

2018-05-25

Two-photon Rabi splitting in a cavity-dot system provides a basis for multiqubit coherent control in a quantum photonic network. Here we report on two-photon Rabi splitting in a strongly coupled cavity-dot system. The quantum dot was grown intentionally large in size for a large oscillation strength and small biexciton binding energy. Both exciton and biexciton transitions couple to a high-quality-factor photonic crystal cavity with large coupling strengths over 130  μeV. Furthermore, the small binding energy enables the cavity to simultaneously couple with two exciton states. Thereby, two-photon Rabi splitting between the biexciton and cavity is achieved, which can be well reproduced by theoretical calculations with quantum master equations.

Two-Photon Rabi Splitting in a Coupled System of a Nanocavity and Exciton Complexes

NASA Astrophysics Data System (ADS)

Qian, Chenjiang; Wu, Shiyao; Song, Feilong; Peng, Kai; Xie, Xin; Yang, Jingnan; Xiao, Shan; Steer, Matthew J.; Thayne, Iain G.; Tang, Chengchun; Zuo, Zhanchun; Jin, Kuijuan; Gu, Changzhi; Xu, Xiulai

2018-05-01

Two-photon Rabi splitting in a cavity-dot system provides a basis for multiqubit coherent control in a quantum photonic network. Here we report on two-photon Rabi splitting in a strongly coupled cavity-dot system. The quantum dot was grown intentionally large in size for a large oscillation strength and small biexciton binding energy. Both exciton and biexciton transitions couple to a high-quality-factor photonic crystal cavity with large coupling strengths over 130 μ eV . Furthermore, the small binding energy enables the cavity to simultaneously couple with two exciton states. Thereby, two-photon Rabi splitting between the biexciton and cavity is achieved, which can be well reproduced by theoretical calculations with quantum master equations.

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

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.

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.

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 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 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.

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

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.

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.

Thermochemistry of the specific binding of C12 surfactants to bovine serum albumin.

PubMed

Nielsen, A D; Borch, K; Westh, P

2000-06-15

The specific binding to bovine serum albumin (BSA) of anionic and non-ionic surfactants with C12 acyl chains has been studied by high sensitivity isothermal titration calorimetry. This method proved particularly effective in resolving the binding of anionic surfactants into separate classes of sites with different affinity. For sodium dodecylsulfate (SDS) the measured binding curves could be rationalized as association to two classes (high affinity/low affinity) of sites comprising, respectively, three and six similar (i.e. thermodynamically equivalent), independent sites. Changes in the thermodynamic functions enthalpy, standard free energy, standard entropy and heat capacity could be discerned for each class of binding site, as well as for micelle formation. These data suggest that binding to low affinity sites (in analogy with micelle formation) exhibits energetic parameters; in particular, a large negative change in heat capacity, which is characteristic of hydrophobic interactions. The thermodynamics of high affinity binding, on the other hand, is indicative of other dominant forces; most likely electrostatic interactions. Other anionic ligands investigated (laurate and dodecyl benzylsulfonate) showed a behavior similar to SDS, the most significant difference being the high affinity binding of the alkylbenzyl sulfonate. For this ligand, the thermodynamic data is indicative of a more loosely associated complex than for SDS and laurate. BSA was found to bind one or two of the non-ionic surfactants (NIS) hepta- or penta(ethylene glycol) monododecyl ether (C12EO7 and C12EO5) with binding constants about three orders of magnitude lower than for SDS. Hence, the free energy of the surfactant in the weakly bound BSA-NIS complex is only slightly favored over the micellar state. The binding process is characterized by very large exothermic enthalpy changes (larger than for the charged surfactants) and a large, positive increment in heat capacity. These observations cannot be reconciled with a molecular picture based on simple hydrophobic condensation onto non-polar patches on the protein surface.

Steric and thermodynamic limits of design for the incorporation of large unnatural amino acids in aminoacyl-tRNA synthetase enzymes.

PubMed

Armen, Roger S; Schiller, Stefan M; Brooks, Charles L

2010-06-01

Orthogonal aminoacyl-tRNA synthetase/tRNA pairs from archaea have been evolved to facilitate site specific in vivo incorporation of unnatural amino acids into proteins in Escherichia coli. Using this approach, unnatural amino acids have been successfully incorporated with high translational efficiency and fidelity. In this study, CHARMM-based molecular docking and free energy calculations were used to evaluate rational design of specific protein-ligand interactions for aminoacyl-tRNA synthetases. A series of novel unnatural amino acid ligands were docked into the p-benzoyl-L-phenylalanine tRNA synthetase, which revealed that the binding pocket of the enzyme does not provide sufficient space for significantly larger ligands. Specific binding site residues were mutated to alanine to create additional space to accommodate larger target ligands, and then mutations were introduced to improve binding free energy. This approach was used to redesign binding sites for several different target ligands, which were then tested against the standard 20 amino acids to verify target specificity. Only the synthetase designed to bind Man-alpha-O-Tyr was predicted to be sufficiently selective for the target ligand and also thermodynamically stable. Our study suggests that extensive redesign of the tRNA synthatase binding pocket for large bulky ligands may be quite thermodynamically unfavorable.

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.

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.

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.

A Computational Analysis of ATP Binding of SV40 Large Tumor Antigen Helicase Motor

PubMed Central

Shi, Yemin; Liu, Hanbin; Gai, Dahai; Ma, Jianpeng; Chen, Xiaojiang S.

2009-01-01

Simian Virus 40 Large Tumor Antigen (LTag) is an efficient helicase motor that unwinds and translocates DNA. The DNA unwinding and translocation of LTag is powered by ATP binding and hydrolysis at the nucleotide pocket between two adjacent subunits of an LTag hexamer. Based on the set of high-resolution hexameric structures of LTag helicase in different nucleotide binding states, we simulated a conformational transition pathway of the ATP binding process using the targeted molecular dynamics method and calculated the corresponding energy profile using the linear response approximation (LRA) version of the semi-macroscopic Protein Dipoles Langevin Dipoles method (PDLD/S). The simulation results suggest a three-step process for the ATP binding from the initial interaction to the final tight binding at the nucleotide pocket, in which ATP is eventually “locked” by three pairs of charge-charge interactions across the pocket. Such a “cross-locking” ATP binding process is similar to the binding zipper model reported for the F1-ATPase hexameric motor. The simulation also shows a transition mechanism of Mg2+ coordination to form the Mg-ATP complex during ATP binding, which is accompanied by the large conformational changes of LTag. This simulation study of the ATP binding process to an LTag and the accompanying conformational changes in the context of a hexamer leads to a refined cooperative iris model that has been proposed previously. PMID:19779548

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

Gaussian Accelerated Molecular Dynamics in NAMD

PubMed Central

2016-01-01

Gaussian accelerated molecular dynamics (GaMD) is a recently developed enhanced sampling technique that provides efficient free energy calculations of biomolecules. Like the previous accelerated molecular dynamics (aMD), GaMD allows for “unconstrained” enhanced sampling without the need to set predefined collective variables and so is useful for studying complex biomolecular conformational changes such as protein folding and ligand binding. Furthermore, because the boost potential is constructed using a harmonic function that follows Gaussian distribution in GaMD, cumulant expansion to the second order can be applied to recover the original free energy profiles of proteins and other large biomolecules, which solves a long-standing energetic reweighting problem of the previous aMD method. Taken together, GaMD offers major advantages for both unconstrained enhanced sampling and free energy calculations of large biomolecules. Here, we have implemented GaMD in the NAMD package on top of the existing aMD feature and validated it on three model systems: alanine dipeptide, the chignolin fast-folding protein, and the M3 muscarinic G protein-coupled receptor (GPCR). For alanine dipeptide, while conventional molecular dynamics (cMD) simulations performed for 30 ns are poorly converged, GaMD simulations of the same length yield free energy profiles that agree quantitatively with those of 1000 ns cMD simulation. Further GaMD simulations have captured folding of the chignolin and binding of the acetylcholine (ACh) endogenous agonist to the M3 muscarinic receptor. The reweighted free energy profiles are used to characterize the protein folding and ligand binding pathways quantitatively. GaMD implemented in the scalable NAMD is widely applicable to enhanced sampling and free energy calculations of large biomolecules. PMID:28034310

Gaussian Accelerated Molecular Dynamics in NAMD.

PubMed

Pang, Yui Tik; Miao, Yinglong; Wang, Yi; McCammon, J Andrew

2017-01-10

Gaussian accelerated molecular dynamics (GaMD) is a recently developed enhanced sampling technique that provides efficient free energy calculations of biomolecules. Like the previous accelerated molecular dynamics (aMD), GaMD allows for "unconstrained" enhanced sampling without the need to set predefined collective variables and so is useful for studying complex biomolecular conformational changes such as protein folding and ligand binding. Furthermore, because the boost potential is constructed using a harmonic function that follows Gaussian distribution in GaMD, cumulant expansion to the second order can be applied to recover the original free energy profiles of proteins and other large biomolecules, which solves a long-standing energetic reweighting problem of the previous aMD method. Taken together, GaMD offers major advantages for both unconstrained enhanced sampling and free energy calculations of large biomolecules. Here, we have implemented GaMD in the NAMD package on top of the existing aMD feature and validated it on three model systems: alanine dipeptide, the chignolin fast-folding protein, and the M 3 muscarinic G protein-coupled receptor (GPCR). For alanine dipeptide, while conventional molecular dynamics (cMD) simulations performed for 30 ns are poorly converged, GaMD simulations of the same length yield free energy profiles that agree quantitatively with those of 1000 ns cMD simulation. Further GaMD simulations have captured folding of the chignolin and binding of the acetylcholine (ACh) endogenous agonist to the M 3 muscarinic receptor. The reweighted free energy profiles are used to characterize the protein folding and ligand binding pathways quantitatively. GaMD implemented in the scalable NAMD is widely applicable to enhanced sampling and free energy calculations of large biomolecules.

Analytic second derivative of the energy for density-functional tight-binding combined with the fragment molecular orbital method

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

Nakata, Hiroya, E-mail: hiroya.nakata.gt@kyocera.jp; Nishimoto, Yoshio; Fedorov, Dmitri G.

2016-07-28

The analytic second derivative of the energy is developed for the fragment molecular orbital (FMO) method combined with density-functional tight-binding (DFTB), enabling simulations of infrared and Raman spectra of large molecular systems. The accuracy of the method is established in comparison to full DFTB without fragmentation for a set of representative systems. The performance of the FMO-DFTB Hessian is discussed for molecular systems containing up to 10 041 atoms. The method is applied to the study of the binding of α-cyclodextrin to polyethylene glycol, and the calculated IR spectrum of an epoxy amine oligomer reproduces experiment reasonably well.

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.

Steric and Thermodynamic Limits of Design for the Incorporation of Large UnNatural Amino Acids in Aminoacyl-tRNA Synthetase Enzymes

PubMed Central

Armen, Roger S.; Schiller, Stefan M.; Brooks, Charles L.

2015-01-01

Orthogonal aminoacyl-tRNA synthetase/tRNA pairs from archaea have been evolved to facilitate site specific in vivo incorporation of unnatural amino acids into proteins in Escherichia coli. Using this approach, unnatural amino acids have been successfully incorporated with high translational efficiency and fidelity. In this study, CHARMM-based molecular docking and free energy calculations were used to evaluate rational design of specific protein-ligand interactions for aminoacyl-tRNA synthetases. A series of novel unnatural amino acid ligands were docked into the p-benzoyl-L-phenylalanine tRNA synthetase, which revealed that the binding pocket of the enzyme does not provide sufficient space for significantly larger ligands. Specific binding site residues were mutated to alanine to create additional space to accommodate larger target ligands, and then mutations were introduced to improve binding free energy. This approach was used to redesign binding sites for several different target ligands, which were then tested against the standard 20 amino acids to verify target specificity. Only the synthetase designed to bind Man-α-O-Tyr was predicted to be sufficiently selective for the target ligand and also thermodynamically stable. Our study suggests that extensive redesign of the tRNA synthatase binding pocket for large bulky ligands may be quite thermodynamically unfavorable. PMID:20310065

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.

Environmental Screening Effects in 2D Materials: Renormalization of the Bandgap, Electronic Structure, and Optical Spectra of Few-Layer Black Phosphorus.

PubMed

Qiu, Diana Y; da Jornada, Felipe H; Louie, Steven G

2017-08-09

Few-layer black phosphorus has recently emerged as a promising 2D semiconductor, notable for its widely tunable bandgap, highly anisotropic properties, and theoretically predicted large exciton binding energies. To avoid degradation, it has become common practice to encapsulate black phosphorus devices. It is generally assumed that this encapsulation does not qualitatively affect their optical properties. Here, we show that the contrary is true. We have performed ab initio GW and GW plus Bethe-Salpeter equation (GW-BSE) calculations to determine the quasiparticle (QP) band structure and optical spectrum of one-layer (1L) through four-layer (4L) black phosphorus, with and without encapsulation between hexagonal boron nitride and sapphire. We show that black phosphorus is exceptionally sensitive to environmental screening. Encapsulation reduces the exciton binding energy in 1L by as much as 70% and completely eliminates the presence of a bound exciton in the 4L structure. The reduction in the exciton binding energies is offset by a similarly large renormalization of the QP bandgap so that the optical gap remains nearly unchanged, but the nature of the excited states and the qualitative features of the absorption spectrum change dramatically.

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.

Temperature and doping dependence of the high-energy kink in cuprates.

PubMed

Zemljic, M M; Prelovsek, P; Tohyama, T

2008-01-25

It is shown that spectral functions within the extended t-J model, evaluated using the finite-temperature diagonalization of small clusters, exhibit the high-energy kink in single-particle dispersion consistent with recent angle-resolved photoemission results on hole-doped cuprates. The kink and waterfall-like features persist up to large doping and to temperatures beyond J; hence, the origin can be generally attributed to strong correlations and incoherent hole propagation at large binding energies. In contrast, our analysis predicts that electron-doped cuprates do not exhibit these phenomena in photoemission.

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.

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.

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

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.

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

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

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.

Stochastic Ratcheting on a Funneled Energy Landscape Is Necessary for Highly Efficient Contractility of Actomyosin Force Dipoles

NASA Astrophysics Data System (ADS)

Komianos, James E.; Papoian, Garegin A.

2018-04-01

Current understanding of how contractility emerges in disordered actomyosin networks of nonmuscle cells is still largely based on the intuition derived from earlier works on muscle contractility. In addition, in disordered networks, passive cross-linkers have been hypothesized to percolate force chains in the network, hence, establishing large-scale connectivity between local contractile clusters. This view, however, largely overlooks the free energy of cross-linker binding at the microscale, which, even in the absence of active fluctuations, provides a thermodynamic drive towards highly overlapping filamentous states. In this work, we use stochastic simulations and mean-field theory to shed light on the dynamics of a single actomyosin force dipole—a pair of antiparallel actin filaments interacting with active myosin II motors and passive cross-linkers. We first show that while passive cross-linking without motor activity can produce significant contraction between a pair of actin filaments, driven by thermodynamic favorability of cross-linker binding, a sharp onset of kinetic arrest exists at large cross-link binding energies, greatly diminishing the effectiveness of this contractility mechanism. Then, when considering an active force dipole containing nonmuscle myosin II, we find that cross-linkers can also serve as a structural ratchet when the motor dissociates stochastically from the actin filaments, resulting in significant force amplification when both molecules are present. Our results provide predictions of how actomyosin force dipoles behave at the molecular level with respect to filament boundary conditions, passive cross-linking, and motor activity, which can explicitly be tested using an optical trapping experiment.

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

PubMed

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

2016-06-30

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

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

PubMed Central

Olsson, Martin A.; Söderhjelm, Pär

2016-01-01

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

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

Reshaping the Energy Landscape Transforms the Mechanism and Binding Kinetics of DNA Threading Intercalation.

PubMed

Clark, Andrew G; Naufer, M Nabuan; Westerlund, Fredrik; Lincoln, Per; Rouzina, Ioulia; Paramanathan, Thayaparan; Williams, Mark C

2018-02-06

Molecules that bind DNA via threading intercalation show high binding affinity as well as slow dissociation kinetics, properties ideal for the development of anticancer drugs. To this end, it is critical to identify the specific molecular characteristics of threading intercalators that result in optimal DNA interactions. Using single-molecule techniques, we quantify the binding of a small metal-organic ruthenium threading intercalator (Δ,Δ-B) and compare its binding characteristics to a similar molecule with significantly larger threading moieties (Δ,Δ-P). The binding affinities of the two molecules are the same, while comparison of the binding kinetics reveals significantly faster kinetics for Δ,Δ-B. However, the kinetics is still much slower than that observed for conventional intercalators. Comparison of the two threading intercalators shows that the binding affinity is modulated independently by the intercalating section and the binding kinetics is modulated by the threading moiety. In order to thread DNA, Δ,Δ-P requires a "lock mechanism", in which a large length increase of the DNA duplex is required for both association and dissociation. In contrast, measurements of the force-dependent binding kinetics show that Δ,Δ-B requires a large DNA length increase for association but no length increase for dissociation from DNA. This contrasts strongly with conventional intercalators, for which almost no DNA length change is required for association but a large DNA length change must occur for dissociation. This result illustrates the fundamentally different mechanism of threading intercalation compared with conventional intercalation and will pave the way for the rational design of therapeutic drugs based on DNA threading intercalation.

A computational study of the open and closed forms of the N-lobe human serum transferrin apoprotein.

PubMed

Rinaldo, David; Field, Martin J

2003-12-01

Human serum transferrin tightly binds ferric ions in the blood stream but is able to release them in cells by a process involving receptor-mediated endocytosis and decrease in pH. Iron binding and release are accompanied by a large conformation change. In this study, we investigate theoretically the open and closed forms of the N-lobe human serum transferrin apoprotein by performing pKa calculations and molecular dynamics and free-energy simulations. In agreement with the hypothesis based on the x-ray crystal structures, our calculations show that there is a shift in the pKa values of the lysines forming the dilysine trigger when the conformation changes. We argue, however, that simple electrostatic repulsion between the lysines is not sufficient to trigger domain opening and, instead, propose an alternative explanation for the dilysine-trigger effect. Analysis of the molecular dynamics and free-energy results indicate that the open form is more mobile than the closed form and is much more stable at pH 5.3, in large part due to entropic effects. Despite a lower free energy, the dynamics simulation of the open form shows that it is flexible enough to sample conformations that are consistent with iron binding.

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.

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.

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.

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

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

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.

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.

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.

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.

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.

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.

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

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.

Basis sets for the calculation of core-electron binding energies

NASA Astrophysics Data System (ADS)

Hanson-Heine, Magnus W. D.; George, Michael W.; Besley, Nicholas A.

2018-05-01

Core-electron binding energies (CEBEs) computed within a Δ self-consistent field approach require large basis sets to achieve convergence with respect to the basis set limit. It is shown that supplementing a basis set with basis functions from the corresponding basis set for the element with the next highest nuclear charge (Z + 1) provides basis sets that give CEBEs close to the basis set limit. This simple procedure provides relatively small basis sets that are well suited for calculations where the description of a core-ionised state is important, such as time-dependent density functional theory calculations of X-ray emission spectroscopy.

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

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

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.

An RNA motif that binds ATP

NASA Technical Reports Server (NTRS)

Sassanfar, M.; Szostak, J. W.

1993-01-01

RNAs that contain specific high-affinity binding sites for small molecule ligands immobilized on a solid support are present at a frequency of roughly one in 10(10)-10(11) in pools of random sequence RNA molecules. Here we describe a new in vitro selection procedure designed to ensure the isolation of RNAs that bind the ligand of interest in solution as well as on a solid support. We have used this method to isolate a remarkably small RNA motif that binds ATP, a substrate in numerous biological reactions and the universal biological high-energy intermediate. The selected ATP-binding RNAs contain a consensus sequence, embedded in a common secondary structure. The binding properties of ATP analogues and modified RNAs show that the binding interaction is characterized by a large number of close contacts between the ATP and RNA, and by a change in the conformation of the RNA.

Computational studies of metal-metal and metal-ligand interactions

NASA Technical Reports Server (NTRS)

Barnes, Leslie A.

1992-01-01

The geometric structure of Cr(CO)6 is optimized at the modified coupled-pair functional (MCPF), single and double excitation coupled-cluster (CCSD) and CCSD(T) levels of theory (including a perturbational estimate for connected triple excitations), and the force constants for the totally symmetric representation are determined. The geometry of Cr(CO)5 is partially optimized at the MCPF, CCSD and CCSD(T) levels of theory. Comparison with experimental data shows that the CCSD(T) method gives the best results for the structures and force constants, and that remaining errors are probably due to deficiencies in the one-particle basis sets used for CO. A detailed comparison of the properties of free CO is therefore given, at both the MCPF and CCSD/CCSD(T) levels of treatment, using a variety of basis sets. With very large one-particle basis sets, the SSCD(T) method gives excellent results for the bond distance, dipole moment and harmonic frequency of free CO. The total binding energies of Cr(CO)6 and Cr(CO)5 are also determined at the MCPF, CCSD and CCSD(T) levels of theory. The CCSD(T) method gives a much larger total binding energy than either the MCPF or CCSD methods. An analysis of the basis set superposition error (BSSE) at the MCPF level of treatment points out limitations in the one-particle basis used here and in a previous study. Calculations using larger basis sets reduced the BSSE, but the total binding energy of Cr(CO)6 is still significantly smaller than the experimental value, although the first CO bond dissociation energy of Cr(CO)6 is well described. An investigation of 3s3p correlation reveals only a small effect. The remaining discrepancy between the experimental and theoretical total binding energy of Cr(CO)6 is probably due to limitations in the one-particle basis, rather than limitations in the correlation treatment. In particular an additional d function and an f function on each C and O are needed to obtain quantitative results. This is underscored by the fact that even using a very large primitive se (1042 primitive functions contracted to 300 basis functions), the superposition error for the total binding energy of Cr(CO)6 is 22 kcal/mol at the MCPF level of treatment.

Energy spectra of small bosonic clusters having a large two-body scattering length

NASA Astrophysics Data System (ADS)

Gattobigio, M.; Kievsky, A.; Viviani, M.

2012-10-01

In this work we investigate small clusters of bosons using the hyperspherical harmonic basis. We consider systems with A=2,3,4,5,6 particles interacting through a soft interparticle potential. In order to make contact with a real system, we use an attractive Gaussian potential that reproduces the values of the dimer binding energy and the atom-atom scattering length obtained with one of the most widely used 4He-4He interactions, the LM2M2 potential of Aziz and Slaman. The intensity of the potential is varied in order to explore the clusters’ spectra in different regions with large positive and large negative values of the two-body scattering length. In addition, we include a repulsive three-body force to reproduce the trimer binding energy. With this model, consisting in the sum of a two- and three-body potential, we have calculated the spectrum of the four-, five-, and six-particle systems. In all the regions explored, we have found that these systems present two states, one deep and one shallow close to the A-1 threshold. Some universal relations between the energy levels are extracted; in particular, we have estimated the universal ratios between thresholds of the three-, four-, and five-particle continua using the two-body Gaussian potential. They agree with recent measurements and theoretical predictions.

Multiple-basin energy landscapes for large-amplitude conformational motions of proteins: Structure-based molecular dynamics simulations

PubMed Central

Okazaki, Kei-ichi; Koga, Nobuyasu; Takada, Shoji; Onuchic, Jose N.; Wolynes, Peter G.

2006-01-01

Biomolecules often undergo large-amplitude motions when they bind or release other molecules. Unlike macroscopic machines, these biomolecular machines can partially disassemble (unfold) and then reassemble (fold) during such transitions. Here we put forward a minimal structure-based model, the “multiple-basin model,” that can directly be used for molecular dynamics simulation of even very large biomolecular systems so long as the endpoints of the conformational change are known. We investigate the model by simulating large-scale motions of four proteins: glutamine-binding protein, S100A6, dihydrofolate reductase, and HIV-1 protease. The mechanisms of conformational transition depend on the protein basin topologies and change with temperature near the folding transition. The conformational transition rate varies linearly with driving force over a fairly large range. This linearity appears to be a consequence of partial unfolding during the conformational transition. PMID:16877541

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.

Free-Energy Landscape of Protein-Ligand Interactions Coupled with Protein Structural Changes.

PubMed

Moritsugu, Kei; Terada, Tohru; Kidera, Akinori

2017-02-02

Protein-ligand interactions are frequently coupled with protein structural changes. Focusing on the coupling, we present the free-energy surface (FES) of the ligand-binding process for glutamine-binding protein (GlnBP) and its ligand, glutamine, in which glutamine binding accompanies large-scale domain closure. All-atom simulations were performed in explicit solvents by multiscale enhanced sampling (MSES), which adopts a multicopy and multiscale scheme to achieve enhanced sampling of systems with a large number of degrees of freedom. The structural ensemble derived from the MSES simulation yielded the FES of the coupling, described in terms of both the ligand's and protein's degrees of freedom at atomic resolution, and revealed the tight coupling between the two degrees of freedom. The derived FES led to the determination of definite structural states, which suggested the dominant pathways of glutamine binding to GlnBP: first, glutamine migrates via diffusion to form a dominant encounter complex with Arg75 on the large domain of GlnBP, through strong polar interactions. Subsequently, the closing motion of GlnBP occurs to form ligand interactions with the small domain, finally completing the native-specific complex structure. The formation of hydrogen bonds between glutamine and the small domain is considered to be a rate-limiting step, inducing desolvation of the protein-ligand interface to form the specific native complex. The key interactions to attain high specificity for glutamine, the "door keeper" existing between the two domains (Asp10-Lys115) and the "hydrophobic sandwich" formed between the ligand glutamine and Phe13/Phe50, have been successfully mapped on the pathway derived from the FES.

Magnetic quantization in monolayer bismuthene

NASA Astrophysics Data System (ADS)

Chen, Szu-Chao; Chiu, Chih-Wei; Lin, Hui-Chi; Lin, Ming-Fa

The magnetic quantization in monolayer bismuthene is investigated by the generalized tight-binding model. The quite large Hamiltonian matrix is built from the tight-binding functions of the various sublattices, atomic orbitals and spin states. Due to the strong spin orbital coupling and sp3 bonding, monolayer bismuthene has the diverse low-lying energy bands such as the parabolic, linear and oscillating energy bands. The main features of band structures are further reflected in the rich magnetic quantization. Under a uniform perpendicular magnetic field (Bz) , three groups of Landau levels (LLs) with distinct features are revealed near the Fermi level. Their Bz-dependent energy spectra display the linear, square-root and non-monotonous dependences, respectively. These LLs are dominated by the combinations of the 6pz orbital and (6px,6py) orbitals as a result of strong sp3 bonding. Specifically, the LL anti-crossings only occur between LLs originating from the oscillating energy band.

Hydrogen molecules and chains in a superstrong magnetic field

NASA Technical Reports Server (NTRS)

Lai, Dong; Salpeter, Edwin E.; Shapiro, Stuart L.

1992-01-01

The electronic structures of hydrogen polymolecules H(n) (n = 2,3,4,...) is studied in a superstrong magnetic field (B greater than about 10 exp 12 G) typically found on the surface of a neutron star. Simple analytical scaling relations for several limiting cases (e.g., large n, high B field) are derived. The binding energies of H(n) molecules are numerically calculated for various magnetic-field strengths. For a given magnetic-field strength, the binding energy per atom in the H(n) molecules is found to approach a constant value as n increases. For typical field strengths of interest, energy saturation is essentially achieved once n exceeds 3 to 4. Also considered is the structure of negative H ions in a high magnetic field. For B about 10 exp 12 G, the dissociation energy of an atom in a hydrogen chain and the ionization potential of H(-) are smaller than the ionization potential of neutral atomic hydrogen.

Many-body effects and excitonic features in 2D biphenylene carbon

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

Lüder, Johann, E-mail: johann.luder@physics.uu.se; Puglia, Carla; Eriksson, Olle

2016-01-14

The remarkable excitonic effects in low dimensional materials in connection to large binding energies of excitons are of great importance for research and technological applications such as in solar energy and quantum information processing as well as for fundamental investigations. In this study, the unique electronic and excitonic properties of the two dimensional carbon network biphenylene carbon were investigated with GW approach and the Bethe-Salpeter equation accounting for electron correlation effects and electron-hole interactions, respectively. Biphenylene carbon exhibits characteristic features including bright and dark excitons populating the optical gap of 0.52 eV and exciton binding energies of 530 meV asmore » well as a technologically relevant intrinsic band gap of 1.05 eV. Biphenylene carbon’s excitonic features, possibly tuned, suggest possible applications in the field of solar energy and quantum information technology in the future.« less

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

Energetic basis for the molecular-scale organization of bone

DOE PAGES

Tao, Jinhui; Battle, Keith C.; Pan, Haihua; ...

2014-12-24

Here, 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 onmore » single 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

Energetic basis for the molecular-scale organization of bone.

PubMed

Tao, Jinhui; Battle, Keith C; Pan, Haihua; Salter, E Alan; Chien, Yung-Ching; Wierzbicki, Andrzej; De Yoreo, James J

2015-01-13

The remarkable properties of bone derive from a highly organized arrangement of coaligned nanometer-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 nonmineralized 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 atomic force microscopy (AFM) observations of collagen adsorption on single 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 transmission electron microscopy (TEM) analyses of native tissues shows that 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.

Benchmark CCSD(T) and DFT study of binding energies in Be7 - 12: in search of reliable DFT functional for beryllium clusters

NASA Astrophysics Data System (ADS)

Labanc, Daniel; Šulka, Martin; Pitoňák, Michal; Černušák, Ivan; Urban, Miroslav; Neogrády, Pavel

2018-05-01

We present a computational study of the stability of small homonuclear beryllium clusters Be7 - 12 in singlet electronic states. Our predictions are based on highly correlated CCSD(T) coupled cluster calculations. Basis set convergence towards the complete basis set limit as well as the role of the 1s core electron correlation are carefully examined. Our CCSD(T) data for binding energies of Be7 - 12 clusters serve as a benchmark for performance assessment of several density functional theory (DFT) methods frequently used in beryllium cluster chemistry. We observe that, from Be10 clusters on, the deviation from CCSD(T) benchmarks is stable with respect to size, and fluctuating within 0.02 eV error bar for most examined functionals. This opens up the possibility of scaling the DFT binding energies for large Be clusters using CCSD(T) benchmark values for smaller clusters. We also tried to find analogies between the performance of DFT functionals for Be clusters and for the valence-isoelectronic Mg clusters investigated recently in Truhlar's group. We conclude that it is difficult to find DFT functionals that perform reasonably well for both beryllium and magnesium clusters. Out of 12 functionals examined, only the M06-2X functional gives reasonably accurate and balanced binding energies for both Be and Mg clusters.

Binding Free Energy Calculations for Lead Optimization: Assessment of Their Accuracy in an Industrial Drug Design Context.

PubMed

Homeyer, Nadine; Stoll, Friederike; Hillisch, Alexander; Gohlke, Holger

2014-08-12

Correctly ranking compounds according to their computed relative binding affinities will be of great value for decision making in the lead optimization phase of industrial drug discovery. However, the performance of existing computationally demanding binding free energy calculation methods in this context is largely unknown. We analyzed the performance of the molecular mechanics continuum solvent, the linear interaction energy (LIE), and the thermodynamic integration (TI) approach for three sets of compounds from industrial lead optimization projects. The data sets pose challenges typical for this early stage of drug discovery. None of the methods was sufficiently predictive when applied out of the box without considering these challenges. Detailed investigations of failures revealed critical points that are essential for good binding free energy predictions. When data set-specific features were considered accordingly, predictions valuable for lead optimization could be obtained for all approaches but LIE. Our findings lead to clear recommendations for when to use which of the above approaches. Our findings also stress the important role of expert knowledge in this process, not least for estimating the accuracy of prediction results by TI, using indicators such as the size and chemical structure of exchanged groups and the statistical error in the predictions. Such knowledge will be invaluable when it comes to the question which of the TI results can be trusted for decision making.

Multi-scale characterization of the energy landscape of proteins with application to the C3D/Efb-C complex.

PubMed

Haspel, Nurit; Geisbrecht, Brian V; Lambris, John; Kavraki, Lydia

2010-03-01

We present a novel multi-level methodology to explore and characterize the low energy landscape and the thermodynamics of proteins. Traditional conformational search methods typically explore only a small portion of the conformational space of proteins and are hard to apply to large proteins due to the large amount of calculations required. In our multi-scale approach, we first provide an initial characterization of the equilibrium state ensemble of a protein using an efficient computational conformational sampling method. We then enrich the obtained ensemble by performing short Molecular Dynamics (MD) simulations on selected conformations from the ensembles as starting points. To facilitate the analysis of the results, we project the resulting conformations on a low-dimensional landscape to efficiently focus on important interactions and examine low energy regions. This methodology provides a more extensive sampling of the low energy landscape than an MD simulation starting from a single crystal structure as it explores multiple trajectories of the protein. This enables us to obtain a broader view of the dynamics of proteins and it can help in understanding complex binding, improving docking results and more. In this work, we apply the methodology to provide an extensive characterization of the bound complexes of the C3d fragment of human Complement component C3 and one of its powerful bacterial inhibitors, the inhibitory domain of Staphylococcus aureus extra-cellular fibrinogen-binding domain (Efb-C) and two of its mutants. We characterize several important interactions along the binding interface and define low free energy regions in the three complexes. Proteins 2010. (c) 2009 Wiley-Liss, Inc.

Efficient computation of optimal oligo-RNA binding.

PubMed

Hodas, Nathan O; Aalberts, Daniel P

2004-01-01

We present an algorithm that calculates the optimal binding conformation and free energy of two RNA molecules, one or both oligomeric. This algorithm has applications to modeling DNA microarrays, RNA splice-site recognitions and other antisense problems. Although other recent algorithms perform the same calculation in time proportional to the sum of the lengths cubed, O((N1 + N2)3), our oligomer binding algorithm, called bindigo, scales as the product of the sequence lengths, O(N1*N2). The algorithm performs well in practice with the aid of a heuristic for large asymmetric loops. To demonstrate its speed and utility, we use bindigo to investigate the binding proclivities of U1 snRNA to mRNA donor splice sites.

Examining the structural evolution of bicarbonate–water clusters: insights from photoelectron spectroscopy, basin-hopping structural search, and comparison with available IR spectral studies

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

Wen, Hui; Hou, Gao-Lei; Liu, Yi-Rong

2016-05-31

Bicarbonate serves a crucial biochemical role in the physiological pH buffering system and also has important atmospheric implications. In the current study, HCO 3 $-$(H 2O) n (n = 0-13) clusters were successfully produced via electrospray ionization of corresponding bulk salt solution, and were characterized by combining negative ion photoelectron spectroscopy and theoretical calculations. The photoelectron spectra reveal that the electron binding energy monotonically increases with the cluster size up to n = 10 and remains largely the same after n > 10. The photo-detaching feature of the solute HCO3$-$itself, which dominates in the small clusters, diminishes with increase ofmore » water coverage. Based on the charge distribution and molecular orbital analyses, the universal high electron binding energy tail that dominates in the larger clusters can be attributed to ionization of water. Thus, the transition of ionization from solute to solvent at the size larger than n=10 has been observed. Extensive theoretical structural search based on the Basin-Hopping unbiased method was carried out, and a plethora of low energy isomers have been obtained for each medium and large size. By comparing the simulated photoelectron spectra and calculated electron binding energies with the experiments, as well as by comparing the simulated infrared spectra with previously reported IR spectra, the probable global minima and the structural evolutionary routes are presented. The nature of bicarbonate-water interactions are mainly electrostatic as implied by the electron localization function (ELF) analysis.« less

Quark-level analogue of nuclear fusion with doubly heavy baryons.

PubMed

Karliner, Marek; Rosner, Jonathan L

2017-11-01

The essence of nuclear fusion is that energy can be released by the rearrangement of nucleons between the initial- and final-state nuclei. The recent discovery of the first doubly charmed baryon , which contains two charm quarks (c) and one up quark (u) and has a mass of about 3,621 megaelectronvolts (MeV) (the mass of the proton is 938 MeV) also revealed a large binding energy of about 130 MeV between the two charm quarks. Here we report that this strong binding enables a quark-rearrangement, exothermic reaction in which two heavy baryons (Λ c ) undergo fusion to produce the doubly charmed baryon and a neutron n (), resulting in an energy release of 12 MeV. This reaction is a quark-level analogue of the deuterium-tritium nuclear fusion reaction (DT → 4 He n). The much larger binding energy (approximately 280 MeV) between two bottom quarks (b) causes the analogous reaction with bottom quarks () to have a much larger energy release of about 138 MeV. We suggest some experimental setups in which the highly exothermic nature of the fusion of two heavy-quark baryons might manifest itself. At present, however, the very short lifetimes of the heavy bottom and charm quarks preclude any practical applications of such reactions.

First-row diatomics: Calculation of the geometry and energetics using self-consistent gradient-functional approximations

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

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

1992-02-15

A fully self-consistent series of nonlocal (gradient) density-functional calculations has been carried out using the augmented-Gaussian-orbital method to determine the magnitude of gradient corrections to the potential-energy curves of the first-row diatomics, Li{sub 2} through F{sub 2}. Both the Langreth-Mehl-Hu and the Perdew-Wang gradient-density functionals were used in calculations of the binding energy, bond length, and vibrational frequency for each dimer. Comparison with results obtained in the local-spin-density approximation (LSDA) using the Vosko-Wilk-Nusair functional, and with experiment, reveals that bond lengths and vibrational frequencies are rather insensitive to details of the gradient functionals, including self-consistency effects, but the gradient correctionsmore » reduce the overbinding commonly observed in the LSDA calculations of first-row diatomics (with the exception of Li{sub 2}, the gradient-functional binding-energy error is only 50--12 % of the LSDA error). The improved binding energies result from a large differential energy lowering, which occurs in open-shell atoms relative to the diatomics. The stabilization of the atom arises from the use of nonspherical charge and spin densities in the gradient-functional calculations. This stabilization is negligibly small in LSDA calculations performed with nonspherical densities.« less

Quark-level analogue of nuclear fusion with doubly heavy baryons

NASA Astrophysics Data System (ADS)

Karliner, Marek; Rosner, Jonathan L.

2017-11-01

The essence of nuclear fusion is that energy can be released by the rearrangement of nucleons between the initial- and final-state nuclei. The recent discovery of the first doubly charmed baryon , which contains two charm quarks (c) and one up quark (u) and has a mass of about 3,621 megaelectronvolts (MeV) (the mass of the proton is 938 MeV) also revealed a large binding energy of about 130 MeV between the two charm quarks. Here we report that this strong binding enables a quark-rearrangement, exothermic reaction in which two heavy baryons (Λc) undergo fusion to produce the doubly charmed baryon and a neutron n (), resulting in an energy release of 12 MeV. This reaction is a quark-level analogue of the deuterium-tritium nuclear fusion reaction (DT → 4He n). The much larger binding energy (approximately 280 MeV) between two bottom quarks (b) causes the analogous reaction with bottom quarks () to have a much larger energy release of about 138 MeV. We suggest some experimental setups in which the highly exothermic nature of the fusion of two heavy-quark baryons might manifest itself. At present, however, the very short lifetimes of the heavy bottom and charm quarks preclude any practical applications of such reactions.

Free Energy Perturbation Calculation of Relative Binding Free Energy between Broadly Neutralizing Antibodies and the gp120 Glycoprotein of HIV-1.

PubMed

Clark, Anthony J; Gindin, Tatyana; Zhang, Baoshan; Wang, Lingle; Abel, Robert; Murret, Colleen S; Xu, Fang; Bao, Amy; Lu, Nina J; Zhou, Tongqing; Kwong, Peter D; Shapiro, Lawrence; Honig, Barry; Friesner, Richard A

2017-04-07

Direct calculation of relative binding affinities between antibodies and antigens is a long-sought goal. However, despite substantial efforts, no generally applicable computational method has been described. Here, we describe a systematic free energy perturbation (FEP) protocol and calculate the binding affinities between the gp120 envelope glycoprotein of HIV-1 and three broadly neutralizing antibodies (bNAbs) of the VRC01 class. The protocol has been adapted from successful studies of small molecules to address the challenges associated with modeling protein-protein interactions. Specifically, we built homology models of the three antibody-gp120 complexes, extended the sampling times for large bulky residues, incorporated the modeling of glycans on the surface of gp120, and utilized continuum solvent-based loop prediction protocols to improve sampling. We present three experimental surface plasmon resonance data sets, in which antibody residues in the antibody/gp120 interface were systematically mutated to alanine. The RMS error in the large set (55 total cases) of FEP tests as compared to these experiments, 0.68kcal/mol, is near experimental accuracy, and it compares favorably with the results obtained from a simpler, empirical methodology. The correlation coefficient for the combined data set including residues with glycan contacts, R 2 =0.49, should be sufficient to guide the choice of residues for antibody optimization projects, assuming that this level of accuracy can be realized in prospective prediction. More generally, these results are encouraging with regard to the possibility of using an FEP approach to calculate the magnitude of protein-protein binding affinities. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Probing excitonic states in suspended two-dimensional semiconductors by photocurrent spectroscopy

NASA Astrophysics Data System (ADS)

Klots, A. R.; Newaz, A. K. M.; Wang, Bin; Prasai, D.; Krzyzanowska, H.; Lin, Junhao; Caudel, D.; Ghimire, N. J.; Yan, J.; Ivanov, B. L.; Velizhanin, K. A.; Burger, A.; Mandrus, D. G.; Tolk, N. H.; Pantelides, S. T.; Bolotin, K. I.

2014-10-01

The optical response of semiconducting monolayer transition-metal dichalcogenides (TMDCs) is dominated by strongly bound excitons that are stable even at room temperature. However, substrate-related effects such as screening and disorder in currently available specimens mask many anticipated physical phenomena and limit device applications of TMDCs. Here, we demonstrate that that these undesirable effects are strongly suppressed in suspended devices. Extremely robust (photogain > 1,000) and fast (response time < 1 ms) photoresponse allow us to study, for the first time, the formation, binding energies, and dissociation mechanisms of excitons in TMDCs through photocurrent spectroscopy. By analyzing the spectral positions of peaks in the photocurrent and by comparing them with first-principles calculations, we obtain binding energies, band gaps and spin-orbit splitting in monolayer TMDCs. For monolayer MoS2, in particular, we obtain an extremely large binding energy for band-edge excitons, Ebind >= 570 meV. Along with band-edge excitons, we observe excitons associated with a van Hove singularity of rather unique nature. The analysis of the source-drain voltage dependence of photocurrent spectra reveals exciton dissociation and photoconversion mechanisms in TMDCs.

Investigating the Role of Phosphorylation in the Binding of Silaffin Peptide R5 to Silica with Molecular Dynamics Simulations.

PubMed

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

2018-01-23

Biomimetic silica formation, a process that is largely driven by proteins, has garnered considerable interest in recent years due to its role in the development of new biotechnologies. However, much remains unknown of the molecular-scale mechanisms underlying the binding of proteins to biomineral surfaces such as silica, or even of the key residue-level interactions between such proteins and surfaces. In this study, we employ molecular dynamics (MD) simulations to study the binding of R5-a 19-residue segment of a native silaffin peptide used for in vitro silica formation-to a silica surface. The metadynamics enhanced sampling method is used to converge the binding behavior of R5 on silica at both neutral (pH 7.5) and acidic (pH 5) conditions. The results show fundamental differences in the mechanism of binding between the two cases, providing unique insight into the pH-dependent ability of R5 and native silaffin to precipitate silica. We also study the effect of phosphorylation of serine residues in R5 on both the binding free energy to silica and the interfacial conformation of the peptide. Results indicate that phosphorylation drastically decreases the binding free energy and changes the structure of silica-adsorbed R5 through the introduction of charge and steric repulsion. New mechanistic insights from this work could inform rational design of new biomaterials and biotechnologies.

RBscore&NBench: a high-level web server for nucleic acid binding residues prediction with a large-scale benchmarking database.

PubMed

Miao, Zhichao; Westhof, Eric

2016-07-08

RBscore&NBench combines a web server, RBscore and a database, NBench. RBscore predicts RNA-/DNA-binding residues in proteins and visualizes the prediction scores and features on protein structures. The scoring scheme of RBscore directly links feature values to nucleic acid binding probabilities and illustrates the nucleic acid binding energy funnel on the protein surface. To avoid dataset, binding site definition and assessment metric biases, we compared RBscore with 18 web servers and 3 stand-alone programs on 41 datasets, which demonstrated the high and stable accuracy of RBscore. A comprehensive comparison led us to develop a benchmark database named NBench. The web server is available on: http://ahsoka.u-strasbg.fr/rbscorenbench/. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Polarizable atomistic calculation of site energy disorder in amorphous Alq3.

PubMed

Nagata, Yuki

2010-02-01

A polarizable molecular dynamics simulation and calculation scheme for site energy disorder is presented in amorphous tris(8-hydroxyquinolinato)aluminum (Alq(3)) by means of the charge response kernel (CRK) method. The CRK fit to the electrostatic potential and the tight-binding approximation are introduced, which enables modeling of the polarizable electrostatic interaction for a large molecule systematically from an ab initio calculation. The site energy disorder for electron and hole transfers is calculated in amorphous Alq(3) and the effect of the polarization on the site energy disorder is discussed.

Analytical RISM-MP2 free energy gradient method: Application to the Schlenk equilibrium of Grignard reagent

NASA Astrophysics Data System (ADS)

Mori, Toshifumi; Kato, Shigeki

2007-03-01

We present a method to evaluate the analytical gradient of reference interaction site model Møller-Plesset second order free energy with respect to solute nuclear coordinates. It is applied to calculate the geometries and energies in the equilibria of the Grignard reagent (CH 3MgCl) in dimethylether solvent. The Mg-Mg and Mg-Cl distances as well as the binding energies of solvents are largely affected by the dynamical electron correlation. The solvent effect on the Schlenk equilibrium is examined.

Influence of the size and charge of gold nanoclusters on complexation with siRNA: a molecular dynamics simulation study.

PubMed

Mudedla, Sathish Kumar; Azhagiya Singam, Ettayapuram Ramaprasad; Balamurugan, Kanagasabai; Subramanian, Venkatesan

2015-11-11

The complexation of small interfering RNA (siRNA) with positively charged gold nanoclusters has been studied in the present investigation with the help of classical molecular dynamics and steered molecular dynamics simulations accompanied by free energy calculations. The results show that gold nanoclusters form a stable complex with siRNA. The wrapping of siRNA around the gold nanocluster depends on the size and charge on the surface of the gold cluster. The binding pattern of the gold nanocluster with siRNA is also influenced by the presence of another cluster. The interaction between the positively charged amines in the gold nanocluster and the negatively charged phosphate group in the siRNA is responsible for the formation of complexes. The binding free energy value increases with the size of the gold cluster and the number of positive charges present on the surface of the gold nanocluster. The results reveal that the binding energy of small gold nanoclusters increases in the presence of another gold nanocluster while the binding of large gold nanoclusters decreases due to the introduction of another gold nanocluster. Overall, the findings have clearly demonstrated the effect of size and charge of gold nanoclusters on their interaction pattern with siRNA.

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.

Kinetic method for the large-scale analysis of the binding mechanism of histone deacetylase inhibitors.

PubMed

Meyners, Christian; Baud, Matthias G J; Fuchter, Matthew J; Meyer-Almes, Franz-Josef

2014-09-01

Performing kinetic studies on protein ligand interactions provides important information on complex formation and dissociation. Beside kinetic parameters such as association rates and residence times, kinetic experiments also reveal insights into reaction mechanisms. Exploiting intrinsic tryptophan fluorescence a parallelized high-throughput Förster resonance energy transfer (FRET)-based reporter displacement assay with very low protein consumption was developed to enable the large-scale kinetic characterization of the binding of ligands to recombinant human histone deacetylases (HDACs) and a bacterial histone deacetylase-like amidohydrolase (HDAH) from Bordetella/Alcaligenes. For the binding of trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), and two other SAHA derivatives to HDAH, two different modes of action, simple one-step binding and a two-step mechanism comprising initial binding and induced fit, were verified. In contrast to HDAH, all compounds bound to human HDAC1, HDAC6, and HDAC8 through a two-step mechanism. A quantitative view on the inhibitor-HDAC systems revealed two types of interaction, fast binding and slow dissociation. We provide arguments for the thesis that the relationship between quantitative kinetic and mechanistic information and chemical structures of compounds will serve as a valuable tool for drug optimization. Copyright © 2014 Elsevier Inc. All rights reserved.

Comparative analyses of the thermodynamic RNA binding signatures of different types of RNA recognition motifs

PubMed Central

Cléry, Antoine; Allain, Frédéric H-T

2017-01-01

Abstract RNA recognition motifs (RRMs) are structurally versatile domains important in regulation of alternative splicing. Structural mechanisms of sequence-specific recognition of single-stranded RNAs (ssRNAs) by RRMs are well understood. The thermodynamic strategies are however unclear. Therefore, we utilized microcalorimetry and semi-empirical analyses to comparatively analyze the cognate ssRNA binding thermodynamics of four different RRM domains, each with a different RNA binding mode. The different binding modes are: canonical binding to the β-sheet surface; canonical binding with involvement of N- and C-termini; binding to conserved loops; and binding to an α-helix. Our results identify enthalpy as the sole and general force driving association at physiological temperatures. Also, networks of weak interactions are a general feature regulating stability of the different RRM–ssRNA complexes. In agreement, non-polyelectrolyte effects contributed between ∼75 and 90% of the overall free energy of binding in the considered complexes. The various RNA binding modes also displayed enormous heat capacity differences, that upon dissection revealed large differential changes in hydration, conformations and dynamics upon binding RNA. Altogether, different modes employed by RRMs to bind cognate ssRNAs utilize various thermodynamics strategies during the association process. PMID:28334819

On the Reliability of Pure and Hybrid DFT Methods for the Evaluation of Halogen, Chalcogen, and Pnicogen Bonds Involving Anionic and Neutral Electron Donors.

PubMed

Bauzá, Antonio; Alkorta, Ibon; Frontera, Antonio; Elguero, José

2013-11-12

In this article, we report a comprehensive theoretical study of halogen, chalcogen, and pnicogen bonding interactions using a large set of pure and hybrid functionals and some ab initio methods. We have observed that the pure and some hybrid functionals largely overestimate the interaction energies when the donor atom is anionic (Cl(-) or Br(-)), especially in the halogen bonding complexes. To evaluate the reliability of the different DFT (BP86, BP86-D3, BLYP, BLYP-D3, B3LYP, B97-D, B97-D3, PBE0, HSE06, APFD, and M06-2X) and ab initio (MP2, RI-MP2, and HF) methods, we have compared the binding energies and equilibrium distances to those obtained using the CCSD(T)/aug-cc-pVTZ level of theory, as reference. The addition of the latest available correction for dispersion (D3) to pure functionals is not recommended for the calculation of halogen, chalcogen, and pnicogen complexes with anions, since it further contributes to the overestimation of the binding energies. In addition, in chalcogen bonding interactions, we have studied how the hybridization of the chalcogen atom influences the interaction energies.

Exploring the molecular basis of RNA recognition by the dimeric RNA-binding protein via molecular simulation methods.

PubMed

Chang, Shan; Zhang, Da-Wei; Xu, Lei; Wan, Hua; Hou, Ting-Jun; Kong, Ren

2016-11-01

RNA-binding protein with multiple splicing (RBPMS) is critical for axon guidance, smooth muscle plasticity, and regulation of cancer cell proliferation and migration. Recently, different states of the RNA-recognition motif (RRM) of RBPMS, one in its free form and another in complex with CAC-containing RNA, were determined by X-ray crystallography. In this article, the free RRM domain, its wild type complex and 2 mutant complex systems are studied by molecular dynamics (MD) simulations. Through comparison of free RRM domain and complex systems, it's found that the RNA binding facilitates stabilizing the RNA-binding interface of RRM domain, especially the C-terminal loop. Although both R38Q and T103A/K104A mutations reduce the binding affinity of RRM domain and RNA, the underlining mechanisms are different. Principal component analysis (PCA) and Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) methods were used to explore the dynamical and recognition mechanisms of RRM domain and RNA. R38Q mutation is positioned on the homodimerization interface and mainly induces the large fluctuations of RRM domains. This mutation does not directly act on the RNA-binding interface, but some interfacial hydrogen bonds are weakened. In contrast, T103A/K104A mutations are located on the RNA-binding interface of RRM domain. These mutations obviously break most of high occupancy hydrogen bonds in the RNA-binding interface. Meanwhile, the key interfacial residues lose their favorable energy contributions upon RNA binding. The ranking of calculated binding energies in 3 complex systems is well consistent with that of experimental binding affinities. These results will be helpful in understanding the RNA recognition mechanisms of RRM domain.

Exploring the molecular basis of RNA recognition by the dimeric RNA-binding protein via molecular simulation methods

PubMed Central

Chang, Shan; Zhang, Da-Wei; Xu, Lei; Wan, Hua; Hou, Ting-Jun; Kong, Ren

2016-01-01

ABSTRACT RNA-binding protein with multiple splicing (RBPMS) is critical for axon guidance, smooth muscle plasticity, and regulation of cancer cell proliferation and migration. Recently, different states of the RNA-recognition motif (RRM) of RBPMS, one in its free form and another in complex with CAC-containing RNA, were determined by X-ray crystallography. In this article, the free RRM domain, its wild type complex and 2 mutant complex systems are studied by molecular dynamics (MD) simulations. Through comparison of free RRM domain and complex systems, it's found that the RNA binding facilitates stabilizing the RNA-binding interface of RRM domain, especially the C-terminal loop. Although both R38Q and T103A/K104A mutations reduce the binding affinity of RRM domain and RNA, the underlining mechanisms are different. Principal component analysis (PCA) and Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) methods were used to explore the dynamical and recognition mechanisms of RRM domain and RNA. R38Q mutation is positioned on the homodimerization interface and mainly induces the large fluctuations of RRM domains. This mutation does not directly act on the RNA-binding interface, but some interfacial hydrogen bonds are weakened. In contrast, T103A/K104A mutations are located on the RNA-binding interface of RRM domain. These mutations obviously break most of high occupancy hydrogen bonds in the RNA-binding interface. Meanwhile, the key interfacial residues lose their favorable energy contributions upon RNA binding. The ranking of calculated binding energies in 3 complex systems is well consistent with that of experimental binding affinities. These results will be helpful in understanding the RNA recognition mechanisms of RRM domain. PMID:27592836

Correlation of Local Effects of DNA Sequence and Position of Beta-Alanine Inserts with Polyamide-DNA Complex Binding Affinities and Kinetics

PubMed Central

Wang, Shuo; Nanjunda, Rupesh; Aston, Karl; Bashkin, James K.; Wilson, W. David

2012-01-01

In order to better understand the effects of β-alanine (β) substitution and the number of heterocycles on DNA binding affinity and selectivity, the interactions of an eight-ring hairpin polyamide (PA) and two β derivatives as well as a six-heterocycle analog have been investigated with their cognate DNA sequence, 5′-TGGCTT-3′. Binding selectivity and the effects of β have been investigated with the cognate and five mutant DNAs. A set of powerful and complementary methods have been employed for both energetic and structural evaluations: UV-melting, biosensor-surface plasmon resonance, isothermal titration calorimetry, circular dichroism and a DNA ligation ladder global structure assay. The reduced number of heterocycles in the six-ring PA weakens the binding affinity; however, the smaller PA aggregates significantly less than the larger PAs, and allows us to obtain the binding thermodynamics. The PA-DNA binding enthalpy is large and negative with a large negative ΔCp, and is the primary driving component of the Gibbs free energy. The complete SPR binding results clearly show that β substitutions can substantially weaken the binding affinity of hairpin PAs in a position-dependent manner. More importantly, the changes in PA binding to the mutant DNAs further confirm the position-dependent effects on PA-DNA interaction affinity. Comparison of mutant DNA sequences also shows a different effect in recognition of T•A versus A•T base pairs. The effects of DNA mutations on binding of a single PA as well as the effects of the position of β substitution on binding tell a clear and very important story about sequence dependent binding of PAs to DNA. PMID:23167504

Conformational Transitions and Convergence of Absolute Binding Free Energy Calculations

PubMed Central

Lapelosa, Mauro; Gallicchio, Emilio; Levy, Ronald M.

2011-01-01

The Binding Energy Distribution Analysis Method (BEDAM) is employed to compute the standard binding free energies of a series of ligands to a FK506 binding protein (FKBP12) with implicit solvation. Binding free energy estimates are in reasonably good agreement with experimental affinities. The conformations of the complexes identified by the simulations are in good agreement with crystallographic data, which was not used to restrain ligand orientations. The BEDAM method is based on λ -hopping Hamiltonian parallel Replica Exchange (HREM) molecular dynamics conformational sampling, the OPLS-AA/AGBNP2 effective potential, and multi-state free energy estimators (MBAR). Achieving converged and accurate results depends on all of these elements of the calculation. Convergence of the binding free energy is tied to the level of convergence of binding energy distributions at critical intermediate states where bound and unbound states are at equilibrium, and where the rate of binding/unbinding conformational transitions is maximal. This finding mirrors similar observations in the context of order/disorder transitions as for example in protein folding. Insights concerning the physical mechanism of ligand binding and unbinding are obtained. Convergence for the largest FK506 ligand is achieved only after imposing strict conformational restraints, which however require accurate prior structural knowledge of the structure of the complex. The analytical AGBNP2 model is found to underestimate the magnitude of the hydrophobic driving force towards binding in these systems characterized by loosely packed protein-ligand binding interfaces. Rescoring of the binding energies using a numerical surface area model corrects this deficiency. This study illustrates the complex interplay between energy models, exploration of conformational space, and free energy estimators needed to obtain robust estimates from binding free energy calculations. PMID:22368530

Core-level binding energy shifts in Pt Ru nanoparticles: A puzzle resolved

NASA Astrophysics Data System (ADS)

Lewera, Adam; Zhou, Wei Ping; Hunger, Ralf; Jaegermann, Wolfram; Wieckowski, Andrzej; Yockel, Scott; Bagus, Paul S.

2007-10-01

Synchrotron measurements of Pt and Ru core-level binding energies, BE's, in Pt-Ru nanoparticles, as a function of Pt content, quantify earlier indications that the Pt 4f BE shift is much larger than the Ru 3d BE shift. A complementary theoretical analysis relates the BE shifts to changes in the metal-metal distances as the composition of the nanoparticle changes. We establish that the large Pt and small Ru BE shifts arise from the different response of these metals to changes in the bond distances, an unexpected result. Our results give evidence that the magnitudes of the BE shifts depend on whether the d band is open, as for Ru, or essentially filled, as for Pt.

Accurate and Reliable Prediction of the Binding Affinities of Macrocycles to Their Protein Targets.

PubMed

Yu, Haoyu S; Deng, Yuqing; Wu, Yujie; Sindhikara, Dan; Rask, Amy R; Kimura, Takayuki; Abel, Robert; Wang, Lingle

2017-12-12

Macrocycles have been emerging as a very important drug class in the past few decades largely due to their expanded chemical diversity benefiting from advances in synthetic methods. Macrocyclization has been recognized as an effective way to restrict the conformational space of acyclic small molecule inhibitors with the hope of improving potency, selectivity, and metabolic stability. Because of their relatively larger size as compared to typical small molecule drugs and the complexity of the structures, efficient sampling of the accessible macrocycle conformational space and accurate prediction of their binding affinities to their target protein receptors poses a great challenge of central importance in computational macrocycle drug design. In this article, we present a novel method for relative binding free energy calculations between macrocycles with different ring sizes and between the macrocycles and their corresponding acyclic counterparts. We have applied the method to seven pharmaceutically interesting data sets taken from recent drug discovery projects including 33 macrocyclic ligands covering a diverse chemical space. The predicted binding free energies are in good agreement with experimental data with an overall root-mean-square error (RMSE) of 0.94 kcal/mol. This is to our knowledge the first time where the free energy of the macrocyclization of linear molecules has been directly calculated with rigorous physics-based free energy calculation methods, and we anticipate the outstanding accuracy demonstrated here across a broad range of target classes may have significant implications for macrocycle drug discovery.

How to deal with multiple binding poses in alchemical relative protein-ligand binding free energy calculations.

PubMed

Kaus, Joseph W; Harder, Edward; Lin, Teng; Abel, Robert; McCammon, J Andrew; Wang, Lingle

2015-06-09

Recent advances in improved force fields and sampling methods have made it possible for the accurate calculation of protein–ligand binding free energies. Alchemical free energy perturbation (FEP) using an explicit solvent model is one of the most rigorous methods to calculate relative binding free energies. However, for cases where there are high energy barriers separating the relevant conformations that are important for ligand binding, the calculated free energy may depend on the initial conformation used in the simulation due to the lack of complete sampling of all the important regions in phase space. This is particularly true for ligands with multiple possible binding modes separated by high energy barriers, making it difficult to sample all relevant binding modes even with modern enhanced sampling methods. In this paper, we apply a previously developed method that provides a corrected binding free energy for ligands with multiple binding modes by combining the free energy results from multiple alchemical FEP calculations starting from all enumerated poses, and the results are compared with Glide docking and MM-GBSA calculations. From these calculations, the dominant ligand binding mode can also be predicted. We apply this method to a series of ligands that bind to c-Jun N-terminal kinase-1 (JNK1) and obtain improved free energy results. The dominant ligand binding modes predicted by this method agree with the available crystallography, while both Glide docking and MM-GBSA calculations incorrectly predict the binding modes for some ligands. The method also helps separate the force field error from the ligand sampling error, such that deviations in the predicted binding free energy from the experimental values likely indicate possible inaccuracies in the force field. An error in the force field for a subset of the ligands studied was identified using this method, and improved free energy results were obtained by correcting the partial charges assigned to the ligands. This improved the root-mean-square error (RMSE) for the predicted binding free energy from 1.9 kcal/mol with the original partial charges to 1.3 kcal/mol with the corrected partial charges.

How To Deal with Multiple Binding Poses in Alchemical Relative Protein–Ligand Binding Free Energy Calculations

PubMed Central

2016-01-01

Recent advances in improved force fields and sampling methods have made it possible for the accurate calculation of protein–ligand binding free energies. Alchemical free energy perturbation (FEP) using an explicit solvent model is one of the most rigorous methods to calculate relative binding free energies. However, for cases where there are high energy barriers separating the relevant conformations that are important for ligand binding, the calculated free energy may depend on the initial conformation used in the simulation due to the lack of complete sampling of all the important regions in phase space. This is particularly true for ligands with multiple possible binding modes separated by high energy barriers, making it difficult to sample all relevant binding modes even with modern enhanced sampling methods. In this paper, we apply a previously developed method that provides a corrected binding free energy for ligands with multiple binding modes by combining the free energy results from multiple alchemical FEP calculations starting from all enumerated poses, and the results are compared with Glide docking and MM-GBSA calculations. From these calculations, the dominant ligand binding mode can also be predicted. We apply this method to a series of ligands that bind to c-Jun N-terminal kinase-1 (JNK1) and obtain improved free energy results. The dominant ligand binding modes predicted by this method agree with the available crystallography, while both Glide docking and MM-GBSA calculations incorrectly predict the binding modes for some ligands. The method also helps separate the force field error from the ligand sampling error, such that deviations in the predicted binding free energy from the experimental values likely indicate possible inaccuracies in the force field. An error in the force field for a subset of the ligands studied was identified using this method, and improved free energy results were obtained by correcting the partial charges assigned to the ligands. This improved the root-mean-square error (RMSE) for the predicted binding free energy from 1.9 kcal/mol with the original partial charges to 1.3 kcal/mol with the corrected partial charges. PMID:26085821

Graded activation and free energy landscapes of a muscarinic G-protein-coupled receptor.

PubMed

Miao, Yinglong; McCammon, J Andrew

2016-10-25

G-protein-coupled receptors (GPCRs) recognize ligands of widely different efficacies, from inverse to partial and full agonists, which transduce cellular signals at differentiated levels. However, the mechanism of such graded activation remains unclear. Using the Gaussian accelerated molecular dynamics (GaMD) method that enables both unconstrained enhanced sampling and free energy calculation, we have performed extensive GaMD simulations (∼19 μs in total) to investigate structural dynamics of the M 2 muscarinic GPCR that is bound by the full agonist iperoxo (IXO), the partial agonist arecoline (ARC), and the inverse agonist 3-quinuclidinyl-benzilate (QNB), in the presence or absence of the G-protein mimetic nanobody. In the receptor-nanobody complex, IXO binding leads to higher fluctuations in the protein-coupling interface than ARC, especially in the receptor transmembrane helix 5 (TM5), TM6, and TM7 intracellular domains that are essential elements for GPCR activation, but less flexibility in the receptor extracellular region due to stronger binding compared with ARC. Two different binding poses are revealed for ARC in the orthosteric pocket. Removal of the nanobody leads to GPCR deactivation that is characterized by inward movement of the TM6 intracellular end. Distinct low-energy intermediate conformational states are identified for the IXO- and ARC-bound M 2 receptor. Both dissociation and binding of an orthosteric ligand are observed in a single all-atom GPCR simulation in the case of partial agonist ARC binding to the M 2 receptor. This study demonstrates the applicability of GaMD for exploring free energy landscapes of large biomolecules and the simulations provide important insights into the GPCR functional mechanism.

Study of degenerate four-quark states with SU(2) lattice Monte Carlo techniques

NASA Astrophysics Data System (ADS)

Green, A. M.; Lukkarinen, J.; Pennanen, P.; Michael, C.

1996-01-01

The energies of four-quark states are calculated for geometries in which the quarks are situated on the corners of a series of tetrahedra and also for geometries that correspond to gradually distorting these tetrahedra into a plane. The interest in tetrahedra arises because they are composed of three degenerate partitions of the four quarks into two two-quark color singlets. This is an extension of earlier work showing that geometries with two degenerate partitions (e.g., squares) experience a large binding energy. It is now found that even larger binding energies do not result, but that for the tetrahedra the ground and first excited states become degenerate in energy. The calculation is carried out using SU(2) for static quarks in the quenched approximation with β=2.4 on a 163×32 lattice. The results are analyzed using the correlation matrix between different Euclidean times and the implications of these results are discussed for a model based on two-quark potentials.

Bandstructure modulation for Si-h and Si-g nanotubes in a transverse electric field: Tight binding approach

NASA Astrophysics Data System (ADS)

Chegel, Raad; Behzad, Somayeh

2013-11-01

We have investigated the electronic properties of SiNTs, under the external electric field, using Tight Binding (TB) approximation. It was found that the energy levels, energy gaps, and density of states (DOS) strongly depend on the electric field strength. The large electric strength leads to coupling the neighbor subbands and induce destruction of subband degeneracy, increase of low-energy states, and strong modulation of energy gap which these effects reflect in the DOS spectrum. It has been shown that, the band gap reduction of Si g-NTs is linearly proportional to the electric field strength. The band gap variation for Si h-NTs increases first and later decreases (Metallic) or first remains constant and then decreases (semiconductor). Also we show that the larger diameter tubes are more sensitive to the field strength than smaller ones. The semiconducting metallic transition or vice versa can be achieved through an increasing of applied fields. Number and position of peaks in DOS spectrum are dependent on electric field strength.

Probing Long-Range Neutrino-Mediated Forces with Atomic and Nuclear Spectroscopy.

PubMed

Stadnik, Yevgeny V

2018-06-01

The exchange of a pair of low-mass neutrinos between electrons, protons, and neutrons produces a "long-range" 1/r^{5} potential, which can be sought for in phenomena originating on the atomic and subatomic length scales. We calculate the effects of neutrino-pair exchange on transition and binding energies in atoms and nuclei. In the case of atomic s-wave states, there is a large enhancement of the induced energy shifts due to the lack of a centrifugal barrier and the highly singular nature of the neutrino-mediated potential. We derive limits on neutrino-mediated forces from measurements of the deuteron binding energy and transition energies in positronium, muonium, hydrogen, and deuterium, as well as isotope-shift measurements in calcium ions. Our limits improve on existing constraints on neutrino-mediated forces from experiments that search for new macroscopic forces by 18 orders of magnitude. Future spectroscopy experiments have the potential to probe long-range forces mediated by the exchange of pairs of standard-model neutrinos and other weakly charged particles.

Probing Long-Range Neutrino-Mediated Forces with Atomic and Nuclear Spectroscopy

NASA Astrophysics Data System (ADS)

Stadnik, Yevgeny V.

2018-06-01

The exchange of a pair of low-mass neutrinos between electrons, protons, and neutrons produces a "long-range" 1 /r5 potential, which can be sought for in phenomena originating on the atomic and subatomic length scales. We calculate the effects of neutrino-pair exchange on transition and binding energies in atoms and nuclei. In the case of atomic s -wave states, there is a large enhancement of the induced energy shifts due to the lack of a centrifugal barrier and the highly singular nature of the neutrino-mediated potential. We derive limits on neutrino-mediated forces from measurements of the deuteron binding energy and transition energies in positronium, muonium, hydrogen, and deuterium, as well as isotope-shift measurements in calcium ions. Our limits improve on existing constraints on neutrino-mediated forces from experiments that search for new macroscopic forces by 18 orders of magnitude. Future spectroscopy experiments have the potential to probe long-range forces mediated by the exchange of pairs of standard-model neutrinos and other weakly charged particles.

Effective Hamiltonian approach to bright and dark excitons in single-walled carbon nanotubes

NASA Astrophysics Data System (ADS)

Choi, Sangkook; Deslippe, Jack; Louie, Steven G.

2009-03-01

Recently, excitons in single-walled carbon nanotubes (SWCNTs) have generated great research interest due to the large binding energies and unique screening properties associated with one-dimensional (1D) materials. Considerable progress in their theoretical understanding has been achieved by studies employing the ab initio GW-Bethe-Salpeter equation methodology. For example, the presence of bright and dark excitons with binding energies of a large fraction of an eV has been predicted and subsequently verified by experiment. Some of these results have also been quantitatively reproduced by recent model calculations using a spatially dependent screened Coulomb interaction between the excited electron and hole, an approach that would be useful for studying large diameter and chiral nanotubes with many atoms per unit cell. However, this previous model neglects the degeneracy of the band states and hence the dark excitons. We present an extension of this exciton model for the SWCNT, incorporating the screened Coulomb interaction as well as state degeneracy, to understand and compute the characteristics of the bright and dark excitons, such as the bright and dark level splittings. Supported by NSF #DMR07-05941, DOE #De-AC02-05CH11231 and computational resources from Teragrid and NERSC.

ATP-induced conformational changes of nucleotide-binding domains in an ABC transporter. Importance of the water-mediated entropic force.

PubMed

Hayashi, Tomohiko; Chiba, Shuntaro; Kaneta, Yusuke; Furuta, Tadaomi; Sakurai, Minoru

2014-11-06

ATP binding cassette (ABC) proteins belong to a superfamily of active transporters. Recent experimental and computational studies have shown that binding of ATP to the nucleotide binding domains (NBDs) of ABC proteins drives the dimerization of NBDs, which, in turn, causes large conformational changes within the transmembrane domains (TMDs). To elucidate the active substrate transport mechanism of ABC proteins, it is first necessary to understand how the NBD dimerization is driven by ATP binding. In this study, we selected MalKs (NBDs of a maltose transporter) as a representative NBD and calculated the free-energy change upon dimerization using molecular mechanics calculations combined with a statistical thermodynamic theory of liquids, as well as a method to calculate the translational, rotational, and vibrational entropy change. This combined method is applied to a large number of snapshot structures obtained from molecular dynamics simulations containing explicit water molecules. The results suggest that the NBD dimerization proceeds with a large gain of water entropy when ATP molecules bind to the NBDs. The energetic gain arising from direct NBD-NBD interactions is canceled by the dehydration penalty and the configurational-entropy loss. ATP hydrolysis induces a loss of the shape complementarity between the NBDs, which leads to the dissociation of the dimer, due to a decrease in the water-entropy gain and an increase in the configurational-entropy loss. This interpretation of the NBD dimerization mechanism in concert with ATP, especially focused on the water-mediated entropy force, is potentially applicable to a wide variety of the ABC transporters.

Temperature and hydrostatic pressure effects on single dopant states in hollow cylindrical core-shell quantum dot

NASA Astrophysics Data System (ADS)

El-Yadri, M.; Aghoutane, N.; El Aouami, A.; Feddi, E.; Dujardin, F.; Duque, C. A.

2018-05-01

This work reports on theoretical investigation of the temperature and hydrostatic pressure effects on the confined donor impurity in a AlGaAs-GaAs hollow cylindrical core-shell quantum dot. The charges are assumed to be completely confined to the interior of the shell with approximately rigid walls. Within the framework of the effective-mass approximation and by using a variational approach, we have computed the donor binding energies as a function of the shell size in order to study the behavior of the electron-impurity attraction for a very small thickness under the influence of both temperature and hydrostatic pressure. Our results show that the temperature and hydrostatic pressure have a significant influence on the impurity binding energy for large shell quantum dots. It will be shown that the binding energy is more pronounced with increasing pressure and decreasing temperature for any impurity position and quantum dot size. The photoionization cross section is also analyzed by considering only the in-plane incident radiation polarization. Its behavior is investigated as a function of photon energy for different values of pressure and temperature. The opposite effects caused by temperature and hydrostatic pressure reveal a big practical interest and offer an alternative way to tuning of correlated electron-impurity transitions in optoelectronic devices.

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

PubMed

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

2016-07-14

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

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

NASA Astrophysics Data System (ADS)

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

2016-07-01

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

Nucleosome stability and accessibility of its DNA to proteins.

PubMed

Prinsen, Peter; Schiessel, Helmut

2010-12-01

In this paper we present a theoretical description of the accessibility of nucleosomal DNA to proteins. We reassess the classical analysis of Polach and Widom (1995) who demonstrated that proteins (in their case restriction enzymes) gain access to buried binding sites inside a nucleosome through spontaneous unwrapping of DNA from the protein spool. We introduce a straightforward nucleosome model the predictions of which show good agreement with experimental data. By fitting the model to the data we obtain the values of two quantities: the adsorption energy to the histone octamer per length of DNA and the extra length that the DNA needs to unwrap beyond the binding site of an enzyme before the enzyme can act as effectively as on bare DNA. Our results indicate that the effective binding energy is surprisingly low which suggests that the nucleosomal parameters are tuned such that two large energies, the DNA bending energy and the pure adsorption energy, nearly cancel. This paper is based on a lecture presented at the summer school "DNA and Chromosomes 2009: Physical and Biological Applications". We follow the lecture as closely as possible which is why we spend more time than usual on issues that are already well-known in the field, and why we discuss some well-known results from a different perspective. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Predicting bioactive conformations and binding modes of macrocycles

NASA Astrophysics Data System (ADS)

Anighoro, Andrew; de la Vega de León, Antonio; Bajorath, Jürgen

2016-10-01

Macrocyclic compounds experience increasing interest in drug discovery. It is often thought that these large and chemically complex molecules provide promising candidates to address difficult targets and interfere with protein-protein interactions. From a computational viewpoint, these molecules are difficult to treat. For example, flexible docking of macrocyclic compounds is hindered by the limited ability of current docking approaches to optimize conformations of extended ring systems for pose prediction. Herein, we report predictions of bioactive conformations of macrocycles using conformational search and binding modes using docking. Conformational ensembles generated using specialized search technique of about 70 % of the tested macrocycles contained accurate bioactive conformations. However, these conformations were difficult to identify on the basis of conformational energies. Moreover, docking calculations with limited ligand flexibility starting from individual low energy conformations rarely yielded highly accurate binding modes. In about 40 % of the test cases, binding modes were approximated with reasonable accuracy. However, when conformational ensembles were subjected to rigid body docking, an increase in meaningful binding mode predictions to more than 50 % of the test cases was observed. Electrostatic effects did not contribute to these predictions in a positive or negative manner. Rather, achieving shape complementarity at macrocycle-target interfaces was a decisive factor. In summary, a combined computational protocol using pre-computed conformational ensembles of macrocycles as a starting point for docking shows promise in modeling binding modes of macrocyclic compounds.

Modeling Ionization Events iduced by Protein Protein Binding

NASA Astrophysics Data System (ADS)

Mitra, Rooplekha; Shyam, Radhey; Alexov, Emil

2009-11-01

The association of two or more biological macromolecules dramatically change the environment of the amino acids situated at binding interface and could change ionization states of titratable groups. The change of ionization due to the binding results in proton uptake/release and causes pH-dependence of the binding free energy. We apply computational method, as implemented in Multi Conformation Continuum Electrostatics (MCCE) algorithm, to study protonation evens on a large set of protein-protein complexes. Our results indicate that proton uptake/release is a common phenomena in protein binding since in vast majority of the cases (70%) the binding caused at least 0.5 units proton change. The proton uptake/release was further investigated with respect to interfacial area and charges of the monomers and it was found that macroscopic characteristics are not important determinants. Instead, charge complementarity across the interface and the number of unpaired ionizable groups at the interface are the primary source of proton uptake/release.

Insights into the binding mode of sulphamates and sulphamides to hCA II: crystallographic studies and binding free energy calculations.

PubMed

De Simone, Giuseppina; Langella, Emma; Esposito, Davide; Supuran, Claudiu T; Monti, Simona Maria; Winum, Jean-Yves; Alterio, Vincenzo

2017-12-01

Sulphamate and sulphamide derivatives have been largely investigated as carbonic anhydrase inhibitors (CAIs) by means of different experimental techniques. However, the structural determinants responsible for their different binding mode to the enzyme active site were not clearly defined so far. In this paper, we report the X-ray crystal structure of hCA II in complex with a sulphamate inhibitor incorporating a nitroimidazole moiety. The comparison with the structure of hCA II in complex with its sulphamide analogue revealed that the two inhibitors adopt a completely different binding mode within the hCA II active site. Starting from these results, we performed a theoretical study on sulphamate and sulphamide derivatives, demonstrating that electrostatic interactions with residues within the enzyme active site play a key role in determining their binding conformation. These findings open new perspectives in the design of effective CAIs using the sulphamate and sulphamide zinc binding groups as lead compounds.

Isoelectronic bound-exciton photoluminescence in strained beryllium-doped Si0.92Ge0.08 epilayers and Si0.92Ge0.08/Si superlattices at ambient and elevated hydrostatic pressure

NASA Astrophysics Data System (ADS)

Kim, Sangsig; Chang, Ganlin; Herman, Irving P.; Bevk, Joze; Moore, Karen L.; Hall, Dennis G.

1997-03-01

Photoluminescence (PL) from a beryllium-doped Si0.92Ge0.08 epilayer and three different beryllium-doped Si0.92Ge0.08/Si superlattices (SL's) commensurately grown on Si(100) substrates is examined at 9 K at ambient pressure and, for the epilayer and one SL, as a function of hydrostatic pressure. In each structure, excitons bind to the isoelectronic Be pairs in the strained Si0.92Ge0.08 layers. The zero-phonon PL peaks of the epilayer and the in situ doped 50-Å Si0.92Ge0.08/100-Å Si SL shift linearly with pressure toward lower energy at the rate of 0.68+/-0.03 and 0.97+/-0.03 meV/kbar, respectively, which are near the 0.77-meV/kbar value for Si:Be. The PL energies at ambient and elevated pressure are analyzed by accounting for strain, quantum confinement, and exciton binding. A modified Hopfield-Thomas-Lynch model is used to model exciton binding to the Be pairs. This model, in which potential wells bind electrons to a site (that then trap holes), predicts a distribution of electron binding energies when an inhomogeneous distribution of potential-well depths is used. This accounts for the large PL linewidth and the decrease of linewidth with increasing pressure, among other observations. In SL's, the exciton binding energy is shown to depend on the width of the wells as well as the spatial distribution of Be dopants in the superlattice. Also, at and above 58 kbar a very unusual peak is observed in one of the SL's, which is associated with a free-exciton peak in Si, that shifts very fast with pressure (-6.02+/-0.03 meV/kbar).

Alchemical Free Energy Calculations for Nucleotide Mutations in Protein-DNA Complexes.

PubMed

Gapsys, Vytautas; de Groot, Bert L

2017-12-12

Nucleotide-sequence-dependent interactions between proteins and DNA are responsible for a wide range of gene regulatory functions. Accurate and generalizable methods to evaluate the strength of protein-DNA binding have long been sought. While numerous computational approaches have been developed, most of them require fitting parameters to experimental data to a certain degree, e.g., machine learning algorithms or knowledge-based statistical potentials. Molecular-dynamics-based free energy calculations offer a robust, system-independent, first-principles-based method to calculate free energy differences upon nucleotide mutation. We present an automated procedure to set up alchemical MD-based calculations to evaluate free energy changes occurring as the result of a nucleotide mutation in DNA. We used these methods to perform a large-scale mutation scan comprising 397 nucleotide mutation cases in 16 protein-DNA complexes. The obtained prediction accuracy reaches 5.6 kJ/mol average unsigned deviation from experiment with a correlation coefficient of 0.57 with respect to the experimentally measured free energies. Overall, the first-principles-based approach performed on par with the molecular modeling approaches Rosetta and FoldX. Subsequently, we utilized the MD-based free energy calculations to construct protein-DNA binding profiles for the zinc finger protein Zif268. The calculation results compare remarkably well with the experimentally determined binding profiles. The software automating the structure and topology setup for alchemical calculations is a part of the pmx package; the utilities have also been made available online at http://pmx.mpibpc.mpg.de/dna_webserver.html .

Relationship between Hot Spot Residues and Ligand Binding Hot Spots in Protein-Protein Interfaces

PubMed Central

Zerbe, Brandon S.; Hall, David R.

2013-01-01

In the context of protein-protein interactions, the term “hot spot” refers to a residue or cluster of residues that makes a major contribution to the binding free energy, as determined by alanine scanning mutagenesis. In contrast, in pharmaceutical research a hot spot is a site on a target protein that has high propensity for ligand binding and hence is potentially important for drug discovery. Here we examine the relationship between these two hot spot concepts by comparing alanine scanning data for a set of 15 proteins with results from mapping the protein surfaces for sites that can bind fragment-sized small molecules. We find the two types of hot spots are largely complementary; the residues protruding into hot spot regions identified by computational mapping or experimental fragment screening are almost always themselves hot spot residues as defined by alanine scanning experiments. Conversely, a residue that is found by alanine scanning to contribute little to binding rarely interacts with hot spot regions on the partner protein identified by fragment mapping. In spite of the strong correlation between the two hot spot concepts, they fundamentally differ, however. In particular, while identification of a hot spot by alanine scanning establishes the potential to generate substantial interaction energy with a binding partner, there are additional topological requirements to be a hot spot for small molecule binding. Hence, only a minority of hot spots identified by alanine scanning represent sites that are potentially useful for small inhibitor binding, and it is this subset that is identified by experimental or computational fragment screening. PMID:22770357

Relationship between hot spot residues and ligand binding hot spots in protein-protein interfaces.

PubMed

Zerbe, Brandon S; Hall, David R; Vajda, Sandor; Whitty, Adrian; Kozakov, Dima

2012-08-27

In the context of protein-protein interactions, the term "hot spot" refers to a residue or cluster of residues that makes a major contribution to the binding free energy, as determined by alanine scanning mutagenesis. In contrast, in pharmaceutical research, a hot spot is a site on a target protein that has high propensity for ligand binding and hence is potentially important for drug discovery. Here we examine the relationship between these two hot spot concepts by comparing alanine scanning data for a set of 15 proteins with results from mapping the protein surfaces for sites that can bind fragment-sized small molecules. We find the two types of hot spots are largely complementary; the residues protruding into hot spot regions identified by computational mapping or experimental fragment screening are almost always themselves hot spot residues as defined by alanine scanning experiments. Conversely, a residue that is found by alanine scanning to contribute little to binding rarely interacts with hot spot regions on the partner protein identified by fragment mapping. In spite of the strong correlation between the two hot spot concepts, they fundamentally differ, however. In particular, while identification of a hot spot by alanine scanning establishes the potential to generate substantial interaction energy with a binding partner, there are additional topological requirements to be a hot spot for small molecule binding. Hence, only a minority of hot spots identified by alanine scanning represent sites that are potentially useful for small inhibitor binding, and it is this subset that is identified by experimental or computational fragment screening.

Improved estimation of ligand macromolecule binding affinities by linear response approach using a combination of multi-mode MD simulation and QM/MM methods

NASA Astrophysics Data System (ADS)

Khandelwal, Akash; Balaz, Stefan

2007-01-01

Structure-based predictions of binding affinities of ligands binding to proteins by coordination bonds with transition metals, covalent bonds, and bonds involving charge re-distributions are hindered by the absence of proper force fields. This shortcoming affects all methods which use force-field-based molecular simulation data on complex formation for affinity predictions. One of the most frequently used methods in this category is the Linear Response (LR) approach of Åquist, correlating binding affinities with van der Waals and electrostatic energies, as extended by Jorgensen's inclusion of solvent-accessible surface areas. All these terms represent the differences, upon binding, in the ensemble averages of pertinent quantities, obtained from molecular dynamics (MD) or Monte Carlo simulations of the complex and of single components. Here we report a modification of the LR approach by: (1) the replacement of the two energy terms through the single-point QM/MM energy of the time-averaged complex structure from an MD simulation; and (2) a rigorous consideration of multiple modes (mm) of binding. The first extension alleviates the force-field related problems, while the second extension deals with the ligands exhibiting large-scale motions in the course of an MD simulation. The second modification results in the correlation equation that is nonlinear in optimized coefficients, but does not lead to an increase in the number of optimized coefficients. The application of the resulting mm QM/MM LR approach to the inhibition of zinc-dependent gelatinase B (matrix metalloproteinase 9) by 28 hydroxamate ligands indicates a significant improvement of descriptive and predictive abilities.

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

Li, Yang; Tu, Xingchen; Wang, Hao

The electronic efficiency and binding energy of contacts formed between graphene electrodes and poly-aromatic hydrocarbon (PAH) anchoring groups have been investigated by the non-equilibrium Green’s function formalism combined with density functional theory. Our calculations show that PAH molecules always bind in the interior and at the edge of graphene in the AB stacking manner, and that the binding energy increases following the increase of the number of carbon and hydrogen atoms constituting the PAH molecule. When we move to analyzing the electronic transport properties of molecular junctions with a six-carbon alkyne chain as the central molecule, the electronic efficiency ofmore » the graphene-PAH contacts is found to depend on the energy gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of the corresponding PAH anchoring group, rather than its size. To be specific, the smaller is the HOMO-LUMO gap of the PAH anchoring group, the higher is the electronic efficiency of the graphene-PAH contact. Although the HOMO-LUMO gap of a PAH molecule depends on its specific configuration, PAH molecules with similar atomic structures show a decreasing trend for their HOMO-LUMO gap as the number of fused benzene rings increases. Therefore, graphene-conjugated molecule-graphene junctions with high-binding and high-conducting graphene-PAH contacts can be realized by choosing appropriate PAH anchor groups with a large area and a small HOMO-LUMO gap.« less

Probing excitonic states in suspended two-dimensional semiconductors by photocurrent spectroscopy

DOE PAGES

Klots, A. R.; Newaz, A. K. M.; Wang, Bin; ...

2014-10-16

The optical response of semiconducting monolayer transition-metal dichalcogenides (TMDCs) is dominated by strongly bound excitons that are stable even at room temperature. However, substrate-related effects such as screening and disorder in currently available specimens mask many anticipated physical phenomena and limit device applications of TMDCs. Here, we demonstrate that that these undesirable effects are strongly suppressed in suspended devices. Extremely robust (photogain > 1,000) and fast (response time < 1 ms) photoresponse allow us to study, for the first time, the formation, binding energies, and dissociation mechanisms of excitons in TMDCs through photocurrent spectroscopy. By analyzing the spectral positions ofmore » peaks in the photocurrent and by comparing them with first-principles calculations, we obtain binding energies, band gaps and spin-orbit splitting in monolayer TMDCs. For monolayer MoS2, in particular, we obtain an extremely large binding energy for band-edge excitons, Ebind ≥ 570 meV. Along with band-edge excitons, we observe excitons associated with a van Hove singularity of rather unique nature. In conclusion, the analysis of the source-drain voltage dependence of photocurrent spectra reveals exciton dissociation and photoconversion mechanisms in TMDCs.« less

Simultaneous effects of temperature and pressure on the donor binding energy in a V-groove quantum wire

NASA Astrophysics Data System (ADS)

Khordad, R.

2010-03-01

The influence of temperature and pressure, simultaneously, on the binding energy of a hydrogenic donor impurity in a ridge GaAs/Ga 1- xAl xAs quantum wire is studied using a variational procedure within the effective mass approximation. The subband energy and the binding energy of the donor impurity in its ground state as a function of the wire bend width and impurity location at different temperatures and pressures are calculated. The results show that, when the temperature increases, the donor binding energy decreases for a constant applied pressure for all wire bend widths. Also, the binding energy increases by increasing the pressure for a constant temperature for all wire bend widths. In addition, when the temperature and pressure are applied simultaneously the binding energy decreases as the quantum wire bend width increases. On the whole, it is deduced that the temperature and pressure have important effects on the donor binding energy in a V-groove quantum wire.

Adsorption and diffusion of Ru adatoms on Ru(0001)-supported graphene: Large-scale first-principles calculations

DOE PAGES

Han, Yong; Evans, James W.

2015-10-27

Large-scale first-principles density functional theory calculations are performed to investigate the adsorption and diffusion of Ru adatoms on monolayer graphene (G) supported on Ru(0001). The G sheet exhibits a periodic moiré-cell superstructure due to lattice mismatch. Within a moiré cell, there are three distinct regions: fcc, hcp, and mound, in which the C6-ring center is above a fcc site, a hcp site, and a surface Ru atom of Ru(0001), respectively. The adsorption energy of a Ru adatom is evaluated at specific sites in these distinct regions. We find the strongest binding at an adsorption site above a C atom inmore » the fcc region, next strongest in the hcp region, then the fcc-hcp boundary (ridge) between these regions, and the weakest binding in the mound region. Behavior is similar to that observed from small-unit-cell calculations of Habenicht et al. [Top. Catal. 57, 69 (2014)], which differ from previous large-scale calculations. We determine the minimum-energy path for local diffusion near the center of the fcc region and obtain a local diffusion barrier of ~0.48 eV. We also estimate a significantly lower local diffusion barrier in the ridge region. These barriers and information on the adsorption energy variation facilitate development of a realistic model for the global potential energy surface for Ru adatoms. Furthermore, this in turn enables simulation studies elucidating diffusion-mediated directed-assembly of Ru nanoclusters during deposition of Ru on G/Ru(0001).« less

Adsorption and diffusion of Ru adatoms on Ru(0001)-supported graphene: Large-scale first-principles calculations

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

Han, Yong; Evans, James W.

2015-10-28

Large-scale first-principles density functional theory calculations are performed to investigate the adsorption and diffusion of Ru adatoms on monolayer graphene (G) supported on Ru(0001). The G sheet exhibits a periodic moiré-cell superstructure due to lattice mismatch. Within a moiré cell, there are three distinct regions: fcc, hcp, and mound, in which the C{sub 6}-ring center is above a fcc site, a hcp site, and a surface Ru atom of Ru(0001), respectively. The adsorption energy of a Ru adatom is evaluated at specific sites in these distinct regions. We find the strongest binding at an adsorption site above a C atommore » in the fcc region, next strongest in the hcp region, then the fcc-hcp boundary (ridge) between these regions, and the weakest binding in the mound region. Behavior is similar to that observed from small-unit-cell calculations of Habenicht et al. [Top. Catal. 57, 69 (2014)], which differ from previous large-scale calculations. We determine the minimum-energy path for local diffusion near the center of the fcc region and obtain a local diffusion barrier of ∼0.48 eV. We also estimate a significantly lower local diffusion barrier in the ridge region. These barriers and information on the adsorption energy variation facilitate development of a realistic model for the global potential energy surface for Ru adatoms. This in turn enables simulation studies elucidating diffusion-mediated directed-assembly of Ru nanoclusters during deposition of Ru on G/Ru(0001)« less

Resonant scattering due to adatoms in graphene: Top, bridge, and hollow positions

NASA Astrophysics Data System (ADS)

Irmer, Susanne; Kochan, Denis; Lee, Jeongsu; Fabian, Jaroslav

2018-02-01

We present a theoretical study of resonance characteristics in graphene from adatoms with s or pz character binding in top, bridge, and hollow positions. The adatoms are described by two tight-binding parameters: on-site energy and hybridization strength. We explore a wide range of different magnitudes of these parameters by employing T -matrix calculations in the single adatom limit and by tight-binding supercell calculations for dilute adatom coverage. We calculate the density of states and the momentum relaxation rate and extract the resonance level and resonance width. The top position with a large hybridization strength or, equivalently, small on-site energy, induces resonances close to zero energy. The bridge position, compared to top, is more sensitive to variation in the orbital tight-binding parameters. Resonances within the experimentally relevant energy window are found mainly for bridge adatoms with negative on-site energies. The effect of resonances from the top and bridge positions on the density of states and momentum relaxation rate is comparable and both positions give rise to a power-law decay of the resonant state in graphene. The hollow position with s orbital character is affected from destructive interference, which is seen from the very narrow resonance peaks in the density of states and momentum relaxation rate. The resonant state shows no clear tendency to a power-law decay around the impurity and its magnitude decreases strongly with lowering the adatom content in the supercell calculations. This is in contrast to the top and bridge positions. We conclude our study with a comparison to models of pointlike vacancies and strong midgap scatterers. The latter model gives rise to significantly higher momentum relaxation rates than caused by single adatoms.

Few residues within an extensive binding interface drive receptor interaction and determine the specificity of arrestin proteins.

PubMed

Vishnivetskiy, Sergey A; Gimenez, Luis E; Francis, Derek J; Hanson, Susan M; Hubbell, Wayne L; Klug, Candice S; Gurevich, Vsevolod V

2011-07-08

Arrestins bind active phosphorylated forms of G protein-coupled receptors, terminating G protein activation, orchestrating receptor trafficking, and redirecting signaling to alternative pathways. Visual arrestin-1 preferentially binds rhodopsin, whereas the two non-visual arrestins interact with hundreds of G protein-coupled receptor subtypes. Here we show that an extensive surface on the concave side of both arrestin-2 domains is involved in receptor binding. We also identified a small number of residues on the receptor binding surface of the N- and C-domains that largely determine the receptor specificity of arrestins. We show that alanine substitution of these residues blocks the binding of arrestin-1 to rhodopsin in vitro and of arrestin-2 and -3 to β2-adrenergic, M2 muscarinic cholinergic, and D2 dopamine receptors in intact cells, suggesting that these elements critically contribute to the energy of the interaction. Thus, in contrast to arrestin-1, where direct phosphate binding is crucial, the interaction of non-visual arrestins with their cognate receptors depends to a lesser extent on phosphate binding and more on the binding to non-phosphorylated receptor elements.

Few Residues within an Extensive Binding Interface Drive Receptor Interaction and Determine the Specificity of Arrestin Proteins*

PubMed Central

Vishnivetskiy, Sergey A.; Gimenez, Luis E.; Francis, Derek J.; Hanson, Susan M.; Hubbell, Wayne L.; Klug, Candice S.; Gurevich, Vsevolod V.

2011-01-01

Arrestins bind active phosphorylated forms of G protein-coupled receptors, terminating G protein activation, orchestrating receptor trafficking, and redirecting signaling to alternative pathways. Visual arrestin-1 preferentially binds rhodopsin, whereas the two non-visual arrestins interact with hundreds of G protein-coupled receptor subtypes. Here we show that an extensive surface on the concave side of both arrestin-2 domains is involved in receptor binding. We also identified a small number of residues on the receptor binding surface of the N- and C-domains that largely determine the receptor specificity of arrestins. We show that alanine substitution of these residues blocks the binding of arrestin-1 to rhodopsin in vitro and of arrestin-2 and -3 to β2-adrenergic, M2 muscarinic cholinergic, and D2 dopamine receptors in intact cells, suggesting that these elements critically contribute to the energy of the interaction. Thus, in contrast to arrestin-1, where direct phosphate binding is crucial, the interaction of non-visual arrestins with their cognate receptors depends to a lesser extent on phosphate binding and more on the binding to non-phosphorylated receptor elements. PMID:21471193

Binding selectivity of dibenzo-18-crown-6 for alkali metal cations in aqueous solution: A density functional theory study using a continuum solvation model.

PubMed

Choi, Chang Min; Heo, Jiyoung; Kim, Nam Joon

2012-08-08

Dibenzo-18-crown-6 (DB18C6) exhibits the binding selectivity for alkali metal cations in solution phase. In this study, we investigate the main forces that determine the binding selectivity of DB18C6 for the metal cations in aqueous solution using the density functional theory (DFT) and the conductor-like polarizable continuum model (CPCM). The bond dissociation free energies (BDFE) of DB18C6 complexes with alkali metal cations (M+-DB18C6, M = Li, Na, K, Rb, and Cs) in aqueous solution are calculated at the B3LYP/6-311++G(d,p)//B3LYP/6-31 + G(d) level using the CPCM. It is found that the theoretical BDFE is the largest for K+-DB18C6 and decreases as the size of the metal cation gets larger or smaller than that of K+, which agrees well with previous experimental results. The solvation energy of M+-DB18C6 in aqueous solution plays a key role in determining the binding selectivity of DB18C6. In particular, the non-electrostatic dispersion interaction between the solute and solvent, which depends strongly on the complex structure, is largely responsible for the different solvation energies of M+-DB18C6. This study shows that the implicit solvation model like the CPCM works reasonably well in predicting the binding selectivity of DB18C6 in aqueous solution.

Calculation of Free Energy Landscape in Multi-Dimensions with Hamiltonian-Exchange Umbrella Sampling on Petascale Supercomputer.

PubMed

Jiang, Wei; Luo, Yun; Maragliano, Luca; Roux, Benoît

2012-11-13

An extremely scalable computational strategy is described for calculations of the potential of mean force (PMF) in multidimensions on massively distributed supercomputers. The approach involves coupling thousands of umbrella sampling (US) simulation windows distributed to cover the space of order parameters with a Hamiltonian molecular dynamics replica-exchange (H-REMD) algorithm to enhance the sampling of each simulation. In the present application, US/H-REMD is carried out in a two-dimensional (2D) space and exchanges are attempted alternatively along the two axes corresponding to the two order parameters. The US/H-REMD strategy is implemented on the basis of parallel/parallel multiple copy protocol at the MPI level, and therefore can fully exploit computing power of large-scale supercomputers. Here the novel technique is illustrated using the leadership supercomputer IBM Blue Gene/P with an application to a typical biomolecular calculation of general interest, namely the binding of calcium ions to the small protein Calbindin D9k. The free energy landscape associated with two order parameters, the distance between the ion and its binding pocket and the root-mean-square deviation (rmsd) of the binding pocket relative the crystal structure, was calculated using the US/H-REMD method. The results are then used to estimate the absolute binding free energy of calcium ion to Calbindin D9k. The tests demonstrate that the 2D US/H-REMD scheme greatly accelerates the configurational sampling of the binding pocket, thereby improving the convergence of the potential of mean force calculation.

Free energy profiles of cocaine esterase-cocaine binding process by molecular dynamics and potential of mean force simulations.

PubMed

Zhang, Yuxin; Huang, Xiaoqin; Han, Keli; Zheng, Fang; Zhan, Chang-Guo

2016-11-25

The combined molecular dynamics (MD) and potential of mean force (PMF) simulations have been performed to determine the free energy profile of the CocE)-(+)-cocaine binding process in comparison with that of the corresponding CocE-(-)-cocaine binding process. According to the MD simulations, the equilibrium CocE-(+)-cocaine binding mode is similar to the CocE-(-)-cocaine binding mode. However, based on the simulated free energy profiles, a significant free energy barrier (∼5 kcal/mol) exists in the CocE-(+)-cocaine binding process whereas no obvious free energy barrier exists in the CocE-(-)-cocaine binding process, although the free energy barrier of ∼5 kcal/mol is not high enough to really slow down the CocE-(+)-cocaine binding process. In addition, the obtained free energy profiles also demonstrate that (+)-cocaine and (-)-cocaine have very close binding free energies with CocE, with a negligible difference (∼0.2 kcal/mol), which is qualitatively consistent with the nearly same experimental K M values of the CocE enzyme for (+)-cocaine and (-)-cocaine. The consistency between the computational results and available experimental data suggests that the mechanistic insights obtained from this study are reasonable. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Prediction of binding free energy for adsorption of antimicrobial peptide lactoferricin B on a POPC membrane

NASA Astrophysics Data System (ADS)

Vivcharuk, Victor; Tomberli, Bruno; Tolokh, Igor S.; Gray, C. G.

2008-03-01

Molecular dynamics (MD) simulations are used to study the interaction of a zwitterionic palmitoyl-oleoyl-phosphatidylcholine (POPC) bilayer with the cationic antimicrobial peptide bovine lactoferricin (LFCinB) in a 100 mM NaCl solution at 310 K. The interaction of LFCinB with POPC is used as a model system for studying the details of membrane-peptide interactions, with the peptide selected because of its antimicrobial nature. Seventy-two 3 ns MD simulations, with six orientations of LFCinB at 12 different distances from a POPC membrane, are carried out to determine the potential of mean force (PMF) or free energy profile for the peptide as a function of the distance between LFCinB and the membrane surface. To calculate the PMF for this relatively large system a new variant of constrained MD and thermodynamic integration is developed. A simplified method for relating the PMF to the LFCinB-membrane binding free energy is described and used to predict a free energy of adsorption (or binding) of -1.05±0.39kcal/mol , and corresponding maximum binding force of about 20 pN, for LFCinB-POPC. The contributions of the ions-LFCinB and the water-LFCinB interactions to the PMF are discussed. The method developed will be a useful starting point for future work simulating peptides interacting with charged membranes and interactions involved in the penetration of membranes, features necessary to understand in order to rationally design peptides as potential alternatives to traditional antibiotics.

Prediction of binding free energy for adsorption of antimicrobial peptide lactoferricin B on a POPC membrane.

PubMed

Vivcharuk, Victor; Tomberli, Bruno; Tolokh, Igor S; Gray, C G

2008-03-01

Molecular dynamics (MD) simulations are used to study the interaction of a zwitterionic palmitoyl-oleoyl-phosphatidylcholine (POPC) bilayer with the cationic antimicrobial peptide bovine lactoferricin (LFCinB) in a 100 mM NaCl solution at 310 K. The interaction of LFCinB with POPC is used as a model system for studying the details of membrane-peptide interactions, with the peptide selected because of its antimicrobial nature. Seventy-two 3 ns MD simulations, with six orientations of LFCinB at 12 different distances from a POPC membrane, are carried out to determine the potential of mean force (PMF) or free energy profile for the peptide as a function of the distance between LFCinB and the membrane surface. To calculate the PMF for this relatively large system a new variant of constrained MD and thermodynamic integration is developed. A simplified method for relating the PMF to the LFCinB-membrane binding free energy is described and used to predict a free energy of adsorption (or binding) of -1.05+/-0.39 kcal/mol , and corresponding maximum binding force of about 20 pN, for LFCinB-POPC. The contributions of the ions-LFCinB and the water-LFCinB interactions to the PMF are discussed. The method developed will be a useful starting point for future work simulating peptides interacting with charged membranes and interactions involved in the penetration of membranes, features necessary to understand in order to rationally design peptides as potential alternatives to traditional antibiotics.

Cloud computing approaches for prediction of ligand binding poses and pathways.

PubMed

Lawrenz, Morgan; Shukla, Diwakar; Pande, Vijay S

2015-01-22

We describe an innovative protocol for ab initio prediction of ligand crystallographic binding poses and highly effective analysis of large datasets generated for protein-ligand dynamics. We include a procedure for setup and performance of distributed molecular dynamics simulations on cloud computing architectures, a model for efficient analysis of simulation data, and a metric for evaluation of model convergence. We give accurate binding pose predictions for five ligands ranging in affinity from 7 nM to > 200 μM for the immunophilin protein FKBP12, for expedited results in cases where experimental structures are difficult to produce. Our approach goes beyond single, low energy ligand poses to give quantitative kinetic information that can inform protein engineering and ligand design.

The Strength of Hydrogen Bonds between Fluoro-Organics and Alcohols, a Theoretical Study.

PubMed

Rosenberg, Robert E

2018-05-10

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 strengths of hydrogen bonds involving fluorine. There are only a few published examples of the strengths of these bonds. This study provides a high level ab initio study of inter- and intramolecular hydrogen bonds between RF and R'OH, where R and R' are aryl, vinyl, alkyl, and cycloalkyl. Intermolecular binding energies average near 5 kcal/mol, while intramolecular binding energies average about 3 kcal/mol. Inclusion of zero-point energies and applying a counterpoise correction lessen the difference. In both series, modest increases in binding energies are seen with increased acidity of R'OH and increased electron donation of R in RF. In the intramolecular compounds, binding energy increases with the rigidity of the F-(C) n -OH ring. Inclusion of free energy corrections at 298 K results in exoergic binding energies for the intramolecular compounds and endoergic binding energies for the intermolecular compounds. Parameters such as bond lengths, vibrational frequencies, and atomic populations are consistent with formation of a hydrogen bond and with slightly stronger binding in the intermolecular cases over the intramolecular cases. However, these parameters correlated poorly with binding energies.

Breaking the bottleneck: Use of molecular tailoring approach for the estimation of binding energies at MP2/CBS limit for large water clusters

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

Singh, Gurmeet; Nandi, Apurba; Gadre, Shridhar R., E-mail: gadre@iitk.ac.in

2016-03-14

A pragmatic method based on the molecular tailoring approach (MTA) for estimating the complete basis set (CBS) limit at Møller-Plesset second order perturbation (MP2) theory accurately for large molecular clusters with limited computational resources is developed. It is applied to water clusters, (H{sub 2}O){sub n} (n = 7, 8, 10, 16, 17, and 25) optimized employing aug-cc-pVDZ (aVDZ) basis-set. Binding energies (BEs) of these clusters are estimated at the MP2/aug-cc-pVNZ (aVNZ) [N = T, Q, and 5 (whenever possible)] levels of theory employing grafted MTA (GMTA) methodology and are found to lie within 0.2 kcal/mol of the corresponding full calculationmore » MP2 BE, wherever available. The results are extrapolated to CBS limit using a three point formula. The GMTA-MP2 calculations are feasible on off-the-shelf hardware and show around 50%–65% saving of computational time. The methodology has a potential for application to molecular clusters containing ∼100 atoms.« less

Asymmetric Assembly of Merkel Cell Polyomavirus Large T-Antigen Origin Binding Domains at the Viral Origin

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

C Harrison; G Meinke; H Kwun

2011-12-31

The double-stranded DNA polyomavirus Merkel cell polyomavirus (MCV) causes Merkel cell carcinoma, an aggressive but rare human skin cancer that most often affects immunosuppressed and elderly persons. As in other polyomaviruses, the large T-antigen of MCV recognizes the viral origin of replication by binding repeating G(A/G)GGC pentamers. The spacing, number, orientation, and necessity of repeats for viral replication differ, however, from other family members such as SV40 and murine polyomavirus. We report here the 2.9 {angstrom} crystal structure of the MCV large T-antigen origin binding domain (OBD) in complex with a DNA fragment from the MCV origin of replication. Consistentmore » with replication data showing that three of the G(A/G)GGC-like binding sites near the center of the origin are required for replication, the crystal structure contains three copies of the OBD. This stoichiometry was verified using isothermal titration calorimetry. The affinity for G(A/G)GGC-containing double-stranded DNA was found to be {approx} 740 nM, approximately 8-fold weaker than the equivalent domain in SV40 for the analogous region of the SV40 origin. The difference in affinity is partially attributable to DNA-binding residue Lys331 (Arg154 in SV40). In contrast to SV40, a small protein-protein interface is observed between MCV OBDs when bound to the central region of the origin. This protein-protein interface is reminiscent of that seen in bovine papilloma virus E1 protein. Mutational analysis indicates, however, that this interface contributes little to DNA binding energy.« less

Computing the binding affinity of a ligand buried deep inside a protein with the hybrid steered molecular dynamics

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

Villarreal, Oscar D.; Yu, Lili; Department of Laboratory Medicine, Yancheng Vocational Institute of Health Sciences, Yancheng, Jiangsu 224006

Computing the ligand-protein binding affinity (or the Gibbs free energy) with chemical accuracy has long been a challenge for which many methods/approaches have been developed and refined with various successful applications. False positives and, even more harmful, false negatives have been and still are a common occurrence in practical applications. Inevitable in all approaches are the errors in the force field parameters we obtain from quantum mechanical computation and/or empirical fittings for the intra- and inter-molecular interactions. These errors propagate to the final results of the computed binding affinities even if we were able to perfectly implement the statistical mechanicsmore » of all the processes relevant to a given problem. And they are actually amplified to various degrees even in the mature, sophisticated computational approaches. In particular, the free energy perturbation (alchemical) approaches amplify the errors in the force field parameters because they rely on extracting the small differences between similarly large numbers. In this paper, we develop a hybrid steered molecular dynamics (hSMD) approach to the difficult binding problems of a ligand buried deep inside a protein. Sampling the transition along a physical (not alchemical) dissociation path of opening up the binding cavity- -pulling out the ligand- -closing back the cavity, we can avoid the problem of error amplifications by not relying on small differences between similar numbers. We tested this new form of hSMD on retinol inside cellular retinol-binding protein 1 and three cases of a ligand (a benzylacetate, a 2-nitrothiophene, and a benzene) inside a T4 lysozyme L99A/M102Q(H) double mutant. In all cases, we obtained binding free energies in close agreement with the experimentally measured values. This indicates that the force field parameters we employed are accurate and that hSMD (a brute force, unsophisticated approach) is free from the problem of error amplification suffered by many sophisticated approaches in the literature.« less

Influence of polarization and self-polarization charges on impurity binding energy in spherical quantum dot with parabolic confinement

NASA Astrophysics Data System (ADS)

Sarkar, Supratik; Sarkar, Samrat; Bose, Chayanika

2018-07-01

We present a general formulation of the ground state binding energy of a shallow hydrogenic impurity in spherical quantum dot with parabolic confinement, considering the effects of polarization and self energy. The variational approach within the effective mass approximation is employed here. The binding energy of an on-center impurity is computed for a GaAs/AlxGa1-xAs quantum dot as a function of the dot size with the dot barrier as parameter. The influence of polarization and self energy are also treated separately. Results indicate that the binding energy increases due to the presence of polarization charge, while decreases due to the self energy of the carrier. An overall enhancement in impurity binding energy, especially for small dots is noted.

The structure and energetics of Cr(CO)6 and Cr(CO)5

NASA Technical Reports Server (NTRS)

Barnes, Leslie A.; Liu, Bowen; Lindh, Roland

1992-01-01

The geometric structure of Cr(CO)6 is optimized at the modified coupled pair functional (MCPF), single and double excitation coupled-cluster (CCSD) and CCSD(T) levels of theory (including a perturbational estimate for connected triple excitations), and the force constants for the totally symmetric representation are determined. The geometry of Cr(CO)5 is partially optimized at the MCPF, CCSD, and CCSD(T) levels of theory. Comparison with experimental data shows that the CCSD(T) method gives the best results for the structures and force constants, and that remaining errors are probably due to deficiencies in the one-particle basis sets used for CO. The total binding energies of Cr(CO)6 and Cr(CO)5 are also determined at the MCPF, CCSD, and CCSD(T) levels of theory. The CCSD(T) method gives a much larger total binding energy than either the MCPF or CCSD methods. An analysis of the basis set superposition error (BSSE) at the MCPF level of treatment points out limitations in the one-particle basis used. Calculations using larger basis sets reduce the BSSE, but the total binding energy of Cr(CO)6 is still significantly smaller than the experimental value, although the first CO bond dissociation energy of Cr(CO)6 is well described. An investigation of 3s3p correlation reveals only a small effect. In the largest basis set, the total CO binding energy of Cr(CO)6 is estimated to be 140 kcal/mol at the CCSD(T) level of theory, or about 86 percent of the experimental value. The remaining discrepancy between the experimental and theoretical value is probably due to limitations in the one-particle basis, rather than limitations in the correlation treatment. In particular an additional d function and an f function on each C and O are needed to obtain quantitative results. This is underscored by the fact that even using a very large primitive set (1042 primitive functions contracted to 300 basis functions), the superposition error for the total binding energy of Cr(CO)6 is 22 kcal/mol at the MCPF level of treatment.

Universal binding energy relations in metallic adhesion

NASA Technical Reports Server (NTRS)

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

1981-01-01

Scaling relations which map metallic adhesive binding energy onto a single universal binding energy curve are discussed in relation to adhesion, friction, and wear in metals. The scaling involved normalizing the energy to the maximum binding energy and normalizing distances by a suitable combination of Thomas-Fermi screening lengths. The universal curve was found to be accurately represented by E*(A*)= -(1+beta A) exp (-Beta A*) where E* is the normalized binding energy, A* is the normalized separation, and beta is the normalized decay constant. The calculated cohesive energies of potassium, barium, copper, molybdenum, and samarium were also found to scale by similar relations, suggesting that the universal relation may be more general than for the simple free electron metals.

Electrostatics, structure prediction, and the energy landscapes for protein folding and binding.

PubMed

Tsai, Min-Yeh; Zheng, Weihua; Balamurugan, D; Schafer, Nicholas P; Kim, Bobby L; Cheung, Margaret S; Wolynes, Peter G

2016-01-01

While being long in range and therefore weakly specific, electrostatic interactions are able to modulate the stability and folding landscapes of some proteins. The relevance of electrostatic forces for steering the docking of proteins to each other is widely acknowledged, however, the role of electrostatics in establishing specifically funneled landscapes and their relevance for protein structure prediction are still not clear. By introducing Debye-Hückel potentials that mimic long-range electrostatic forces into the Associative memory, Water mediated, Structure, and Energy Model (AWSEM), a transferable protein model capable of predicting tertiary structures, we assess the effects of electrostatics on the landscapes of thirteen monomeric proteins and four dimers. For the monomers, we find that adding electrostatic interactions does not improve structure prediction. Simulations of ribosomal protein S6 show, however, that folding stability depends monotonically on electrostatic strength. The trend in predicted melting temperatures of the S6 variants agrees with experimental observations. Electrostatic effects can play a range of roles in binding. The binding of the protein complex KIX-pKID is largely assisted by electrostatic interactions, which provide direct charge-charge stabilization of the native state and contribute to the funneling of the binding landscape. In contrast, for several other proteins, including the DNA-binding protein FIS, electrostatics causes frustration in the DNA-binding region, which favors its binding with DNA but not with its protein partner. This study highlights the importance of long-range electrostatics in functional responses to problems where proteins interact with their charged partners, such as DNA, RNA, as well as membranes. © 2015 The Protein Society.

Transport of Indirect Excitons in High Magnetic Fields

NASA Astrophysics Data System (ADS)

Dorow, C. J.; Kuznetsova, Y. Y.; Calman, E. V.; Butov, L. V.; Wilkes, J.; Campman, K. L.; Gossard, A. C.

Spatially- and spectrally-resolved photoluminescence measurements of indirect excitons in high magnetic fields are presented. The high magnetic field regime for excitons is realized when the cyclotron splitting compares to the exciton binding energy. Due to small mass and binding energy, the high magnetic field regime for excitons is achievable in lab, requiring a few Tesla. Long indirect exciton lifetimes allow large exciton transport distances before recombination, giving an opportunity to study transport and relaxation kinetics of indirect magnetoexcitons via optical imaging. Indirect excitons in several Landau level states are realized. 0e -0h indirect magnetoexcitons (formed from electrons and holes at zeroth Landau levels) travel over large distances and form an emission ring around the excitation spot. In contrast, the 1e -1h and 2e -2h states do not exhibit long transport distances, and the spatial profiles of the emission closely follow the laser excitation. The 0e -0h indirect magnetoexciton transport distance reduces with increasing magnetic field. Accompanying theoretical work explains these effects in terms of magnetoexciton energy relaxation and effective mass enhancement. Supported by NSF Grant No. 1407277. J.W. was supported by the EPSRC (Grant EP/L022990/1). C.J.D. was supported by the NSF Graduate Research Fellowship Program under Grant No. DGE-1144086.

Thermodynamics of Aryl-Dihydroxyphenyl-Thiadiazole Binding to Human Hsp90

PubMed Central

Kazlauskas, Egidijus; Petrikaitė, Vilma; Michailovienė, Vilma; Revuckienė, Jurgita; Matulienė, Jurgita; Grinius, Leonas; Matulis, Daumantas

2012-01-01

The design of specific inhibitors against the Hsp90 chaperone and other enzyme relies on the detailed and correct understanding of both the thermodynamics of inhibitor binding and the structural features of the protein-inhibitor complex. Here we present a detailed thermodynamic study of binding of aryl-dihydroxyphenyl-thiadiazole inhibitor series to recombinant human Hsp90 alpha isozyme. The inhibitors are highly potent, with the intrinsic Kd approximately equal to 1 nM as determined by isothermal titration calorimetry (ITC) and thermal shift assay (TSA). Dissection of protonation contributions yielded the intrinsic thermodynamic parameters of binding, such as enthalpy, entropy, Gibbs free energy, and the heat capacity. The differences in binding thermodynamic parameters between the series of inhibitors revealed contributions of the functional groups, thus providing insight into molecular reasons for improved or diminished binding efficiency. The inhibitor binding to Hsp90 alpha primarily depended on a large favorable enthalpic contribution combined with the smaller favorable entropic contribution, thus suggesting that their binding was both enthalpically and entropically optimized. The enthalpy-entropy compensation phenomenon was highly evident when comparing the inhibitor binding enthalpies and entropies. This study illustrates how detailed thermodynamic analysis helps to understand energetic reasons for the binding efficiency and develop more potent inhibitors that could be applied for therapeutic use as Hsp90 inhibitors. PMID:22655030

Adaptive Biasing Combined with Hamiltonian Replica Exchange to Improve Umbrella Sampling Free Energy Simulations.

PubMed

Zeller, Fabian; Zacharias, Martin

2014-02-11

The accurate calculation of potentials of mean force for ligand-receptor binding is one of the most important applications of molecular simulation techniques. Typically, the separation distance between ligand and receptor is chosen as a reaction coordinate along which a PMF can be calculated with the aid of umbrella sampling (US) techniques. In addition, restraints can be applied on the relative position and orientation of the partner molecules to reduce accessible phase space. An approach combining such phase space reduction with flattening of the free energy landscape and configurational exchanges has been developed, which significantly improves the convergence of PMF calculations in comparison with standard umbrella sampling. The free energy surface along the reaction coordinate is smoothened by iteratively adapting biasing potentials corresponding to previously calculated PMFs. Configurations are allowed to exchange between the umbrella simulation windows via the Hamiltonian replica exchange method. The application to a DNA molecule in complex with a minor groove binding ligand indicates significantly improved convergence and complete reversibility of the sampling along the pathway. The calculated binding free energy is in excellent agreement with experimental results. In contrast, the application of standard US resulted in large differences between PMFs calculated for association and dissociation pathways. The approach could be a useful alternative to standard US for computational studies on biomolecular recognition processes.

Effects of Molecular Stresses on Energy Transfer Pathways in Opto- and Electro-Excited Conjugated Polymers for High-Efficiency Optoelectronic Devices

DTIC Science & Technology

2014-10-20

unless it hops, and lead to obstructed recombination for PL or charge separation for solar cells and the reduced quantum efficiencies of the...excitons (Fig. 1a and 1b). For the free-moving delocalized states of the Wannier-Mott excitons, the binding energy in silicon , for example, is around...typically encompass many unit cells and typically exist in materials of small bandgap and large dielectric constant. In converse, the the tightly

Binding free energy calculations between bovine β-lactoglobulin and four fatty acids using the MMGBSA method.

PubMed

Bello, Martiniano

2014-10-01

The bovine dairy protein β-lactoglobulin (βlg) is a promiscuous protein that has the ability to bind several hydrophobic ligands. In this study, based on known experimental data, the dynamic interaction mechanism between bovine βlg and four fatty acids was investigated by a protocol combining molecular dynamics (MD) simulations and molecular mechanics generalized Born surface area (MMGBSA) binding free energy calculations. Energetic analyses revealed binding free energy trends that corroborated known experimental findings; larger ligand size corresponded to greater binding affinity. Finally, binding free energy decomposition provided detailed information about the key residues stabilizing the complex. © 2014 Wiley Periodicals, Inc.

A Prediction Method of Binding Free Energy of Protein and Ligand

NASA Astrophysics Data System (ADS)

Yang, Kun; Wang, Xicheng

2010-05-01

Predicting the binding free energy is an important problem in bimolecular simulation. Such prediction would be great benefit in understanding protein functions, and may be useful for computational prediction of ligand binding strengths, e.g., in discovering pharmaceutical drugs. Free energy perturbation (FEP)/thermodynamics integration (TI) is a classical method to explicitly predict free energy. However, this method need plenty of time to collect datum, and that attempts to deal with some simple systems and small changes of molecular structures. Another one for estimating ligand binding affinities is linear interaction energy (LIE) method. This method employs averages of interaction potential energy terms from molecular dynamics simulations or other thermal conformational sampling techniques. Incorporation of systematic deviations from electrostatic linear response, derived from free energy perturbation studies, into the absolute binding free energy expression significantly enhances the accuracy of the approach. However, it also is time-consuming work. In this paper, a new prediction method based on steered molecular dynamics (SMD) with direction optimization is developed to compute binding free energy. Jarzynski's equality is used to derive the PMF or free-energy. The results for two numerical examples are presented, showing that the method has good accuracy and efficiency. The novel method can also simulate whole binding proceeding and give some important structural information about development of new drugs.

Large-Scale Conformational Dynamics Control H5N1 Influenza Polymerase PB2 Binding to Importin α.

PubMed

Delaforge, Elise; Milles, Sigrid; Bouvignies, Guillaume; Bouvier, Denis; Boivin, Stephane; Salvi, Nicola; Maurin, Damien; Martel, Anne; Round, Adam; Lemke, Edward A; Jensen, Malene Ringkjøbing; Hart, Darren J; Blackledge, Martin

2015-12-09

Influenza A RNA polymerase complex is formed from three components, PA, PB1, and PB2. PB2 is independently imported into the nucleus prior to polymerase reconstitution. All crystallographic structures of the PB2 C-terminus (residues 536-759) reveal two globular domains, 627 and NLS, that form a tightly packed heterodimer. The molecular basis of the affinity of 627-NLS for importins remained unclear from these structures, apparently requiring large-scale conformational changes prior to importin binding. Using a combination of solution-state NMR, small-angle neutron scattering, small-angle X-ray scattering (SAXS), and Förster resonance energy transfer (FRET), we show that 627-NLS populates a temperature-dependent dynamic equilibrium between closed and open states. The closed state is stabilized by a tripartite salt bridge involving the 627-NLS interface and the linker, that becomes flexible in the open state, with 627 and NLS dislocating into a highly dynamic ensemble. Activation enthalpies and entropies associated with the rupture of this interface were derived from simultaneous analysis of temperature-dependent chemical exchange saturation transfer measurements, revealing a strong temperature dependence of both open-state population and exchange rate. Single-molecule FRET and SAXS demonstrate that only the open-form is capable of binding to importin α and that, upon binding, the 627 domain samples a dynamic conformational equilibrium in the vicinity of the C-terminus of importin α. This intrinsic large-scale conformational flexibility therefore enables 627-NLS to bind importin through conformational selection from a temperature-dependent equilibrium comprising both functional forms of the protein.

Zinc finger protein binding to DNA: an energy perspective using molecular dynamics simulation and free energy calculations on mutants of both zinc finger domains and their specific DNA bases.

PubMed

Hamed, Mazen Y; Arya, Gaurav

2016-05-01

Energy calculations based on MM-GBSA were employed to study various zinc finger protein (ZF) motifs binding to DNA. Mutants of both the DNA bound to their specific amino acids were studied. Calculated energies gave evidence for a relationship between binding energy and affinity of ZF motifs to their sites on DNA. ΔG values were -15.82(12), -3.66(12), and -12.14(11.6) kcal/mol for finger one, finger two, and finger three, respectively. The mutations in the DNA bases reduced the value of the negative energies of binding (maximum value for ΔΔG = 42Kcal/mol for F1 when GCG mutated to GGG, and ΔΔG = 22 kcal/mol for F2, the loss in total energy of binding originated in the loss in electrostatic energies upon mutation (r = .98). The mutations in key amino acids in the ZF motif in positions-1, 2, 3, and 6 showed reduced binding energies to DNA with correlation coefficients between total free energy and electrostatic was .99 and with Van der Waal was .93. Results agree with experimentally found selectivity which showed that Arginine in position-1 is specific to G, while Aspartic acid (D) in position 2 plays a complicated role in binding. There is a correlation between the MD calculated free energies of binding and those obtained experimentally for prepared ZF motifs bound to triplet bases in other reports (), our results may help in the design of ZF motifs based on the established recognition codes based on energies and contributing energies to the total energy.

Functional anatomy of an allosteric protein

NASA Astrophysics Data System (ADS)

Purohit, Prasad; Gupta, Shaweta; Jadey, Snehal; Auerbach, Anthony

2013-12-01

Synaptic receptors are allosteric proteins that switch on and off to regulate cell signalling. Here, we use single-channel electrophysiology to measure and map energy changes in the gating conformational change of a nicotinic acetylcholine receptor. Two separated regions in the α-subunits—the transmitter-binding sites and αM2-αM3 linkers in the membrane domain—have the highest ϕ-values (change conformation the earliest), followed by the extracellular domain, most of the membrane domain and the gate. Large gating-energy changes occur at the transmitter-binding sites, α-subunit interfaces, the αM1 helix and the gate. We hypothesize that rearrangements of the linkers trigger the global allosteric transition, and that the hydrophobic gate unlocks in three steps. The mostly local character of side-chain energy changes and the similarly high ϕ-values of separated domains, both with and without ligands, suggest that gating is not strictly a mechanical process initiated by the affinity change for the agonist.

A study of planar anchor groups for graphene-based single-molecule electronics.

PubMed

Bailey, Steven; Visontai, David; Lambert, Colin J; Bryce, Martin R; Frampton, Harry; Chappell, David

2014-02-07

To identify families of stable planar anchor groups for use in single molecule electronics, we report detailed results for the binding energies of two families of anthracene and pyrene derivatives adsorbed onto graphene. We find that all the selected derivatives functionalized with either electron donating or electron accepting substituents bind more strongly to graphene than the parent non-functionalized anthracene or pyrene. The binding energy is sensitive to the detailed atomic alignment of substituent groups over the graphene substrate leading to larger than expected binding energies for -OH and -CN derivatives. Furthermore, the ordering of the binding energies within the anthracene and pyrene series does not simply follow the electron affinities of the substituents. Energy barriers to rotation or displacement on the graphene surface are much lower than binding energies for adsorption and therefore at room temperature, although the molecules are bound to the graphene, they are almost free to move along the graphene surface. Binding energies can be increased by incorporating electrically inert side chains and are sensitive to the conformation of such chains.

A study of planar anchor groups for graphene-based single-molecule electronics

NASA Astrophysics Data System (ADS)

Bailey, Steven; Visontai, David; Lambert, Colin J.; Bryce, Martin R.; Frampton, Harry; Chappell, David

2014-02-01

To identify families of stable planar anchor groups for use in single molecule electronics, we report detailed results for the binding energies of two families of anthracene and pyrene derivatives adsorbed onto graphene. We find that all the selected derivatives functionalized with either electron donating or electron accepting substituents bind more strongly to graphene than the parent non-functionalized anthracene or pyrene. The binding energy is sensitive to the detailed atomic alignment of substituent groups over the graphene substrate leading to larger than expected binding energies for -OH and -CN derivatives. Furthermore, the ordering of the binding energies within the anthracene and pyrene series does not simply follow the electron affinities of the substituents. Energy barriers to rotation or displacement on the graphene surface are much lower than binding energies for adsorption and therefore at room temperature, although the molecules are bound to the graphene, they are almost free to move along the graphene surface. Binding energies can be increased by incorporating electrically inert side chains and are sensitive to the conformation of such chains.

Interaction of promethazine and adiphenine to human hemoglobin: A comparative spectroscopic and computational analysis

NASA Astrophysics Data System (ADS)

Maurya, Neha; ud din Parray, Mehraj; Maurya, Jitendra Kumar; Kumar, Amit; Patel, Rajan

2018-06-01

The binding nature of amphiphilic drugs viz. promethazine hydrochloride (PMT) and adiphenine hydrochloride (ADP), with human hemoglobin (Hb) was unraveled by fluorescence, absorbance, time resolved fluorescence, fluorescence resonance energy transfer (FRET) and circular dichroism (CD) spectral techniques in combination with molecular docking and molecular dynamic simulation methods. The steady state fluorescence spectra indicated that both PMT and ADP quenches the fluorescence of Hb through static quenching mechanism which was further confirmed by time resolved fluorescence spectra. The UV-Vis spectroscopy suggested ground state complex formation. The activation energy (Ea) was observed more in the case of Hb-ADP than Hb-PMT interaction system. The FRET result indicates the high probability of energy transfer from β Trp37 residue of Hb to the PMT (r = 2.02 nm) and ADP (r = 2.33 nm). The thermodynamic data reveal that binding of PMT with Hb are exothermic in nature involving hydrogen bonding and van der Waal interaction whereas in the case of ADP hydrophobic forces play the major role and binding process is endothermic in nature. The CD results show that both PMT and ADP, induced secondary structural changes of Hb and unfold the protein by losing a large helical content while the effect is more pronounced with ADP. Additionally, we also utilized computational approaches for deep insight into the binding of these drugs with Hb and the results are well matched with our experimental results.

Prediction of Protein-Protein Interaction Sites Using Electrostatic Desolvation Profiles

PubMed Central

Fiorucci, Sébastien; Zacharias, Martin

2010-01-01

Abstract Protein-protein complex formation involves removal of water from the interface region. Surface regions with a small free energy penalty for water removal or desolvation may correspond to preferred interaction sites. A method to calculate the electrostatic free energy of placing a neutral low-dielectric probe at various protein surface positions has been designed and applied to characterize putative interaction sites. Based on solutions of the finite-difference Poisson equation, this method also includes long-range electrostatic contributions and the protein solvent boundary shape in contrast to accessible-surface-area-based solvation energies. Calculations on a large set of proteins indicate that in many cases (>90%), the known binding site overlaps with one of the six regions of lowest electrostatic desolvation penalty (overlap with the lowest desolvation region for 48% of proteins). Since the onset of electrostatic desolvation occurs even before direct protein-protein contact formation, it may help guide proteins toward the binding region in the final stage of complex formation. It is interesting that the probe desolvation properties associated with residue types were found to depend to some degree on whether the residue was outside of or part of a binding site. The probe desolvation penalty was on average smaller if the residue was part of a binding site compared to other surface locations. Applications to several antigen-antibody complexes demonstrated that the approach might be useful not only to predict protein interaction sites in general but to map potential antigenic epitopes on protein surfaces. PMID:20441756

On the nature of the {SO2-4}/{Ag(111) } and {SO2-4}/{Au(111) } surface bonding

NASA Astrophysics Data System (ADS)

Patrito, E. M.; Olivera, P. Paredes; Sellers, Harrell

1997-05-01

The nature of sulfate-Ag(111) and sulfate-Au(111) surface bonding has been investigated at the SCF + MP2 level of theory. Convergence of binding energy with cluster size is investigated and, unlike neutral adsorbates, large clusters are required in order to obtain reliable binding energies. In the most stable adsorption mode, sulfate binds to the surface via three oxygen atoms (C 3v symmetry) with a binding energy of 159.3 kcal/mol on Ag(111) and 143.9 kcal/mol on Au(111). The geometry of adsorbed sulfate was optimized at the SCF level. While the bond length between sulfur and the oxygens coordinated to the surface increases, the sulfur-uncoordinated oxygen bond length decreases. This weakening and strengthening of the bonds, respectively, is consistent with bond order conservation in adsorbates on metal surfaces. Although a charge transfer of 0.4 electrons towards the metal is observed, the adsorbate remains very much sulfate-like. The molecular orbital analysis indicates that there is also some charge back-donation towards unoccupied orbitals of sulfate. This results in an increased electron density around sulfur as revealed in the electron density difference maps. Analysis of the Laplacian of the charge density of free sulfate provides a suitable framework to understand the nature of the different charge transfer processes and allows us to establish some similarities with the CO- and SO 2-metal bondings.

Interaction of promethazine and adiphenine to human hemoglobin: A comparative spectroscopic and computational analysis.

PubMed

Maurya, Neha; Ud Din Parray, Mehraj; Maurya, Jitendra Kumar; Kumar, Amit; Patel, Rajan

2018-06-15

The binding nature of amphiphilic drugs viz. promethazine hydrochloride (PMT) and adiphenine hydrochloride (ADP), with human hemoglobin (Hb) was unraveled by fluorescence, absorbance, time resolved fluorescence, fluorescence resonance energy transfer (FRET) and circular dichroism (CD) spectral techniques in combination with molecular docking and molecular dynamic simulation methods. The steady state fluorescence spectra indicated that both PMT and ADP quenches the fluorescence of Hb through static quenching mechanism which was further confirmed by time resolved fluorescence spectra. The UV-Vis spectroscopy suggested ground state complex formation. The activation energy (E a ) was observed more in the case of Hb-ADP than Hb-PMT interaction system. The FRET result indicates the high probability of energy transfer from β Trp37 residue of Hb to the PMT (r=2.02nm) and ADP (r=2.33nm). The thermodynamic data reveal that binding of PMT with Hb are exothermic in nature involving hydrogen bonding and van der Waal interaction whereas in the case of ADP hydrophobic forces play the major role and binding process is endothermic in nature. The CD results show that both PMT and ADP, induced secondary structural changes of Hb and unfold the protein by losing a large helical content while the effect is more pronounced with ADP. Additionally, we also utilized computational approaches for deep insight into the binding of these drugs with Hb and the results are well matched with our experimental results. Copyright © 2018 Elsevier B.V. All rights reserved.

Kinetic rate constant prediction supports the conformational selection mechanism of protein binding.

PubMed

Moal, Iain H; Bates, Paul A

2012-01-01

The prediction of protein-protein kinetic rate constants provides a fundamental test of our understanding of molecular recognition, and will play an important role in the modeling of complex biological systems. In this paper, a feature selection and regression algorithm is applied to mine a large set of molecular descriptors and construct simple models for association and dissociation rate constants using empirical data. Using separate test data for validation, the predicted rate constants can be combined to calculate binding affinity with accuracy matching that of state of the art empirical free energy functions. The models show that the rate of association is linearly related to the proportion of unbound proteins in the bound conformational ensemble relative to the unbound conformational ensemble, indicating that the binding partners must adopt a geometry near to that of the bound prior to binding. Mirroring the conformational selection and population shift mechanism of protein binding, the models provide a strong separate line of evidence for the preponderance of this mechanism in protein-protein binding, complementing structural and theoretical studies.

Theoretical study of transition-metal ions bound to benzene

NASA Technical Reports Server (NTRS)

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

1992-01-01

Theoretical binding energies are reported for all first-row and selected second-row transition metal ions (M+) bound to benzene. The calculations employ basis sets of at least double-zeta plus polarization quality and account for electron correlation using the modified coupled-pair functional method. While the bending is predominantly electrostatic, the binding energies are significantly increased by electron correlation, because the donation from the metal d orbitals to the benzene pi* orbitals is not well described at the self-consistent-field level. The uncertainties in the computed binding energies are estimated to be about 5 kcal/mol. Although the calculated and experimental binding energies generally agree to within their combined uncertainties, it is likely that the true binding energies lie in the lower portion of the experimental range. This is supported by the very good agreement between the theoretical and recent experimental binding energies for AgC6H6(+).

Efficiency of muscle contraction. The chemimechanic equilibrium

NASA Astrophysics Data System (ADS)

Becker, E. W.

1991-10-01

Although muscle contraction is one of the principal themes of biological research, the exact mechanism whereby the chemical free energy of ATP hydrolysis is converted into mechanical work remains elusive. The high thermodynamic efficiency of the process, above all, is difficult to explain on the basis of present theories. A model of the elementary effect in muscle contraction is proposed which aims at high thermodynamic efficiency based on an approximate equilibrium between chemical and mechanical forces throughout the transfer of free energy. The experimental results described in the literature support the assumption that chemimechanic equilibrium is approximated by a free energy transfer system based on the binding of divalent metal ions to the myosin light chains. Muscle contraction demonstrated without light chains is expected to proceed with a considerably lower efficiency. Free energy transfer systems based on the binding of ions to proteins seem to be widespread in the cell. By establishing an approximate chemimechanic equilibrium, they could facilitate biological reactions considerably and save large amounts of free energy. The concept of chemimechanic equilibrium is seen as a supplementation to the concept of chemiosmotic equilibrium introduced for the membrane transport by P. Mitchell.

De-Excitation of High-Rydberg Antihydrogen in a Strongly Magnetized Pure Positron Plasma

NASA Astrophysics Data System (ADS)

Bass, E. M.

2005-10-01

The rate at which highly excited atoms relax to deeper binding is found with classical theories and simulations. This rate relates to antihydrogen formation experiments where such atoms are formed in pure-positron, Penning trap plasmas.ootnotetextG.Gabrielse, N.S. Bowden, P. Oxley, et al., Phys. Rev. Lett. 89, 213401 (2002); M. Amoretti, C. Amsler, G. Bonomi, et al., Nature (London) 419, 456 (2002). The analysis concerns atoms that have passed the kinetic bottleneck at binding energy ɛ 4kT.ootnotetextM.E. Glinsky and T.M. O'Neil, Phys. Fluids B 3, 1279 (1991). Energy loss caused by collisions between atoms and plasma positrons is calculated in two ways: For close collisions, a molecular dynamics simulation gives the energy loss; for large-impact parameter collisions, theoretical expressions based on Fokker-Planck theory are employed.ootnotetextEric M. Bass and Daniel H.E. Dubin, Phys. Plasmas 11, 1240 (2004). For a finite magnetic field, the energy loss rate scales as 1/ɛ, just as for infinite field,^2 but with a larger coefficient. A statistical description of energy loss by radiation and Stark mixing will also be discussed.

Fluorescence resonance energy transfer analysis of escherichia coli RNA polymerase and polymerase-DNA complexes.

PubMed

Heyduk, T; Niedziela-Majka, A

Fluorescence resonance energy transfer (FRET) is a technique allowing measurements of atomic-scale distances in diluted solutions of macromolecules under native conditions. This feature makes FRET a powerful tool to study complicated biological assemblies. In this report we review the applications of FRET to studies of transcription initiation by Escherichia coli RNA polymerase. The versatility of FRET for studies of a large macromolecular assembly such as RNA polymerase is illustrated by examples of using FRET to address several different aspects of transcription initiation by polymerase. FRET has been used to determine the architecture of polymerase, its complex with single-stranded DNA, and the conformation of promoter fragment bound to polymerase. FRET has been also used as a binding assay to determine the thermodynamics of promoter DNA fragment binding to the polymerase. Functional conformational changes in the specificity subunit of polymerase responsible for the modulation of the promoter binding activity of the enzyme and the mechanistic aspects of the transition from the initiation to the elongation complex were also investigated. Copyright 2002 Wiley Periodicals, Inc.

Excitonic complexes in single zinc-blende GaN/AlN quantum dots grown by droplet epitaxy

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

Sergent, S.; Kako, S.; Bürger, M.

2014-10-06

We study by microphotoluminescence the optical properties of single zinc-blende GaN/AlN quantum dots grown by droplet epitaxy. We show evidences of both excitonic and multiexcitonic recombinations in individual quantum dots with radiative lifetimes shorter than 287 ± 8 ps. Owing to large band offsets and a large exciton binding energy, the excitonic recombinations of single zinc-blende GaN/AlN quantum dots can be observed up to 300 K.

Correlating hydrogen oxidation and evolution activity on platinum at different pH with measured hydrogen binding energy

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

Sheng, WC; Zhuang, ZB; Gao, MR

2015-01-08

The hydrogen oxidation/evolution reactions are two of the most fundamental reactions in distributed renewable electrochemical energy conversion and storage systems. The identification of the reaction descriptor is therefore of critical importance for the rational catalyst design and development. Here we report the correlation between hydrogen oxidation/evolution activity and experimentally measured hydrogen binding energy for polycrystalline platinum examined in several buffer solutions in a wide range of electrolyte pH from 0 to 13. The hydrogen oxidation/evolution activity obtained using the rotating disk electrode method is found to decrease with the pH, while the hydrogen binding energy, obtained from cyclic voltammograms, linearlymore » increases with the pH. Correlating the hydrogen oxidation/evolution activity to the hydrogen binding energy renders a monotonic decreasing hydrogen oxidation/evolution activity with the hydrogen binding energy, strongly supporting the hypothesis that hydrogen binding energy is the sole reaction descriptor for the hydrogen oxidation/evolution activity on monometallic platinum.« less

Anisotropic energy flow and allosteric ligand binding in albumin

NASA Astrophysics Data System (ADS)

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

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

Calculating the binding free energies of charged species based on explicit-solvent simulations employing lattice-sum methods: An accurate correction scheme for electrostatic finite-size effects

PubMed Central

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

2013-01-01

The calculation of a protein-ligand binding free energy based on molecular dynamics (MD) simulations generally relies on a thermodynamic cycle in which the ligand is alchemically inserted into the system, both in the solvated protein and free in solution. The corresponding ligand-insertion free energies are typically calculated in nanoscale computational boxes simulated under periodic boundary conditions and considering electrostatic interactions defined by a periodic lattice-sum. This is distinct from the ideal bulk situation of a system of macroscopic size simulated under non-periodic boundary conditions with Coulombic electrostatic interactions. This discrepancy results in finite-size effects, which affect primarily the charging component of the insertion free energy, are dependent on the box size, and can be large when the ligand bears a net charge, especially if the protein is charged as well. This article investigates finite-size effects on calculated charging free energies using as a test case the binding of the ligand 2-amino-5-methylthiazole (net charge +1 e) to a mutant form of yeast cytochrome c peroxidase in water. Considering different charge isoforms of the protein (net charges −5, 0, +3, or +9 e), either in the absence or the presence of neutralizing counter-ions, and sizes of the cubic computational box (edges ranging from 7.42 to 11.02 nm), the potentially large magnitude of finite-size effects on the raw charging free energies (up to 17.1 kJ mol−1) is demonstrated. Two correction schemes are then proposed to eliminate these effects, a numerical and an analytical one. Both schemes are based on a continuum-electrostatics analysis and require performing Poisson-Boltzmann (PB) calculations on the protein-ligand system. While the numerical scheme requires PB calculations under both non-periodic and periodic boundary conditions, the latter at the box size considered in the MD simulations, the analytical scheme only requires three non-periodic PB calculations for a given system, its dependence on the box size being analytical. The latter scheme also provides insight into the physical origin of the finite-size effects. These two schemes also encompass a correction for discrete solvent effects that persists even in the limit of infinite box sizes. Application of either scheme essentially eliminates the size dependence of the corrected charging free energies (maximal deviation of 1.5 kJ mol−1). Because it is simple to apply, the analytical correction scheme offers a general solution to the problem of finite-size effects in free-energy calculations involving charged solutes, as encountered in calculations concerning, e.g., protein-ligand binding, biomolecular association, residue mutation, pKa and redox potential estimation, substrate transformation, solvation, and solvent-solvent partitioning. PMID:24320250

Calculating the binding free energies of charged species based on explicit-solvent simulations employing lattice-sum methods: an accurate correction scheme for electrostatic finite-size effects.

PubMed

Rocklin, Gabriel J; Mobley, David L; Dill, Ken A; Hünenberger, Philippe H

2013-11-14

The calculation of a protein-ligand binding free energy based on molecular dynamics (MD) simulations generally relies on a thermodynamic cycle in which the ligand is alchemically inserted into the system, both in the solvated protein and free in solution. The corresponding ligand-insertion free energies are typically calculated in nanoscale computational boxes simulated under periodic boundary conditions and considering electrostatic interactions defined by a periodic lattice-sum. This is distinct from the ideal bulk situation of a system of macroscopic size simulated under non-periodic boundary conditions with Coulombic electrostatic interactions. This discrepancy results in finite-size effects, which affect primarily the charging component of the insertion free energy, are dependent on the box size, and can be large when the ligand bears a net charge, especially if the protein is charged as well. This article investigates finite-size effects on calculated charging free energies using as a test case the binding of the ligand 2-amino-5-methylthiazole (net charge +1 e) to a mutant form of yeast cytochrome c peroxidase in water. Considering different charge isoforms of the protein (net charges -5, 0, +3, or +9 e), either in the absence or the presence of neutralizing counter-ions, and sizes of the cubic computational box (edges ranging from 7.42 to 11.02 nm), the potentially large magnitude of finite-size effects on the raw charging free energies (up to 17.1 kJ mol(-1)) is demonstrated. Two correction schemes are then proposed to eliminate these effects, a numerical and an analytical one. Both schemes are based on a continuum-electrostatics analysis and require performing Poisson-Boltzmann (PB) calculations on the protein-ligand system. While the numerical scheme requires PB calculations under both non-periodic and periodic boundary conditions, the latter at the box size considered in the MD simulations, the analytical scheme only requires three non-periodic PB calculations for a given system, its dependence on the box size being analytical. The latter scheme also provides insight into the physical origin of the finite-size effects. These two schemes also encompass a correction for discrete solvent effects that persists even in the limit of infinite box sizes. Application of either scheme essentially eliminates the size dependence of the corrected charging free energies (maximal deviation of 1.5 kJ mol(-1)). Because it is simple to apply, the analytical correction scheme offers a general solution to the problem of finite-size effects in free-energy calculations involving charged solutes, as encountered in calculations concerning, e.g., protein-ligand binding, biomolecular association, residue mutation, pKa and redox potential estimation, substrate transformation, solvation, and solvent-solvent partitioning.

Calculating the binding free energies of charged species based on explicit-solvent simulations employing lattice-sum methods: An accurate correction scheme for electrostatic finite-size effects

NASA Astrophysics Data System (ADS)

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

2013-11-01

The calculation of a protein-ligand binding free energy based on molecular dynamics (MD) simulations generally relies on a thermodynamic cycle in which the ligand is alchemically inserted into the system, both in the solvated protein and free in solution. The corresponding ligand-insertion free energies are typically calculated in nanoscale computational boxes simulated under periodic boundary conditions and considering electrostatic interactions defined by a periodic lattice-sum. This is distinct from the ideal bulk situation of a system of macroscopic size simulated under non-periodic boundary conditions with Coulombic electrostatic interactions. This discrepancy results in finite-size effects, which affect primarily the charging component of the insertion free energy, are dependent on the box size, and can be large when the ligand bears a net charge, especially if the protein is charged as well. This article investigates finite-size effects on calculated charging free energies using as a test case the binding of the ligand 2-amino-5-methylthiazole (net charge +1 e) to a mutant form of yeast cytochrome c peroxidase in water. Considering different charge isoforms of the protein (net charges -5, 0, +3, or +9 e), either in the absence or the presence of neutralizing counter-ions, and sizes of the cubic computational box (edges ranging from 7.42 to 11.02 nm), the potentially large magnitude of finite-size effects on the raw charging free energies (up to 17.1 kJ mol-1) is demonstrated. Two correction schemes are then proposed to eliminate these effects, a numerical and an analytical one. Both schemes are based on a continuum-electrostatics analysis and require performing Poisson-Boltzmann (PB) calculations on the protein-ligand system. While the numerical scheme requires PB calculations under both non-periodic and periodic boundary conditions, the latter at the box size considered in the MD simulations, the analytical scheme only requires three non-periodic PB calculations for a given system, its dependence on the box size being analytical. The latter scheme also provides insight into the physical origin of the finite-size effects. These two schemes also encompass a correction for discrete solvent effects that persists even in the limit of infinite box sizes. Application of either scheme essentially eliminates the size dependence of the corrected charging free energies (maximal deviation of 1.5 kJ mol-1). Because it is simple to apply, the analytical correction scheme offers a general solution to the problem of finite-size effects in free-energy calculations involving charged solutes, as encountered in calculations concerning, e.g., protein-ligand binding, biomolecular association, residue mutation, pKa and redox potential estimation, substrate transformation, solvation, and solvent-solvent partitioning.

Specificity in Transition State Binding: The Pauling Model Revisited

PubMed Central

Amyes, Tina L.; Richard, John P.

2013-01-01

Linus Pauling proposed that the large rate accelerations for enzymes are due to the high specificity of the protein catalyst for binding the reaction transition state. The observation that stable analogs of the transition states for enzymatic reactions often act as tight-binding binding inhibitors provided early support for this simple and elegant proposal. We review experimental results which support the proposal that Pauling’s model provides a satisfactory explanation for the rate accelerations for many heterolytic enzymatic reactions through high energy reaction intermediates, such as proton transfer and decarboxylation. Specificity in transition state binding is obtained when the total intrinsic binding energy of the substrate is significantly larger than the binding energy observed at the Michaelis complex. The results of recent studies to characterize the specificity in binding of the enolate oxygen at the transition state for the 1,3-isomerization reaction catalyzed by ketosteroid isomerase are reviewed. Interactions between pig heart succinyl-CoA:3-oxoacid coenzyme A transferase (SCOT) and the nonreacting portions of CoA are responsible for a rate increase of 3 × 1012-fold, which is close to the estimated total 5 × 1013-fold enzymatic rate acceleration. Studies that partition the interactions between SCOT and CoA into their contributing parts are reviewed. Interactions of the protein with the substrate phosphodianion group provide a ca. 12 kcal/mol stabilization of the transition state for the reactions catalyzed by triosephosphate isomerase, orotidine 5′-monophosphate decarboxylase and α-glycerol phosphate dehydrogenase. The interactions of these enzymes with the substrate piece phosphite dianion provide a 6 – 8 kcal/mol stabilization of the transition state for reaction of the appropriate truncated substrate. Enzyme activation by phosphite dianion reflects the higher dianion affinity for binding to the enzyme-transition state complex compared with the free enzyme. Evidence is presented that supports a model in which the binding energy of the phosphite dianion piece, or the phosphodianion group of the whole substrate, is utilized to drive an enzyme conformational change from an inactive open form EO to an active closed form EC, by closure of a phosphodianion gripper loop. Members of the enolase and haloalkanoic acid dehalogenase superfamilies use variable capping domains to interact with nonreacting portions of the substrate and sequester the substrate from interaction with bulk solvent. Interactions of this capping domain with the phenyl group of mandelate have been shown to activate mandelate racemase for catalysis of deprotonation of α-carbonyl carbon. We propose that an important function of these capping domains is to utilize the binding interactions with nonreacting portions of the substrate to activate the enzyme for catalysis. PMID:23327224

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)

What Is the Structure of the Naphthalene-Benzene Heterodimer Radical Cation? Binding Energy, Charge Delocalization, and Unexpected Charge-Transfer Interaction in Stacked Dimer and Trimer Radical Cations.

PubMed

Attah, Isaac K; Platt, Sean P; Meot-Ner Mautner, Michael; El-Shall, M Samy; Peverati, Roberto; Head-Gordon, Martin

2015-04-02

The binding energy of the naphthalene(+•)(benzene) heterodimer cation has been determined to be 7.9 ± 1 kcal/mol for C10H8(+•)(C6H6) and 8.1 ± 1 kcal/mol for C10H8(+•)(C6D6) by equilibrium thermochemical measurements using the mass-selected drift cell technique. A second benzene molecule binds to the C10H8(+•)(C6D6) dimer with essentially the same energy (8.4 ± 1 kcal/mol), suggesting that the two benzene molecules are stacked on opposite sides of the naphthalene cation in the (C6D6)C10H8(+•)(C6D6) heterotrimer. The lowest-energy isomers of the C10H8(+•)(C6D6) and (C6D6)C10H8(+•)(C6D6) dimer and trimer calculated using the M11/cc-pVTZ method have parallel stacked structures with enthalpies of binding (-ΔH°) of 8.4 and 9.0 kcal/mol, respectively, in excellent agreement with the experimental values. The stacked face-to-face class of isomers is calculated to have substantial charge-transfer stabilization of about 45% of the total interaction energy despite the large difference between the ionization energies of benzene and naphthalene. Similarly, significant delocalization of the positive charge is found among all three fragments of the (C6D6)C10H8(+•)(C6D6) heterotrimer, thus leaving only 46% of the total charge on the central naphthalene moiety. This unexpectedly high charge-transfer component results in activating two benzene molecules in the naphthalene(+•)(benzene)2 heterotrimer cation to associate with a third benzene molecule at 219 K to form a benzene trimer cation and a neutral naphthalene molecule. The global minimum of the C10H8(+•)(C6H6)2 heterotrimer is found to be the one where the naphthalene cation is sandwiched between two benzene molecules. It is remarkable, and rather unusual, that the binding energy of the second benzene molecule is essentially the same as that of the first. This is attributed to the enhanced charge-transfer interaction in the stacked trimer radical cation.

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.

Specificity and non-specificity in RNA–protein interactions

PubMed Central

Jankowsky, Eckhard; Harris, Michael E.

2016-01-01

Gene expression is regulated by complex networks of interactions between RNAs and proteins. Proteins that interact with RNA have been traditionally viewed as either specific or non-specific; specific proteins interact preferentially with defined RNA sequence or structure motifs, whereas non-specific proteins interact with RNA sites devoid of such characteristics. Recent studies indicate that the binary “specific vs. non-specific” classification is insufficient to describe the full spectrum of RNA–protein interactions. Here, we review new methods that enable quantitative measurements of protein binding to large numbers of RNA variants, and the concepts aimed as describing resulting binding spectra: affinity distributions, comprehensive binding models and free energy landscapes. We discuss how these new methodologies and associated concepts enable work towards inclusive, quantitative models for specific and non-specific RNA–protein interactions. PMID:26285679

Imaging of the outer valence orbitals of CO by electron momentum spectroscopy — Comparison with high level MRSD-CI and DFT calculations

NASA Astrophysics Data System (ADS)

Fan, X. W.; Chen, X. J.; Zhou, S. J.; Zheng, Y.; Brion, C. E.; Frey, R.; Davidson, E. R.

1997-09-01

A newly constructed energy dispersive multichannel electron momentum spectrometer has been used to image the electron density of the outer valence orbitals of CO with high precision. Binding energy spectra are obtained at a coincidence energy resolution of 1.2 eV fwhm. The measured electron density profiles in momentum space for the outer valence orbitals of CO are compared with cross sections calculated using SCF wavefunctions with basis sets of varying complexity up to near-Hartree-Fock limit in quality. The effects of correlation and electronic relaxation on the calculated momentum profiles are investigated using large MRSD-CI calculations of the full ion-neutral overlap distributions, as well as large basis set DFT calculations with local and non-local (gradient corrected) functionals.

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

Comparative study of flavins binding with human serum albumin: a fluorometric, thermodynamic, and molecular dynamics approach.

PubMed

Sengupta, Abhigyan; Sasikala, Wilbee D; Mukherjee, Arnab; Hazra, Partha

2012-06-04

Flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) are derivatives of riboflavin (RF), a water-soluble vitamin, more commonly known as vitamin B(2). Flavins have attracted special attention in the last few years because of the recent discovery of a large number of flavoproteins. In this work, these flavins are used as extrinsic fluorescence markers for probing the microheterogeneous environment of a well-known transport protein, human serum albumin (HSA). Steady-state and time-resolved fluorescence experiments confirm that both FMN and FAD bind to the Sudlow's site-1 (SS1) binding pocket of HSA, where Trp214 resides. In the case of RF, a fraction of RF molecules binds at the SS1, whereas the major fraction of RF molecules remains unbound or surface bound to the protein. Moreover, flavin(s)-HSA interactions are monitored with the help of isothermal titration calorimetry, which provides free energy, enthalpy, and entropy changes of binding along with the binding constants. The molecular picture of binding interaction between flavins and HSA is well explored by docking and molecular dynamics studies. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Assessing Carbon-Based Anodes for Lithium-Ion Batteries: A Universal Description of Charge-Transfer Binding

DOE PAGES

Liu, Yuanyue; Wang, Y. Morris; Yakobson, Boris I.; ...

2014-07-11

Many key performance characteristics of carbon-based lithium-ion battery anodes are largely determined by the strength of binding between lithium (Li) and sp 2 carbon (C), which can vary significantly with subtle changes in substrate structure, chemistry, and morphology. We use density functional theory calculations to investigate the interactions of Li with a wide variety of sp 2 C substrates, including pristine, defective, and strained graphene, planar C clusters, nanotubes, C edges, and multilayer stacks. In almost all cases, we find a universal linear relation between the Li-C binding energy and the work required to fill previously unoccupied electronic states withinmore » the substrate. This suggests that Li capacity is predominantly determined by two key factors—namely, intrinsic quantum capacitance limitations and the absolute placement of the Fermi level. This simple descriptor allows for straightforward prediction of the Li-C binding energy and related battery characteristics in candidate C materials based solely on the substrate electronic structure. It further suggests specific guidelines for designing more effective C-based anodes. Furthermore, this method should be broadly applicable to charge-transfer adsorption on planar substrates, and provides a phenomenological connection to established principles in supercapacitor and catalyst design.« 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.

Exploring the binding pathways of the 14-3-3ζ protein: Structural and free-energy profiles revealed by Hamiltonian replica exchange molecular dynamics with distancefield distance restraints

PubMed Central

Nagy, Gabor; Oostenbrink, Chris; Hritz, Jozef

2017-01-01

The 14-3-3 protein family performs regulatory functions in eukaryotic organisms by binding to a large number of phosphorylated protein partners. Whilst the binding mode of the phosphopeptides within the primary 14-3-3 binding site is well established based on the crystal structures of their complexes, little is known about the binding process itself. We present a computational study of the process by which phosphopeptides bind to the 14-3-3ζ protein. Applying a novel scheme combining Hamiltonian replica exchange molecular dynamics and distancefield restraints allowed us to map and compare the most likely phosphopeptide-binding pathways to the 14-3-3ζ protein. The most important structural changes to the protein and peptides involved in the binding process were identified. In order to bind phosphopeptides to the primary interaction site, the 14-3-3ζ adopted a newly found wide-opened conformation. Based on our findings we additionally propose a secondary interaction site on the inner surface of the 14-3-3ζ dimer, and a direct interference on the binding process by the flexible C-terminal tail. A minimalistic model was designed to allow for the efficient calculation of absolute binding affinities. Binding affinities calculated from the potential of mean force along the binding pathway are in line with the available experimental estimates for two of the studied systems. PMID:28727767

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.

Electrostatic field of the large fragment of Escherichia coli DNA polymerase I.

PubMed

Warwicker, J; Ollis, D; Richards, F M; Steitz, T A

1985-12-05

The electrostatic field of the large fragment of Escherichia coli DNA polymerase I (Klenow fragment) has been calculated by the finite difference procedure on a 2 A grid. The potential field is substantially negative at physiological pH (reflecting the net negative charge at this pH). The largest regions of positive potential are in the deep crevice of the C-terminal domain, which is the proposed binding site for the DNA substrate. Within the crevice, the electrostatic potential has a partly helical form. If the DNA is positioned to fulfil stereochemical requirements, then the positive potential generally follows the major groove and (to a lesser extent) the negative potential is in the minor groove. Such an arrangement could stabilize DNA configurations related by screw symmetry. The histidine residues of the Klenow fragment give the positive field of the groove a sensitivity to relatively small pH changes around neutrality. We suggest that the histidine residues could change their ionization states in response to DNA binding, and that this effect could contribute to the protein-DNA binding energy.

Interaction energies for the purine inhibitor roscovitine with cyclin-dependent kinase 2: correlated ab initio quantum-chemical, DFT and empirical calculations.

PubMed

Dobes, Petr; Otyepka, Michal; Strnad, Miroslav; Hobza, Pavel

2006-05-24

The interaction between roscovitine and cyclin-dependent kinase 2 (cdk2) was investigated by performing correlated ab initio quantum-chemical calculations. The whole protein was fragmented into smaller systems consisting of one or a few amino acids, and the interaction energies of these fragments with roscovitine were determined by using the MP2 method with the extended aug-cc-pVDZ basis set. For selected complexes, the complete basis set limit MP2 interaction energies, as well as the coupled-cluster corrections with inclusion of single, double and noninteractive triples contributions [CCSD(T)], were also evaluated. The energies of interaction between roscovitine and small fragments and between roscovitine and substantial sections of protein (722 atoms) were also computed by using density-functional tight-binding methods covering dispersion energy (DFTB-D) and the Cornell empirical potential. Total stabilisation energy originates predominantly from dispersion energy and methods that do not account for the dispersion energy cannot, therefore, be recommended for the study of protein-inhibitor interactions. The Cornell empirical potential describes reasonably well the interaction between roscovitine and protein; therefore, this method can be applied in future thermodynamic calculations. A limited number of amino acid residues contribute significantly to the binding of roscovitine and cdk2, whereas a rather large number of amino acids make a negligible contribution.

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.

Simultaneous prediction of binding free energy and specificity for PDZ domain-peptide interactions

NASA Astrophysics Data System (ADS)

Crivelli, Joseph J.; Lemmon, Gordon; Kaufmann, Kristian W.; Meiler, Jens

2013-12-01

Interactions between protein domains and linear peptides underlie many biological processes. Among these interactions, the recognition of C-terminal peptides by PDZ domains is one of the most ubiquitous. In this work, we present a mathematical model for PDZ domain-peptide interactions capable of predicting both affinity and specificity of binding based on X-ray crystal structures and comparative modeling with R osetta. We developed our mathematical model using a large phage display dataset describing binding specificity for a wild type PDZ domain and 91 single mutants, as well as binding affinity data for a wild type PDZ domain binding to 28 different peptides. Structural refinement was carried out through several R osetta protocols, the most accurate of which included flexible peptide docking and several iterations of side chain repacking and backbone minimization. Our findings emphasize the importance of backbone flexibility and the energetic contributions of side chain-side chain hydrogen bonds in accurately predicting interactions. We also determined that predicting PDZ domain-peptide interactions became increasingly challenging as the length of the peptide increased in the N-terminal direction. In the training dataset, predicted binding energies correlated with those derived through calorimetry and specificity switches introduced through single mutations at interface positions were recapitulated. In independent tests, our best performing protocol was capable of predicting dissociation constants well within one order of magnitude of the experimental values and specificity profiles at the level of accuracy of previous studies. To our knowledge, this approach represents the first integrated protocol for predicting both affinity and specificity for PDZ domain-peptide interactions.

Role of Altered Sialylation of the I-Like Domain of β1 Integrin in the Binding of Fibronectin to β1 Integrin: Thermodynamics and Conformational Analyses

PubMed Central

Pan, Di; Song, Yuhua

2010-01-01

Abstract N-glycosylation of the I-like domain of β1 integrin plays an essential role in integrin structure and function, and the altered sialylation of β1 integrin regulates β1 integrin binding to fibronectin. However, the structural basis underlying the effect of altered sialylation of the β1 I-like domain on β1 integrin binding to fibronectin remains largely unknown. In this study, we used a combination of molecular dynamics simulations and binding free energy analyses to investigate changes in binding thermodynamics and in conformation of the glycosylated β1 I-like domain-FN-III9-10 complex caused by altered sialylation of the β1 I-like domain. Binding free energy analyses showed that desialylation of β1 I-like domain increased β1 integrin binding to fibronectin, consistent with experimental results. Interaction analyses showed that altered sialylation of the β1 I-like domain resulted in significant changes in the interaction of the N-glycans of the I-like domain with both the I-like domain and fibronectin, and these changes could directly affect the allosteric regulation of the interaction between the I-like domain and fibronectin. Altered sialylation of the β1 I-like domain caused significant conformational changes in key functional sites of both the β1 I-like domain and fibronectin. In addition, altered sialylation of the β1 I-like domain resulted in changes in the degree of correlated motions between residues in the I-like domain and residues in fibronectin, and in the degree of motion changes in fibronectin, which could affect β1 integrin binding to fibronectin. We believe results from this study provide thermodynamic and structural evidence for a role of altered sialylation of β1 integrin in regulating β1 integrin binding to fibronectin and it's induced cellular activities. PMID:20655849

Effect of Detergents on Galactoside Binding by Melibiose Permeases.

PubMed

Amin, Anowarul; Hariharan, Parameswaran; Chae, Pil Seok; Guan, Lan

2015-09-29

The effect of various detergents on the stability and function of the melibiose permeases of Escherichia coli (MelBEc) and Salmonella typhimurium (MelBSt) was studied. In n-dodecyl-β-d-maltoside (DDM) or n-undecyl-β-d-maltoside (UDM), WT MelBSt binds melibiose with an affinity similar to that in the membrane. However, with WT MelBEc or MelBSt mutants (Arg141 → Cys, Arg295 → Cys, or Arg363 → Cys), galactoside binding is not detected in these detergents, but binding to the phosphotransferase protein IIA(Glc) is maintained. In the amphiphiles lauryl maltose neopentyl glycol (MNG-3) or glyco-diosgenin (GDN), galactoside binding with all of the MelB proteins is observed, with slightly reduced affinities. MelBSt is more thermostable than MelBEc, and the thermostability of either MelB is largely increased in MNG-3 or GDN. Therefore, the functional defect with DDM or UDM likely results from the relative instability of the sensitive MelB proteins, and stability, as well as galactoside binding, is retained in MNG-3 or GDN. Furthermore, isothermal titration calorimetry of melibiose binding with MelBSt shows that the favorable entropic contribution to the binding free energy is decreased in MNG-3, indicating that the conformational dynamics of MelB is restricted in this detergent.

Effect of detergents on galactoside binding by melibiose permeases

PubMed Central

Amin, Anowarul; Hariharan, Parameswaran; Chae, Pil Seok; Guan, Lan

2015-01-01

The effect of various detergents on the stability and function of melibiose permeases of Escherichia coli (MelBEc) or Salmonella typhimurium (MelBSt) were studied. In n-dodecyl-β-d-maltoside (DDM) or n-undecyl-β-d-maltoside (UDM), WT MelBSt binds melibiose with an affinity similar to that in the membrane. However, with WT MelBEc or MelBSt mutants (Arg141→Cys, Arg295→Cys or Arg363→Cys), galactoside binding is not detected in these detergents, but binding to the phosphotransferase protein IIAGlc is maintained. In the amphiphiles lauryl maltose neopentyl glycol (MNG-3) or glyco-diosgenin (GDN), galactoside binding with all the MelB proteins is observed, with slightly reduced affinities. MelBSt is more thermostable than MelBEc, and the thermostability of either MelB is largely increased in MNG-3 or GDN. Therefore, the functional defect with DDM or UDM likely results from relative instability of the sensitive MelB proteins, and stability, as well as galactoside binding, is retained in MNG-3 or GDN. Furthermore, isothermal titration calorimetry of melibiose binding with MelBSt shows that the favorable entropic contribution to the binding free energy is decreased in MNG-3, indicating that the conformational dynamics of MelB is restricted in this detergent. PMID:26352464

Screening effect of graphite and bilayer graphene on excitons in MoSe2 monolayer

NASA Astrophysics Data System (ADS)

Wang, Yuan; Zhang, Shuai; Huang, Di; Cheng, Jingxin; Li, Yingguo; Wu, Shiwei

2017-03-01

Excitons in transition metal dichalcogenide monolayer have recently attracted great interest due to their extremely large binding energy, causing giant bandgap renormalization. In this work, we examined the screening effect of graphite and bilayer graphene on the excitons in molybdenum diselenide (MoSe2) monolayer grown by molecular beam epitaxy (MBE). Through the combinational study of scanning tunneling spectroscopy (STS) and photoluminescence (PL) measurements, we determined the binding energy of ~0.58 eV for MoSe2 monolayer on both substrates at 16 K, and no obvious difference between them. Our result is consistent with a previous report [Zhang et al 2015 Nano Letters 15, 6494], but is contradictory to another one [Ugeda 2014 Nature Materials 13, 1091]. Physical picture for no noticeable difference on screening effect between bilayer graphene and graphite substrate is discussed. Possible reasons for causing the discrepancy are also mentioned.

Accurate high-throughput structure mapping and prediction with transition metal ion FRET

PubMed Central

Yu, Xiaozhen; Wu, Xiongwu; Bermejo, Guillermo A.; Brooks, Bernard R.; Taraska, Justin W.

2013-01-01

Mapping the landscape of a protein’s conformational space is essential to understanding its functions and regulation. The limitations of many structural methods have made this process challenging for most proteins. Here, we report that transition metal ion FRET (tmFRET) can be used in a rapid, highly parallel screen, to determine distances from multiple locations within a protein at extremely low concentrations. The distances generated through this screen for the protein Maltose Binding Protein (MBP) match distances from the crystal structure to within a few angstroms. Furthermore, energy transfer accurately detects structural changes during ligand binding. Finally, fluorescence-derived distances can be used to guide molecular simulations to find low energy states. Our results open the door to rapid, accurate mapping and prediction of protein structures at low concentrations, in large complex systems, and in living cells. PMID:23273426

Nature of the Active Sites for CO Reduction on Copper Nanoparticles; Suggestions for Optimizing Performance.

PubMed

Cheng, Tao; Xiao, Hai; Goddard, William A

2017-08-30

Recent experiments show that the grain boundaries (GBs) of copper nanoparticles (NPs) lead to an outstanding performance in reducing CO 2 and CO to alcohol products. We report here multiscale simulations that simulate experimental synthesis conditions to predict the structure of a 10 nm Cu NP (158 555 atoms). To identify active sites, we first predict the CO binding at a large number of sites and select four exhibiting CO binding stronger than the (211) step surface. Then, we predict the formation energy of the *OCCOH intermediate as a descriptor for C-C coupling, identifying two active sites, both of which have an under-coordinated surface square site adjacent to a subsurface stacking fault. We then propose a periodic Cu surface (4 by 4 supercell) with a similar site that substantially decreases the formation energy of *OCCOH, by 0.14 eV.

Conduction Band-Edge Non-Parabolicity Effects on Impurity States in (In,Ga)N/GaN Cylindrical QWWs

NASA Astrophysics Data System (ADS)

Haddou El, Ghazi; Anouar, Jorio

2014-02-01

In this paper, the conduction band-edge non-parabolicity (NP) and the circular cross-section radius effects on hydrogenic shallow-donor impurity ground-state binding energy in zinc-blende (ZB) InGaN/GaN cylindrical QWWs are reported. The finite potential barrier between (In,Ga)N well and GaN environment is considered. Two models of the conduction band-edge non-parabolicity are taking into account. The variational approach is used within the framework of single band effective-mass approximation with one-parametric 1S-hydrogenic trial wave-function. It is found that NP effect is more pronounced in the wire of radius equal to effective Bohr radius than in large and narrow wires. Moreover, the binding energy peak shifts to narrow wire under NP effect. A good agreement is shown compared to the findings results.

Two-Photon Absorption and Two-Photon-Induced Gain in Perovskite Quantum Dots.

PubMed

Nagamine, Gabriel; Rocha, Jaqueline O; Bonato, Luiz G; Nogueira, Ana F; Zaharieva, Zhanet; Watt, Andrew A R; de Brito Cruz, Carlos H; Padilha, Lazaro A

2018-06-21

Perovskite quantum dots (PQDs) emerged as a promising class of material for applications in lighting devices, including light emitting diodes and lasers. In this work, we explore nonlinear absorption properties of PQDs showing the spectral signatures and the size dependence of their two-photon absorption (2PA) cross-section, which can reach values higher than 10 6 GM. The large 2PA cross section allows for low threshold two-photon induced amplified spontaneous emission (ASE), which can be as low as 1.6 mJ/cm 2 . We also show that the ASE properties are strongly dependent on the nanomaterial size, and that the ASE threshold, in terms of the average number of excitons, decreases for smaller PQDs. Investigating the PQDs biexciton binding energy, we observe strong correlation between the increasing on the biexciton binding energy and the decreasing on the ASE threshold, suggesting that ASE in PQDs is a biexciton-assisted process.

Energy landscape of the reactions governing the Na+ deeply occluded state of the Na+/K+-ATPase in the giant axon of the Humboldt squid

PubMed Central

Castillo, Juan P.; De Giorgis, Daniela; Basilio, Daniel; Gadsby, David C.; Rosenthal, Joshua J. C.; Latorre, Ramon; Holmgren, Miguel; Bezanilla, Francisco

2011-01-01

The Na+/K+ pump is a nearly ubiquitous membrane protein in animal cells that uses the free energy of ATP hydrolysis to alternatively export 3Na+ from the cell and import 2K+ per cycle. This exchange of ions produces a steady-state outwardly directed current, which is proportional in magnitude to the turnover rate. Under certain ionic conditions, a sudden voltage jump generates temporally distinct transient currents mediated by the Na+/K+ pump that represent the kinetics of extracellular Na+ binding/release and Na+ occlusion/deocclusion transitions. For many years, these events have escaped a proper thermodynamic treatment due to the relatively small electrical signal. Here, taking the advantages offered by the large diameter of the axons from the squid Dosidicus gigas, we have been able to separate the kinetic components of the transient currents in an extended temperature range and thus characterize the energetic landscape of the pump cycle and those transitions associated with the extracellular release of the first Na+ from the deeply occluded state. Occlusion/deocclusion transition involves large changes in enthalpy and entropy as the ion is exposed to the external milieu for release. Binding/unbinding is substantially less costly, yet larger than predicted for the energetic cost of an ion diffusing through a permeation pathway, which suggests that ion binding/unbinding must involve amino acid side-chain rearrangements at the site. PMID:22143771

Energy landscape of the reactions governing the Na+ deeply occluded state of the Na+/K+-ATPase in the giant axon of the Humboldt squid.

PubMed

Castillo, Juan P; De Giorgis, Daniela; Basilio, Daniel; Gadsby, David C; Rosenthal, Joshua J C; Latorre, Ramon; Holmgren, Miguel; Bezanilla, Francisco

2011-12-20

The Na(+)/K(+) pump is a nearly ubiquitous membrane protein in animal cells that uses the free energy of ATP hydrolysis to alternatively export 3Na(+) from the cell and import 2K(+) per cycle. This exchange of ions produces a steady-state outwardly directed current, which is proportional in magnitude to the turnover rate. Under certain ionic conditions, a sudden voltage jump generates temporally distinct transient currents mediated by the Na(+)/K(+) pump that represent the kinetics of extracellular Na(+) binding/release and Na(+) occlusion/deocclusion transitions. For many years, these events have escaped a proper thermodynamic treatment due to the relatively small electrical signal. Here, taking the advantages offered by the large diameter of the axons from the squid Dosidicus gigas, we have been able to separate the kinetic components of the transient currents in an extended temperature range and thus characterize the energetic landscape of the pump cycle and those transitions associated with the extracellular release of the first Na(+) from the deeply occluded state. Occlusion/deocclusion transition involves large changes in enthalpy and entropy as the ion is exposed to the external milieu for release. Binding/unbinding is substantially less costly, yet larger than predicted for the energetic cost of an ion diffusing through a permeation pathway, which suggests that ion binding/unbinding must involve amino acid side-chain rearrangements at the site.

Homogeneous and heterogeneous noncovalent dimers of formaldehyde and thioformaldehyde: structures, energetics, and vibrational frequencies.

PubMed

Van Dornshuld, Eric; Holy, Christina M; Tschumper, Gregory S

2014-05-08

This work provides the first characterization of five stationary points of the homogeneous thioformaldehyde dimer, (CH2S)2, and seven stationary points of the heterogeneous formaldehyde/thioformaldehyde dimer, CH2O/CH2S, with correlated ab initio electronic structure methods. Full geometry optimizations and corresponding harmonic vibrational frequencies were computed with second-order Møller-Plesset perturbation theory (MP2) and 13 different density functionals in conjunction with triple-ζ basis sets augmented with diffuse and multiple sets of polarization functions. The MP2 results indicate that the three stationary points of (CH2S)2 and four of CH2O/CH2S are minima, in contrast to two stationary points of the formaldehyde dimer, (CH2O)2. Single-point energies were also computed using the explicitly correlated MP2-F12 and CCSD(T)-F12 methods and basis sets as large as heavy-aug-cc-pVTZ. The (CH2O)2 and CH2O/CH2S MP2 and MP2-F12 binding energies deviated from the CCSD(T)-F12 binding energies by no more than 0.2 and 0.4 kcal mol(-1), respectively. The (CH2O)2 and CH2O/CH2S global minimum is the same at every level of theory. However, the MP2 methods overbind (CH2S)2 by as much as 1.1 kcal mol(-1), effectively altering the energetic ordering of the thioformaldehyde dimer minima relative to the CCSD(T)-F12 energies. The CCSD(T)-F12 binding energies of the (CH2O)2 and CH2O/CH2S stationary points are quite similar, with the former ranging from around -2.4 to -4.6 kcal mol(-1) and the latter from about -1.1 to -4.4 kcal mol(-1). Corresponding (CH2S)2 stationary points have appreciably smaller CCSD(T)-F12 binding energies ranging from ca. -1.1 to -3.4 kcal mol(-1). The vibrational frequency shifts upon dimerization are also reported for each minimum on the MP2 potential energy surfaces.

Binding Energies of the Proton-Bound Amino Acid Dimers Gly·Gly, Ala·Ala, Gly·Ala, and Lys·Lys Measured by Blackbody Infrared Radiative Dissociation

PubMed Central

Price, William D.; Schnier, Paul D.

2005-01-01

Arrhenius activation energies in the zero-pressure limit for dissociation of gas-phase proton-bound homodimers of N,N-dimethylacetamide (N,N-DMA), glycine, alanine, and lysine and the heterodimer alanine·glycine were measured using blackbody infrared radiative dissociation (BIRD). In combination with master equation modeling of the kinetic data, binding energies of these dimers were determined. A value of 1.25 ± 0.05 eV is obtained for N,N-DMA and is in excellent agreement with that reported in the literature. The value obtained from the truncated Boltzmann model is significantly higher, indicating that the assumptions of this model do not apply to these ions. This is due to the competitive rates of photon emission and dissociation for these relatively large ions. The binding energies of the amino acid dimers are ~1.15 ± 0.05 eV and are indistinguishable despite the difference in their gas-phase basicity and structure. The threshold dissociation energies can be accurately modeled using a range of dissociation parameters and absorption/emission rates. However, the absolute values of the dissociation rates depend more strongly on the absorption/emission rates. For N,N-DMA and glycine, an accurate fit was obtained using frequencies and transition dipole moments calculated at the ab initio RHF/2-31G* and MP2/2-31G* level, respectively. In order to obtain a similar accuracy using values obtained from AM1 semiempirical calculations, it was necessary to multiply the transition dipole moments by a factor of 3. These results demonstrate that in combination with master equation modeling, BIRD can be used to obtain accurate threshold dissociation energies of relatively small ions of biological interest. PMID:17235378

Estimation of relative free energies of binding using pre-computed ensembles based on the single-step free energy perturbation and the site-identification by Ligand competitive saturation approaches.

PubMed

Raman, E Prabhu; Lakkaraju, Sirish Kaushik; Denny, Rajiah Aldrin; MacKerell, Alexander D

2017-06-05

Accurate and rapid estimation of relative binding affinities of ligand-protein complexes is a requirement of computational methods for their effective use in rational ligand design. Of the approaches commonly used, free energy perturbation (FEP) methods are considered one of the most accurate, although they require significant computational resources. Accordingly, it is desirable to have alternative methods of similar accuracy but greater computational efficiency to facilitate ligand design. In the present study relative free energies of binding are estimated for one or two non-hydrogen atom changes in compounds targeting the proteins ACK1 and p38 MAP kinase using three methods. The methods include standard FEP, single-step free energy perturbation (SSFEP) and the site-identification by ligand competitive saturation (SILCS) ligand grid free energy (LGFE) approach. Results show the SSFEP and SILCS LGFE methods to be competitive with or better than the FEP results for the studied systems, with SILCS LGFE giving the best agreement with experimental results. This is supported by additional comparisons with published FEP data on p38 MAP kinase inhibitors. While both the SSFEP and SILCS LGFE approaches require a significant upfront computational investment, they offer a 1000-fold computational savings over FEP for calculating the relative affinities of ligand modifications once those pre-computations are complete. An illustrative example of the potential application of these methods in the context of screening large numbers of transformations is presented. Thus, the SSFEP and SILCS LGFE approaches represent viable alternatives for actively driving ligand design during drug discovery and development. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Specificity in transition state binding: the Pauling model revisited.

PubMed

Amyes, Tina L; Richard, John P

2013-03-26

Linus Pauling proposed that the large rate accelerations for enzymes are caused by the high specificity of the protein catalyst for binding the reaction transition state. The observation that stable analogues of the transition states for enzymatic reactions often act as tight-binding inhibitors provided early support for this simple and elegant proposal. We review experimental results that support the proposal that Pauling's model provides a satisfactory explanation for the rate accelerations for many heterolytic enzymatic reactions through high-energy reaction intermediates, such as proton transfer and decarboxylation. Specificity in transition state binding is obtained when the total intrinsic binding energy of the substrate is significantly larger than the binding energy observed at the Michaelis complex. The results of recent studies that aimed to characterize the specificity in binding of the enolate oxygen at the transition state for the 1,3-isomerization reaction catalyzed by ketosteroid isomerase are reviewed. Interactions between pig heart succinyl-coenzyme A:3-oxoacid coenzyme A transferase (SCOT) and the nonreacting portions of coenzyme A (CoA) are responsible for a rate increase of 3 × 10(12)-fold, which is close to the estimated total 5 × 10(13)-fold enzymatic rate acceleration. Studies that partition the interactions between SCOT and CoA into their contributing parts are reviewed. Interactions of the protein with the substrate phosphodianion group provide an ~12 kcal/mol stabilization of the transition state for the reactions catalyzed by triosephosphate isomerase, orotidine 5'-monophosphate decarboxylase, and α-glycerol phosphate dehydrogenase. The interactions of these enzymes with the substrate piece phosphite dianion provide a 6-8 kcal/mol stabilization of the transition state for reaction of the appropriate truncated substrate. Enzyme activation by phosphite dianion reflects the higher dianion affinity for binding to the enzyme-transition state complex compared with that of the free enzyme. Evidence is presented that supports a model in which the binding energy of the phosphite dianion piece, or the phosphodianion group of the whole substrate, is utilized to drive an enzyme conformational change from an inactive open form E(O) to an active closed form E(C), by closure of a phosphodianion gripper loop. Members of the enolase and haloalkanoic acid dehalogenase superfamilies use variable capping domains to interact with nonreacting portions of the substrate and sequester the substrate from interaction with bulk solvent. Interactions of this capping domain with the phenyl group of mandelate have been shown to activate mandelate racemase for catalysis of deprotonation of α-carbonyl carbon. We propose that an important function of these capping domains is to utilize the binding interactions with nonreacting portions of the substrate to activate the enzyme for catalysis.

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 energy and counterion release for adsorption of the antimicrobial peptide lactoferricin B on a POPG membrane.

PubMed

Tolokh, Igor S; Vivcharuk, Victor; Tomberli, Bruno; Gray, C G

2009-09-01

Molecular dynamics (MD) simulations are used to study the interaction of an anionic palmitoyl-oleoyl-phosphatidylglycerol (POPG) bilayer with the cationic antimicrobial peptide bovine lactoferricin (LFCinB) in a 100 mM NaCl solution at 310 K. The interaction of LFCinB with a POPG bilayer is employed as a model system for studying the details of membrane adsorption selectivity of cationic antimicrobial peptides. Seventy eight 4 ns MD production run trajectories of the equilibrated system, with six restrained orientations of LFCinB at 13 different separations from the POPG membrane, are generated to determine the free energy profile for the peptide as a function of the distance between LFCinB and the membrane surface. To calculate the profile for this relatively large system, a variant of constrained MD and thermodynamic integration is used. A simplified method for relating the free energy profile to the LFCinB-POPG membrane binding constant is employed to predict a free energy of adsorption of -5.4+/-1.3 kcal/mol and a corresponding maximum adsorption binding force of about 58 pN. We analyze the results using Poisson-Boltzmann theory. We find the peptide-membrane attraction to be dominated by the entropy increase due to the release of counterions and polarized water from the region between the charged membrane and peptide, as the two approach each other. We contrast these results with those found earlier for adsorption of LFCinB on the mammalianlike palmitoyl-oleoyl-phosphatidylcholine membrane.

Characteristic vibration patterns of odor compounds from bread-baking volatiles upon protein binding: density functional and ONIOM study and principal component analysis.

PubMed

Treesuwan, Witcha; Hirao, Hajime; Morokuma, Keiji; Hannongbua, Supa

2012-05-01

As the mechanism underlying the sense of smell is unclear, different models have been used to rationalize structure-odor relationships. To gain insight into odorant molecules from bread baking, binding energies and vibration spectra in the gas phase and in the protein environment [7-transmembrane helices (7TMHs) of rhodopsin] were calculated using density functional theory [B3LYP/6-311++G(d,p)] and ONIOM [B3LYP/6-311++G(d,p):PM3] methods. It was found that acetaldehyde ("acid" category) binds strongly in the large cavity inside the receptor, whereas 2-ethyl-3-methylpyrazine ("roasted") binds weakly. Lys296, Tyr268, Thr118 and Ala117 were identified as key residues in the binding site. More emphasis was placed on how vibrational frequencies are shifted and intensities modified in the receptor protein environment. Principal component analysis (PCA) suggested that the frequency shifts of C-C stretching, CH(3) umbrella, C = O stretching and CH(3) stretching modes have a significant effect on odor quality. In fact, the frequency shifts of the C-C stretching and C = O stretching modes, as well as CH(3) umbrella and CH(3) symmetric stretching modes, exhibit different behaviors in the PCA loadings plot. A large frequency shift in the CH(3) symmetric stretching mode is associated with the sweet-roasted odor category and separates this from the acid odor category. A large frequency shift of the C-C stretching mode describes the roasted and oily-popcorn odor categories, and separates these from the buttery and acid odor categories.

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.

Entropy-enthalpy compensation at the single protein level: pH sensing in the bacterial channel OmpF.

PubMed

Alcaraz, Antonio; Queralt-Martín, María; Verdiá-Báguena, Carmina; Aguilella, Vicente M; Mafé, Salvador

2014-12-21

The pH sensing mechanism of the OmpF channel operates via ligand modification: increasing acidity induces the replacement of cations with protons in critical binding sites decreasing the channel conductance. Aside from the change in enthalpy associated with the binding, there is also a change in the microscopic arrangements of ligands, receptors and the surrounding solvent. We show that the pH-modulation of the single channel conduction involves small free energy changes because large enthalpic and entropic contributions change in opposite ways, demonstrating an approximate enthalpy-entropy compensation for different salts and concentrations.

DNA complexes with dyes designed for energy transfer as fluorescent markers

DOEpatents

Glazer, Alexander M.; Benson, Scott C.

1999-01-01

Heteromultimeric fluorophores are provided for binding to DNA, which allow for the detection of DNA in electrical separations and preparation of probes having high-fluorescent efficiencies and large Stokes shifts. In addition, by appropriate choice of fluorescent molecules, one can use a single narrow wavelength band excitation light source, while obtaining fluorescent emissions having sufficient separation to be readily discriminated.

DNA complexes with dyes designed for energy transfer as fluorescent markers

DOEpatents

Glazer, Alexander M.; Benson, Scott C.

1998-01-01

Heteromultimeric fluorophores are provided for binding to DNA, which allow for the detection of DNA in electrical separations and preparation of probes having high-fluorescent efficiencies and large Stokes shifts. In addition, by appropriate choice of fluorescent molecules, one can use a single narrow wavelength band excitation light source, while obtaining fluorescent emissions having sufficient separation to be readily discriminated.

DNA complexes with dyes designed for energy transfer as fluorescent markers

DOEpatents

Glazer, Alexander N.; Benson, Scott C.

1995-01-01

Heteromultimeric fluorophores are provided for binding to DNA, which allow for the detection of DNA in electrical separations and preparation of probes having high-fluorescent efficiencies and large Stokes shifts. In addition, by appropriate choice of fluorescent molecules, one can use a single narrow wavelength band excitation light source, while obtaining fluorescent emissions having sufficient separation to be readily discriminated.

DNA complexes with dyes designed for energy transfer as fluorescent markers

DOEpatents

Glazer, Alexander N.; Benson, Scott C.

1997-01-01

Heteromultimeric fluorophores are provided for binding to DNA, which allow for the detection of DNA in electrical separations and preparation of probes having high-fluorescent efficiencies and large Stokes shifts. In addition, by appropriate choice of fluorescent molecules, one can use a single narrow wavelength band excitation light source, while obtaining fluorescent emissions having sufficient separation to be readily discriminated.

Insight into the molecular mechanism of yeast acetyl-coenzyme A carboxylase mutants F510I, N485G, I69E, E477R, and K73R resistant to soraphen A

NASA Astrophysics Data System (ADS)

Gao, Jian; Liang, Li; Chen, Qingqing; Zhang, Ling; Huang, Tonghui

2018-02-01

Acetyl-coenzyme A carboxylases (ACCs) is the first committed enzyme of fatty acid synthesis pathway. The inhibition of ACC is thought to be beneficial not only for diseases related to metabolism, such as type-2 diabetes, but also for infectious disease like bacterial infection disease. Soraphen A, a potent allosteric inhibitor of BC domain of yeast ACC, exhibit lower binding affinities to several yeast ACC mutants and the corresponding drug resistance mechanisms are still unknown. We report here a theoretical study of binding of soraphen A to wild type and yeast ACC mutants (including F510I, N485G, I69E, E477R, and K73R) via molecular dynamic simulation and molecular mechanics/generalized Born surface area free energy calculations methods. The calculated binding free energies of soraphen A to yeast ACC mutants are weaker than to wild type, which is highly consistent with the experimental results. The mutant F510I weakens the binding affinity of soraphen A to yeast ACC mainly by decreasing the van der Waals contributions, while the weaker binding affinities of Soraphen A to other yeast ACC mutants including N485G, I69E, E477R, and K73R are largely attributed to the decreased net electrostatic (ΔE ele + ΔG GB) interactions. Our simulation results could provide important insights for the development of more potent ACC inhibitors.

Unusual structures of MgF5- superhalogen anion

NASA Astrophysics Data System (ADS)

Anusiewicz, Iwona; Skurski, Piotr

2007-05-01

The vertical electron detachment energies (VDE) of three MgF5- anions were calculated at the outer valence Green function level with the 6-311 + G(3df) basis sets. This species was found to form unusual geometrical structures each of which corresponds to an anionic state exhibiting superhalogen nature. The global minimum structure was described as a system in which two central magnesium atoms are linked via symmetrical triangle formed by three fluorine atoms. Extremely large electron binding energies of these anions (exceeding 8.5 eV in all cases) were predicted and discussed.

Exploring excited eigenstates of many-body systems using the functional renormalization group

NASA Astrophysics Data System (ADS)

Klöckner, Christian; Kennes, Dante Marvin; Karrasch, Christoph

2018-05-01

We introduce approximate, functional renormalization group based schemes to obtain correlation functions in pure excited eigenstates of large fermionic many-body systems at arbitrary energies. The algorithms are thoroughly benchmarked and their strengths and shortcomings are documented using a one-dimensional interacting tight-binding chain as a prototypical testbed. We study two "toy applications" from the world of Luttinger liquid physics: the survival of power laws in lowly excited states as well as the spectral function of high-energy "block" excitations, which feature several single-particle Fermi edges.

Protein pharmacophore selection using hydration-site analysis

PubMed Central

Hu, Bingjie; Lill, Markus A.

2012-01-01

Virtual screening using pharmacophore models is an efficient method to identify potential lead compounds for target proteins. Pharmacophore models based on protein structures are advantageous because a priori knowledge of active ligands is not required and the models are not biased by the chemical space of previously identified actives. However, in order to capture most potential interactions between all potentially binding ligands and the protein, the size of the pharmacophore model, i.e. number of pharmacophore elements, is typically quite large and therefore reduces the efficiency of pharmacophore based screening. We have developed a new method to select important pharmacophore elements using hydration-site information. The basic premise is that ligand functional groups that replace water molecules in the apo protein contribute strongly to the overall binding affinity of the ligand, due to the additional free energy gained from releasing the water molecule into the bulk solvent. We computed the free energy of water released from the binding site for each hydration site using thermodynamic analysis of molecular dynamics (MD) simulations. Pharmacophores which are co-localized with hydration sites with estimated favorable contributions to the free energy of binding are selected to generate a reduced pharmacophore model. We constructed reduced pharmacophore models for three protein systems and demonstrated good enrichment quality combined with high efficiency. The reduction in pharmacophore model size reduces the required screening time by a factor of 200–500 compared to using all protein pharmacophore elements. We also describe a training process using a small set of known actives to reliably select the optimal set of criteria for pharmacophore selection for each protein system. PMID:22397751

Prediction of protein-protein interaction sites using electrostatic desolvation profiles.

PubMed

Fiorucci, Sébastien; Zacharias, Martin

2010-05-19

Protein-protein complex formation involves removal of water from the interface region. Surface regions with a small free energy penalty for water removal or desolvation may correspond to preferred interaction sites. A method to calculate the electrostatic free energy of placing a neutral low-dielectric probe at various protein surface positions has been designed and applied to characterize putative interaction sites. Based on solutions of the finite-difference Poisson equation, this method also includes long-range electrostatic contributions and the protein solvent boundary shape in contrast to accessible-surface-area-based solvation energies. Calculations on a large set of proteins indicate that in many cases (>90%), the known binding site overlaps with one of the six regions of lowest electrostatic desolvation penalty (overlap with the lowest desolvation region for 48% of proteins). Since the onset of electrostatic desolvation occurs even before direct protein-protein contact formation, it may help guide proteins toward the binding region in the final stage of complex formation. It is interesting that the probe desolvation properties associated with residue types were found to depend to some degree on whether the residue was outside of or part of a binding site. The probe desolvation penalty was on average smaller if the residue was part of a binding site compared to other surface locations. Applications to several antigen-antibody complexes demonstrated that the approach might be useful not only to predict protein interaction sites in general but to map potential antigenic epitopes on protein surfaces. Copyright (c) 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

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

Benchmarking density functional tight binding models for barrier heights and reaction energetics of organic molecules.

PubMed

Gruden, Maja; Andjeklović, Ljubica; Jissy, Akkarapattiakal Kuriappan; Stepanović, Stepan; Zlatar, Matija; Cui, Qiang; Elstner, Marcus

2017-09-30

Density Functional Tight Binding (DFTB) models are two to three orders of magnitude faster than ab initio and Density Functional Theory (DFT) methods and therefore are particularly attractive in applications to large molecules and condensed phase systems. To establish the applicability of DFTB models to general chemical reactions, we conduct benchmark calculations for barrier heights and reaction energetics of organic molecules using existing databases and several new ones compiled in this study. Structures for the transition states and stable species have been fully optimized at the DFTB level, making it possible to characterize the reliability of DFTB models in a more thorough fashion compared to conducting single point energy calculations as done in previous benchmark studies. The encouraging results for the diverse sets of reactions studied here suggest that DFTB models, especially the most recent third-order version (DFTB3/3OB augmented with dispersion correction), in most cases provide satisfactory description of organic chemical reactions with accuracy almost comparable to popular DFT methods with large basis sets, although larger errors are also seen for certain cases. Therefore, DFTB models can be effective for mechanistic analysis (e.g., transition state search) of large (bio)molecules, especially when coupled with single point energy calculations at higher levels of theory. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Collapse of axion stars

DOE PAGES

Eby, Joshua; Leembruggen, Madelyn; Suranyi, Peter; ...

2016-12-15

Axion stars, gravitationally bound states of low-energy axion particles, have a maximum mass allowed by gravitational stability. Weakly bound states obtaining this maximum mass have sufficiently large radii such that they are dilute, and as a result, they are well described by a leading-order expansion of the axion potential. Here, heavier states are susceptible to gravitational collapse. Inclusion of higher-order interactions, present in the full potential, can give qualitatively different results in the analysis of collapsing heavy states, as compared to the leading-order expansion. In this work, we find that collapsing axion stars are stabilized by repulsive interactions present inmore » the full potential, providing evidence that such objects do not form black holes. In the last moments of collapse, the binding energy of the axion star grows rapidly, and we provide evidence that a large amount of its energy is lost through rapid emission of relativistic axions.« 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

Ab initio study of novel carbon nanofoam structure as an anode material for Li secondary battery

NASA Astrophysics Data System (ADS)

Park, Hanjin; Park, Sora; Kang, Seoung-Hun; Kwon, Young-Kyun

2014-03-01

Using ab inito density functional theory, we investigate the adsorption and diffusion properties of Li atoms on a new carbon nanostructure, which may be used as an anode of Li secondary battery. We focus on a special carbon nanofoam structure consisting of Schwarzite structures with negative Gaussian curvature as core parts, which are interconnected through (4,4) CNT segments. Considering the symmetry of the nanofoam structure, we find various Li adsorption sites exhibiting relatively large binding energies (>= 2 . 00 eV). Based on these adsorption sites, we identify several diffusion paths on the outside or inside surface of the nanofoam structure and examine the diffusion barriers along the paths. Our results show that Li atom can diffuse almost freely due to its low energy barriers on both outside and inside surfaces. Finally, we also evaluate the energy gain tendency and the volume expansion as well as the average binding energy while adding Li atoms to estimate the Li-capacity and recyclability of the system, which are important characterisitics for anode materials. We conclude that the carbon nanofoam structure would be better as an anode material than graphite in Li capacity and volume expansion.

Heavy quarkonia in a potential model: binding energy, decay width, and survival probability

NASA Astrophysics Data System (ADS)

Srivastava, P. K.; Chaturvedi, O. S. K.; Thakur, Lata

2018-06-01

Recently a lot of progress has been made in deriving the heavy quark potential within a QCD medium. In this article we have considered heavy quarkonium in a hot quark gluon plasma phase. The heavy-quark potential has been modeled properly for short as well as long distances. The potential at long distances is modeled as a QCD string which is screened at the same scale as the Coulomb field. We have numerically solved the 1+1-dimensional Schrodinger equation for this potential and obtained the eigen wavefunction and binding energy for the 1 S and 2 S states of charmonium and bottomonium. Further, we have calculated the decay width and dissociation temperature of quarkonium states in the QCD plasma. Finally, we have used our recently proposed unified model with these new values of decay widths to calculate the survival probability of the various quarkonium states with respect to centrality at relativistic heavy ion collider and large hadron collider energies. This study provides a unified, consistent and comprehensive description of spectroscopic properties of various quarkonium states at finite temperatures along with their nuclear modification factor at different collision energies.

Poly(amidoamine) dendrimers on lipid bilayers II: Effects of bilayer phase and dendrimer termination.

PubMed

Kelly, Christopher V; Leroueil, Pascale R; Orr, Bradford G; Banaszak Holl, Mark M; Andricioaei, Ioan

2008-08-07

The molecular structures and enthalpy release of poly(amidoamine) (PAMAM) dendrimers binding to 1,2-dimyristoyl- sn-glycero-3-phosphocholine (DMPC) bilayers were explored through atomistic molecular dynamics. Three PAMAM dendrimer terminations were examined: protonated primary amine, neutral acetamide, and deprotonated carboxylic acid. Fluid and gel lipid phases were examined to extract the effects of lipid tail mobility on the binding of generation-3 dendrimers, which are directly relevant to the nanoparticle interactions involving lipid rafts, endocytosis, lipid removal, and/or membrane pores. Upon binding to gel phase lipids, dendrimers remained spherical, had a constant radius of gyration, and approximately one-quarter of the terminal groups were in close proximity to the lipids. In contrast, upon binding to fluid phase bilayers, dendrimers flattened out with a large increase in their asphericity and radii of gyration. Although over twice as many dendrimer-lipid contacts were formed on fluid versus gel phase lipids, the dendrimer-lipid interaction energy was only 20% stronger. The greatest enthalpy release upon binding was between the charged dendrimers and the lipid bilayer. However, the stronger binding to fluid versus gel phase lipids was driven by the hydrophobic interactions between the inner dendrimer and lipid tails.

Interaction of the dietary pigment curcumin with hemoglobin: energetics of the complexation.

PubMed

Basu, Anirban; Kumar, Gopinatha Suresh

2014-08-01

Thermodynamics of the interaction of the chemotherapeutic and chemopreventive dietary pigment, curcumin, with hemoglobin was studied by isothermal titration calorimetry. The binding was characterized to be exothermic. At 293.15 K, the equilibrium constant for curcumin-Hb complexation was found to be (4.88 ± 0.06) × 10(5) M(-1). The binding stoichiometry was calculated to be 1.08 ± 0.05, confirming a 1:1 complexation. The binding was driven by a large negative standard molar enthalpy change (ΔH(0) = -118.45 ± 0.05 kJ mol(-1)) and an unfavorable standard molar entropy change (TΔS(0) = -86.53 ± 0.01 kJ mol(-1)) at 293.15 K. Increasing the temperature favoured the binding, and the magnitude of the negative standard molar heat capacity change suggested the involvement of significant hydrophobic forces in the binding process. With increasing salt concentration, the magnitude of the equilibrium constant decreased slightly; and the complexation mostly involved non-polyelectrolytic forces contributing about 92-94% of the standard molar Gibbs energy change. DSC studies revealed that curcumin binding caused a partial unfolding of the protein.

Spectroscopic and microcalorimetric studies on the molecular binding of food colorant acid red 27 with deoxyribonucleic acid.

PubMed

Basu, Anirban; Kumar, Gopinatha Suresh

2016-08-01

Interaction of the food colorant acid red 27 with double stranded DNA was investigated using spectroscopic and calorimetric methods. Absorbance and fluorescence studies suggested an intimate binding interaction between the dye and DNA. The quantum efficiency value testified an effective energy transfer from the DNA base pairs to the dye molecules. Minor groove displacement assay with Hoechst 33258 revealed that the binding occurs in the minor groove of DNA. Circular dichroism studies revealed that acid red 27 induces moderate conformational perturbations in DNA. Results of calorimetric studies suggested that the complexation process was driven largely by positive entropic contribution with a smaller favorable enthalpy contribution. The equilibrium constant of the binding was calculated to be (3.04 ± 0.09) × 10(4)  M(-1) at 298.15 K. Negative heat capacity value along with the enthalpy-entropy compensation phenomenon established the involvement of dominant hydrophobic forces in the binding process. Differential scanning calorimetry studies presented evidence for an increased thermal stability of DNA on binding of acid red 27. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Competition effects in cation binding to humic acid: Conditional affinity spectra for fixed total metal concentration conditions

NASA Astrophysics Data System (ADS)

David, Calin; Mongin, Sandrine; Rey-Castro, Carlos; Galceran, Josep; Companys, Encarnació; Garcés, José Luis; Salvador, José; Puy, Jaume; Cecilia, Joan; Lodeiro, Pablo; Mas, Francesc

2010-09-01

Information on the Pb and Cd binding to a purified Aldrich humic acid (HA) is obtained from the influence of different fixed total metal concentrations on the acid-base titrations of this ligand. NICA (Non-Ideal Competitive Adsorption) isotherm has been used for a global quantitative description of the binding, which has then been interpreted by plotting the Conditional Affinity Spectra of the H + binding at fixed total metal concentrations (CAScTM). This new physicochemical tool, here introduced, allows the interpretation of binding results in terms of distributions of proton binding energies. A large increase in the acidity of the phenolic sites as the total metal concentration increases, especially in presence of Pb, is revealed from the shift of the CAScTM towards lower affinities. The variance of the CAScTM distribution, which can be used as a direct measure of the heterogeneity, also shows a significant dependence on the total metal concentration. A discussion of the factors that influence the heterogeneity of the HA under the conditions of each experiment is provided, so that the smoothed pattern exhibited by the titration curves can be justified.

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

Target engagement and drug residence time can be observed in living cells with BRET

PubMed Central

Robers, Matthew B.; Dart, Melanie L.; Woodroofe, Carolyn C.; Zimprich, Chad A.; Kirkland, Thomas A.; Machleidt, Thomas; Kupcho, Kevin R.; Levin, Sergiy; Hartnett, James R.; Zimmerman, Kristopher; Niles, Andrew L.; Ohana, Rachel Friedman; Daniels, Danette L.; Slater, Michael; Wood, Monika G.; Cong, Mei; Cheng, Yi-Qiang; Wood, Keith V.

2015-01-01

The therapeutic action of drugs is predicated on their physical engagement with cellular targets. Here we describe a broadly applicable method using bioluminescence resonance energy transfer (BRET) to reveal the binding characteristics of a drug with selected targets within intact cells. Cell-permeable fluorescent tracers are used in a competitive binding format to quantify drug engagement with the target proteins fused to Nanoluc luciferase. The approach enabled us to profile isozyme-specific engagement and binding kinetics for a panel of histone deacetylase (HDAC) inhibitors. Our analysis was directed particularly to the clinically approved prodrug FK228 (Istodax/Romidepsin) because of its unique and largely unexplained mechanism of sustained intracellular action. Analysis of the binding kinetics by BRET revealed remarkably long intracellular residence times for FK228 at HDAC1, explaining the protracted intracellular behaviour of this prodrug. Our results demonstrate a novel application of BRET for assessing target engagement within the complex milieu of the intracellular environment. PMID:26631872

Molecular Mechanism of Wide Photoabsorption Spectral Shifts of Color Variants of Human Cellular Retinol Binding Protein II.

PubMed

Cheng, Cheng; Kamiya, Motoshi; Uchida, Yoshihiro; Hayashi, Shigehiko

2015-10-21

Color variants of human cellular retinol binding protein II (hCRBPII) created by protein engineering were recently shown to exhibit anomalously wide photoabsorption spectral shifts over ∼200 nm across the visible region. The remarkable phenomenon provides a unique opportunity to gain insight into the molecular basis of the color tuning of retinal binding proteins for understanding of color vision as well as for engineering of novel color variants of retinal binding photoreceptor proteins employed in optogenetics. Here, we report a theoretical investigation of the molecular mechanism underlying the anomalously wide spectral shifts of the color variants of hCRBPII. Computational modeling of the color variants with hybrid molecular simulations of free energy geometry optimization succeeded in reproducing the experimentally observed wide spectral shifts, and revealed that protein flexibility, through which the active site structure of the protein and bound water molecules is altered by remote mutations, plays a significant role in inducing the large spectral shifts.

Decoding the patterns of ubiquitin recognition by ubiquitin-associated domains from free energy simulations.

PubMed

Bouvier, Benjamin

2014-01-07

Ubiquitin is a highly conserved, highly represented protein acting as a regulating signal in numerous cellular processes. It leverages a single hydrophobic binding patch to recognize and bind a large variety of protein domains with remarkable specificity, but can also self-assemble into chains of poly-diubiquitin units in which these interfaces are sequestered, profoundly altering the individual monomers' recognition characteristics. Despite numerous studies, the origins of this varied specificity and the competition between substrates for the binding of the ubiquitin interface patch remain under heated debate. This study uses enhanced sampling all-atom molecular dynamics to simulate the unbinding of complexes of mono- or K48-linked diubiquitin bound to several ubiquitin-associated domains, providing insights into the mechanism and free energetics of ubiquitin recognition and binding. The implications for the subtle tradeoff between the stability of the polyubiquitin signal and its easy recognition by target protein assemblies are discussed, as is the enhanced affinity of the latter for long polyubiquitin chains compared to isolated mono- or diubiquitin.

Computing conformational free energy differences in explicit solvent: An efficient thermodynamic cycle using an auxiliary potential and a free energy functional constructed from the end points.

PubMed

Harris, Robert C; Deng, Nanjie; Levy, Ronald M; Ishizuka, Ryosuke; Matubayasi, Nobuyuki

2017-06-05

Many biomolecules undergo conformational changes associated with allostery or ligand binding. Observing these changes in computer simulations is difficult if their timescales are long. These calculations can be accelerated by observing the transition on an auxiliary free energy surface with a simpler Hamiltonian and connecting this free energy surface to the target free energy surface with free energy calculations. Here, we show that the free energy legs of the cycle can be replaced with energy representation (ER) density functional approximations. We compute: (1) The conformational free energy changes for alanine dipeptide transitioning from the right-handed free energy basin to the left-handed basin and (2) the free energy difference between the open and closed conformations of β-cyclodextrin, a "host" molecule that serves as a model for molecular recognition in host-guest binding. β-cyclodextrin contains 147 atoms compared to 22 atoms for alanine dipeptide, making β-cyclodextrin a large molecule for which to compute solvation free energies by free energy perturbation or integration methods and the largest system for which the ER method has been compared to exact free energy methods. The ER method replaced the 28 simulations to compute each coupling free energy with two endpoint simulations, reducing the computational time for the alanine dipeptide calculation by about 70% and for the β-cyclodextrin by > 95%. The method works even when the distribution of conformations on the auxiliary free energy surface differs substantially from that on the target free energy surface, although some degree of overlap between the two surfaces is required. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Study of iridium silicide monolayers using density functional theory

NASA Astrophysics Data System (ADS)

Popis, Minh D.; Popis, Sylvester V.; Oncel, Nuri; Hoffmann, Mark R.; ćakır, Deniz

2018-02-01

In this study, we investigated physical and electronic properties of possible two-dimensional structures formed by Si (silicon) and Ir (iridium). To this end, different plausible structures were modeled by using density functional theory and the cohesive energies calculated for the geometry of optimized structures, with the lowest equilibrium lattice constants. Among several candidate structures, we identified three mechanically (via elastic constants and Young's modulus), dynamically (via phonon calculations), and thermodynamically stable iridium silicide monolayer structures. The lowest energy structure has a chemical formula of Ir2Si4 (called r-IrSi2), with a rectangular lattice (Pmmn space group). Its cohesive energy was calculated to be -0.248 eV (per IrSi2 unit) with respect to bulk Ir and bulk Si. The band structure indicates that the Ir2Si4 monolayer exhibits metallic properties. Other stable structures have hexagonal (P-3m1) and tetragonal (P4/nmm) cell structures with 0.12 and 0.20 eV/f.u. higher cohesive energies, respectively. Our calculations showed that Ir-Si monolayers are reactive. Although O2 molecules exothermically dissociate on the surface of the free-standing iridium silicide monolayers with large binding energies, H2O molecules bind to the monolayers with a rather weak interaction.

Enhanced conformational sampling to visualize a free-energy landscape of protein complex formation

PubMed Central

Iida, Shinji; Nakamura, Haruki; Higo, Junichi

2016-01-01

We introduce various, recently developed, generalized ensemble methods, which are useful to sample various molecular configurations emerging in the process of protein–protein or protein–ligand binding. The methods introduced here are those that have been or will be applied to biomolecular binding, where the biomolecules are treated as flexible molecules expressed by an all-atom model in an explicit solvent. Sampling produces an ensemble of conformations (snapshots) that are thermodynamically probable at room temperature. Then, projection of those conformations to an abstract low-dimensional space generates a free-energy landscape. As an example, we show a landscape of homo-dimer formation of an endothelin-1-like molecule computed using a generalized ensemble method. The lowest free-energy cluster at room temperature coincided precisely with the experimentally determined complex structure. Two minor clusters were also found in the landscape, which were largely different from the native complex form. Although those clusters were isolated at room temperature, with rising temperature a pathway emerged linking the lowest and second-lowest free-energy clusters, and a further temperature increment connected all the clusters. This exemplifies that the generalized ensemble method is a powerful tool for computing the free-energy landscape, by which one can discuss the thermodynamic stability of clusters and the temperature dependence of the cluster networks. PMID:27288028

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

Infrared Dielectric Screening Determines the Low Exciton Binding Energy of Metal-Halide Perovskites.

PubMed

Umari, Paolo; Mosconi, Edoardo; De Angelis, Filippo

2018-02-01

The performance of lead-halide perovskites in optoelectronic devices is due to a unique combination of factors, including highly efficient generation, transport, and collection of photogenerated charge carriers. The mechanism behind efficient charge generation in lead-halide perovskites is still largely unknown. Here, we investigate the factors that influence the exciton binding energy (E b ) in a series of metal-halide perovskites using accurate first-principles calculations based on solution of the Bethe-Salpeter equation, coupled to ab initio molecular dynamics simulations. We find that E b is strongly modulated by screening from low-energy phonons, which account for a factor ∼2 E b reduction, while dynamic disorder and rotational motion of the organic cations play a minor role. We calculate E b = 15 meV for MAPbI 3 , in excellent agreement with recent experimental estimates. We then explore how different material combinations (e.g., replacing Pb → Pb:Sn→ Sn; and MA → FA → Cs) may lead to different E b values and highlight the mechanisms underlying E b tuning.

Membrane Fusion Proteins as Nanomachines

NASA Astrophysics Data System (ADS)

Tamm, Lukas

2009-03-01

Membrane fusion is key to fertilization, virus infection, and neurotransmission. Specific proteins work like nanomachines to stitch together fluid, yet highly ordered lipid bilayers. The energy gained from large exothermic conformational changes of these proteins is utilized to fuse lipid bilayers that do not fuse spontaneously. Structural studies using x-ray crystallography and NMR spectroscopy have yielded detailed information about architecture and inner workings of these molecular machines. The question now is: how is mechanical energy gained from such protein transformations harnessed to transform membrane topology? To answer this question, we have determined that a boomerang-shaped structure of the influenza fusion peptide is critical to generate a high-energy binding intermediate in the target membrane and to return the ``boomerang'' to its place of release near the viral membrane for completion of the fusion cycle. In presynaptic exocytosis, receptor and acceptor SNAREs are zippered to form a helical bundle that is arrested shortly before the membrane. Ca binding to interlocked synaptotagmin releases the fusion block. Structural NMR and single molecule fluorescence data are combined to arrive at and further refine this picture.

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

Jimenez-Orozco, Carlos; Florez, Elizabeth; Moreno, Andres

A systematic study of ethylene adsorption over δ-MoC(001), TiC(001), and ZrC(001) surfaces was conducted by means of calculations based on periodic density functional theory. The structure and electronic properties of each carbide pristine surface had a strong influence in the bonding of ethylene. It was found that the metal and carbon sites of the carbide could participate in the adsorption process. As a consequence of this, very different bonding mechanisms were seen on δ-MoC(001) and TiC(001). The bonding of the molecule on the TMC(001) systems showed only minor similarities to the type of bonding found on a typical metal likemore » Pt(111). In general, the ethylene binding energy follow the trend in stability: ZrC(001) < TiC(001) < δ-MoC(001) < Pt(111). The van der Waals correction to the energy produces large binding energy values, modifies the stability orders and drives the ethylene closer to the surface but the adsorbate geometry parameters remain unchanged. Ethylene was activated on clearly defined binding geometries, changing its hybridization from sp 2 to sp 3 with an elongation (0.16–0.31 Å) of the C=C bond. As a result, on the basis of this theoretical study, δ-MoC(001) is proposed as a potential catalyst for the hydrogenation of olefins, whereas TiC(001) could be useful for their hydrogenolysis.« less

Characterization of an alternative low energy fold for bovine α-lactalbumin formed by disulfide bond shuffling.

PubMed

Lewney, Sarah; Smith, Lorna J

2012-03-01

Bovine α-lactalbumin (αLA) forms a misfolded disulfide bond shuffled isomer, X-αLA. This X-αLA isomer contains two native disulfide bridges (Cys 6-Cys 120 and Cys 28-Cys 111) and two non-native disulfide bridges (Cys 61-Cys 73 and Cys 77-Cys 91). MD simulations have been used to characterize the X-αLA isomer and its formation via disulfide bond shuffling and to compare it with the native fold of αLA. In the simulations of the X-αLA isomer the structure of the α-domain of native αLA is largely retained in agreement with experimental data. However, there are significant rearrangements in the β-domain, including the loss of the native β-sheet and calcium binding site. Interestingly, the energies of X-αLA and native αLA in simulations in the absence of calcium are closely similar. Thus, the X-αLA isomer represents a different low energy fold for the protein. Calcium binding to native αLA is shown to help preserve the structure of the β-domain of the protein limiting possibilities for disulfide bond shuffling. Hence, binding calcium plays an important role in both maintaining the native structure of αLA and providing a mechanism for distinguishing between folded and misfolded species. Copyright © 2011 Wiley Periodicals, Inc.

H2 Ortho-to-para Conversion on Grains: A Route to Fast Deuterium Fractionation in Dense Cloud Cores?

NASA Astrophysics Data System (ADS)

Bovino, S.; Grassi, T.; Schleicher, D. R. G.; Caselli, P.

2017-11-01

Deuterium fractionation, I.e., the enhancement of deuterated species with respect to non-deuterated ones, is considered to be a reliable chemical clock of star-forming regions. This process is strongly affected by the ortho-to-para H2 ratio. In this Letter we explore the effect of the ortho-para (o-p) H2 conversion on grains on the deuteration timescale in fully-depleted dense cores, including the most relevant uncertainties that affect this complex process. We show that (I) the o-p H2 conversion on grains is not strongly influenced by the uncertainties on the conversion time and the sticking coefficient, and (II) that the process is controlled by the temperature and the residence time of ortho-H2 on the surface, I.e., by the binding energy. We find that for binding energies between 330 and 550 K, depending on the temperature, the o-p H2 conversion on grains can shorten the deuterium fractionation timescale by orders of magnitude, opening a new route for explaining the large observed deuteration fraction D frac in dense molecular cloud cores. Our results suggest that the star formation timescale, when estimated through the timescale to reach the observed deuteration fractions, might be shorter than previously proposed. However, more accurate measurements of the binding energy are needed in order to better assess the overall role of this process.

Systematic spatial and stoichiometric screening towards understanding the surface of ultrasmall oxygenated silicon nanocrystal

NASA Astrophysics Data System (ADS)

Niaz, Shanawer; Zdetsis, Aristides D.; Koukaras, Emmanuel N.; Gülseren, Oǧuz; Sadiq, Imran

2016-11-01

In most of the realistic ab initio and model calculations which have appeared on the emission of light from silicon nanocrystals, the role of surface oxygen has been usually ignored, underestimated or completely ruled out. We investigate theoretically, by density functional theory (DFT/B3LYP) possible modes of oxygen bonding in hydrogen terminated silicon quantum dots using as a representative case of the Si29 nanocrystal. We have considered Bridge-bonded oxygen (BBO), Doubly-bonded oxygen (DBO), hydroxyl (OH) and Mix of these oxidizing agents. Due to stoichiometry, all comparisons performed are unbiased with respect to composition whereas spatial distribution of oxygen species pointed out drastic change in electronic and cohesive characteristics of nanocrytals. From an overall perspective of this study, it is shown that bridge bonded oxygenated Si nanocrystals accompanied by Mix have higher binding energies and large electronic gap compared to nanocrystals with doubly bonded oxygen atoms. In addition, it is observed that the presence of OH along with BBO, DBO and mixed configurations further lowers electronic gaps and binding energies but trends in same fashion. It is also demonstrated that within same composition, oxidizing constituent, along with their spatial distribution substantially alters binding energy, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) gap (up to 1.48 eV) and localization of frontier orbitals.

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.

Multispectroscopic and calorimetric studies on the binding of the food colorant tartrazine with human hemoglobin.

PubMed

Basu, Anirban; Suresh Kumar, Gopinatha

2016-11-15

Interaction of the food colorant tartrazine with human hemoglobin was studied using multispectroscopic and microcalorimetric techniques to gain insights into the binding mechanism and thereby the toxicity aspects. Hemoglobin spectrum showed hypochromic changes in the presence of tartrazine. Quenching of the fluorescence of hemoglobin occurred and the quenching mechanism was through a static mode as revealed from temperature dependent and time-resolved fluorescence studies. According to the FRET theory the distance between β-Trp37 of hemoglobin and bound tartrazine was evaluated to be 3.44nm. Synchronous fluorescence studies showed that tartrazine binding led to alteration of the microenvironment around the tryptophans more in comparison to tyrosines. 3D fluorescence and FTIR data provided evidence for conformational changes in the protein on binding. Circular dichroism studies revealed that the binding led to significant loss in the helicity of hemoglobin. The esterase activity assay further complemented the circular dichroism data. Microcalorimetric study using isothermal titration calorimetry revealed the binding to be exothermic and driven largely by positive entropic contribution. Dissection of the Gibbs energy change proposed the protein-dye complexation to be dominated by non-polyelectrolytic forces. Negative heat capacity change also corroborated the involvement of hydrophobic forces in the binding process. Copyright © 2016 Elsevier B.V. All rights reserved.

Discovery of 12-mer peptides that bind to wood lignin

PubMed Central

Yamaguchi, Asako; Isozaki, Katsuhiro; Nakamura, Masaharu; Takaya, Hikaru; Watanabe, Takashi

2016-01-01

Lignin, an abundant terrestrial polymer, is the only large-volume renewable feedstock composed of an aromatic skeleton. Lignin has been used mostly as an energy source during paper production; however, recent interest in replacing fossil fuels with renewable resources has highlighted its potential value in providing aromatic chemicals. Highly selective degradation of lignin is pivotal for industrial production of paper, biofuels, chemicals, and materials. However, few studies have examined natural and synthetic molecular components recognizing the heterogeneous aromatic polymer. Here, we report the first identification of lignin-binding peptides possessing characteristic sequences using a phage display technique. The consensus sequence HFPSP was found in several lignin-binding peptides, and the outer amino acid sequence affected the binding affinity of the peptides. Substitution of phenylalanine7 with Ile in the lignin-binding peptide C416 (HFPSPIFQRHSH) decreased the affinity of the peptide for softwood lignin without changing its affinity for hardwood lignin, indicating that C416 recognised structural differences between the lignins. Circular dichroism spectroscopy demonstrated that this peptide adopted a highly flexible random coil structure, allowing key residues to be appropriately arranged in relation to the binding site in lignin. These results provide a useful platform for designing synthetic and biological catalysts selectively bind to lignin. PMID:26903196

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.

Correlating Calcium Binding, Förster Resonance Energy Transfer, and Conformational Change in the Biosensor TN-XXL

PubMed Central

Geiger, Anselm; Russo, Luigi; Gensch, Thomas; Thestrup, Thomas; Becker, Stefan; Hopfner, Karl-Peter; Griesinger, Christian; Witte, Gregor; Griesbeck, Oliver

2012-01-01

Genetically encoded calcium indicators have become instrumental in imaging signaling in complex tissues and neuronal circuits in vivo. Despite their importance, structure-function relationships of these sensors often remain largely uncharacterized due to their artificial and multimodular composition. Here, we describe a combination of protein engineering and kinetic, spectroscopic, and biophysical analysis of the Förster resonance energy transfer (FRET)-based calcium biosensor TN-XXL. Using fluorescence spectroscopy of engineered tyrosines, we show that two of the four calcium binding EF-hands dominate the FRET output of TN-XXL and that local conformational changes of these hands match the kinetics of FRET change. Using small-angle x-ray scattering and NMR spectroscopy, we show that TN-XXL changes from a flexible elongated to a rigid globular shape upon binding calcium, thus resulting in FRET signal output. Furthermore, we compare calcium titrations using fluorescence lifetime spectroscopy with the ratiometric approach and investigate potential non-FRET effects that may affect the fluorophores. Thus, our data characterize the biophysics of TN-XXL in detail and may form a basis for further rational engineering of FRET-based biosensors. PMID:22677394

Theoretical study of the adsorption of DNA bases on the acidic external surface of montmorillonite.

PubMed

Mignon, Pierre; Sodupe, Mariona

2012-01-14

In the present study, DFT periodic plane wave calculations, at the PBE-D level of theory, were carried out to investigate the interaction of DNA nucleobases with acidic montmorillonite. The surface model was considered in its octahedral (Osub) and tetrahedral (Tsub) substituted forms, known to have different acidic properties. The adsorption of adenine, guanine and cytosine was considered in both orthogonal and coplanar orientations with the surface, interacting with the proton via a given heteroatom. In almost all considered cases, adsorption involved the spontaneous proton transfer to the nucleobase, with a more pronounced character in the Osub structures. The binding energy is about 10 kcal mol(-1) larger for Osub than for Tsub complexes mainly due to the larger acidity in Osub surfaces and due to the better stabilization by H-bond contacts between the negatively charged surface and the protonated base. The binding energy of coplanar orientations of the base is observed to be as large as the orthogonal ones due to a balance between electrostatic and dispersion contributions. Finally the binding of guanine and adenine on the acidic surface amounts to 50 kcal mol(-1) while that of cytosine rises to 44 kcal mol(-1).

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.

Edge currents in frustrated Josephson junction ladders

NASA Astrophysics Data System (ADS)

Marques, A. M.; Santos, F. D. R.; Dias, R. G.

2016-09-01

We present a numerical study of quasi-1D frustrated Josephson junction ladders with diagonal couplings and open boundary conditions, in the large capacitance limit. We derive a correspondence between the energy of this Josephson junction ladder and the expectation value of the Hamiltonian of an analogous tight-binding model, and show how the overall superconducting state of the chain is equivalent to the minimum energy state of the tight-binding model in the subspace of one-particle states with uniform density. To satisfy the constraint of uniform density, the superconducting state of the ladder is written as a linear combination of the allowed k-states of the tight-binding model with open boundaries. Above a critical value of the parameter t (ratio between the intra-rung and inter-rung Josephson couplings) the ladder spontaneously develops currents at the edges, which spread to the bulk as t is increased until complete coverage is reached. Above a certain value of t, which varies with ladder size (t = 1 for an infinite-sized ladder), the edge currents are destroyed. The value t = 1 corresponds, in the tight-binding model, to the opening of a gap between two bands. We argue that the disappearance of the edge currents with this gap opening is not coincidental, and that this points to a topological origin for these edge current states.

Impact of mutations on the allosteric conformational equilibrium

PubMed Central

Weinkam, Patrick; Chen, Yao Chi; Pons, Jaume; Sali, Andrej

2012-01-01

Allostery in a protein involves effector binding at an allosteric site that changes the structure and/or dynamics at a distant, functional site. In addition to the chemical equilibrium of ligand binding, allostery involves a conformational equilibrium between one protein substate that binds the effector and a second substate that less strongly binds the effector. We run molecular dynamics simulations using simple, smooth energy landscapes to sample specific ligand-induced conformational transitions, as defined by the effector-bound and unbound protein structures. These simulations can be performed using our web server: http://salilab.org/allosmod/. We then develop a set of features to analyze the simulations and capture the relevant thermodynamic properties of the allosteric conformational equilibrium. These features are based on molecular mechanics energy functions, stereochemical effects, and structural/dynamic coupling between sites. Using a machine-learning algorithm on a dataset of 10 proteins and 179 mutations, we predict both the magnitude and sign of the allosteric conformational equilibrium shift by the mutation; the impact of a large identifiable fraction of the mutations can be predicted with an average unsigned error of 1 kBT. With similar accuracy, we predict the mutation effects for an 11th protein that was omitted from the initial training and testing of the machine-learning algorithm. We also assess which calculated thermodynamic properties contribute most to the accuracy of the prediction. PMID:23228330

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.

DNA complexes with dyes designed for energy transfer as fluorescent markers

DOEpatents

Glazer, A.N.; Benson, S.C.

1997-07-08

Heteromultimeric fluorophores are provided for binding to DNA, which allow for the detection of DNA in electrical separations and preparation of probes having high-fluorescent efficiencies and large Stokes shifts. In addition, by appropriate choice of fluorescent molecules, one can use a single narrow wavelength band excitation light source, while obtaining fluorescent emissions having sufficient separation to be readily discriminated. 4 figs.

DNA complexes with dyes designed for energy transfer as fluorescent markers

DOEpatents

Glazer, A.M.; Benson, S.C.

1998-06-16

Heteromultimeric fluorophores are provided for binding to DNA, which allow for the detection of DNA in electrical separations and preparation of probes having high-fluorescent efficiencies and large Stokes shifts. In addition, by appropriate choice of fluorescent molecules, one can use a single narrow wavelength band excitation light source, while obtaining fluorescent emissions having sufficient separation to be readily discriminated. 4 figs.

DNA complexes with dyes designed for energy transfer as fluorescent markers

DOEpatents

Glazer, A.N.; Benson, S.C.

1995-03-28

Heteromultimeric fluorophores are provided for binding to DNA, which allow for the detection of DNA in electrical separations and preparation of probes having high-fluorescent efficiencies and large Stokes shifts. In addition, by appropriate choice of fluorescent molecules, one can use a single narrow wavelength band excitation light source, while obtaining fluorescent emissions having sufficient separation to be readily discriminated. 4 figures.

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/.

Application of the Interacting Quantum Atoms Approach to the S66 and Ionic-Hydrogen-Bond Datasets for Noncovalent Interactions.

PubMed

Suárez, Dimas; Díaz, Natalia; Francisco, Evelio; Martín Pendás, Angel

2018-04-17

The interacting quantum atoms (IQA) method can assess, systematically and in great detail, the strength and physics of both covalent and noncovalent interactions. The lack of a pair density in density functional theory (DFT), which precludes the direct IQA decomposition of the characteristic exchange-correlation energy, has been recently overcome by means of a scaling technique, which can largely expand the applicability of the method. To better assess the utility of the augmented IQA methodology to derive quantum chemical decompositions at the atomic and molecular levels, we report the results of Hartree-Fock (HF) and DFT calculations on the complexes included in the S66 and the ionic H-bond databases of benchmark geometry and binding energies. For all structures, we perform single-point and geometry optimizations using HF and selected DFT methods with triple-ζ basis sets followed by full IQA calculations. Pairwise dispersion energies are accounted for by the D3 method. We analyze the goodness of the HF-D3 and DFT-D3 binding energies, the magnitude of numerical errors, the fragment and atomic distribution of formation energies, etc. It is shown that fragment-based IQA decomposes the formation energies in comparable terms to those of perturbative approaches and that the atomic IQA energies hold the promise of rigorously quantifying atomic and group energy contributions in larger biomolecular systems. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

Effects of Co doping on the metamagnetic states of the ferromagnetic fcc Fe-Co alloy.

PubMed

Ortiz-Chi, Filiberto; Aguayo, Aarón; de Coss, Romeo

2013-01-16

The evolution of the metamagnetic states in the ferromagnetic face centered cubic (fcc) Fe(1-x)Co(x) alloy as a function of Co concentration has been studied by means of first-principles calculations. The ground state properties were obtained using the full-potential linear augmented plane wave method and the generalized gradient approximation for the exchange-correlation functional. The alloying was modeled using the virtual crystal approximation and the magnetic states were obtained from the calculations of the total energy as a function of the spin moment, using the fixed spin moment method. For ferromagnetic fcc Fe, the binding-energy curve shows metamagnetic behavior, with two minima corresponding to a small-volume, low-spin (LS) state and a large-volume, high-spin (HS) state, which are separated by a small energy (E(LS) ≲ E(HS)). The evolution of the magnetic moment, the exchange integral (J), and the binding-energy curve is analyzed in the whole range of Co concentrations (x). The magnetic moment corresponding to the HS state decreases monotonically from 2.6 μ(B)/atom in fcc Fe to 1.7 μ(B)/atom in fcc Co. In contrast, the exchange integral for the HS state shows a maximum at around x = 0.45. The thermal dependence of the lattice parameter is evaluated with a method based on statistical mechanics using the binding-energy curve as an effective potential. It is observed that the behavior of the lattice parameter with temperature is tuned by Co doping, from negative thermal expansion in fcc Fe to positive thermal expansion in fcc Co, through the modification of the energetics of the metamagnetic states.

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.

Adsorption of formaldehyde on graphene and graphyne

NASA Astrophysics Data System (ADS)

Majidi, R.; Karami, A. R.

2014-05-01

The adsorption of formaldehyde on graphene and graphyne was investigated to search high sensitivity sensors for detection of formaldehyde. We have used density functional theory to study the effect of formaldehyde on the electronic properties of graphene and graphyne. It is found that formaldehyde is physisorbed on the graphene and graphyne with small binding energy, large binding distance, and small charge transfer. The calculations also indicate that formaldehyde adsorption modifies the electronic properties of semimetallic graphene, α-graphyne, and β-graphyne and semiconducting γ-graphyne. The graphene and graphyne show semiconducting property in the presence of formaldehyde. The effect of formaldehyde on the electronic properties of graphene and graphyne suggests the potential application of these carbon nanomaterials for formaldehyde detection.

Binding free energy and counterion release for adsorption of the antimicrobial peptide lactoferricin B on a POPG membrane

NASA Astrophysics Data System (ADS)

Tolokh, Igor S.; Vivcharuk, Victor; Tomberli, Bruno; Gray, C. G.

2009-09-01

Molecular dynamics (MD) simulations are used to study the interaction of an anionic palmitoyl-oleoyl-phosphatidylglycerol (POPG) bilayer with the cationic antimicrobial peptide bovine lactoferricin (LFCinB) in a 100 mM NaCl solution at 310 K. The interaction of LFCinB with a POPG bilayer is employed as a model system for studying the details of membrane adsorption selectivity of cationic antimicrobial peptides. Seventy eight 4 ns MD production run trajectories of the equilibrated system, with six restrained orientations of LFCinB at 13 different separations from the POPG membrane, are generated to determine the free energy profile for the peptide as a function of the distance between LFCinB and the membrane surface. To calculate the profile for this relatively large system, a variant of constrained MD and thermodynamic integration is used. A simplified method for relating the free energy profile to the LFCinB-POPG membrane binding constant is employed to predict a free energy of adsorption of -5.4±1.3kcal/mol and a corresponding maximum adsorption binding force of about 58 pN. We analyze the results using Poisson-Boltzmann theory. We find the peptide-membrane attraction to be dominated by the entropy increase due to the release of counterions and polarized water from the region between the charged membrane and peptide, as the two approach each other. We contrast these results with those found earlier for adsorption of LFCinB on the mammalianlike palmitoyl-oleoyl-phosphatidylcholine membrane.

Ground-State Properties of Mg Isotopes in and Beyond the Island of Inversion through Reaction Cross Sections

NASA Astrophysics Data System (ADS)

Watanabe, Shin; Minomo, Kosho; Shimada, Mitsuhiro; Tagami, Shingo; Kimura, Masaaki; Takechi, Maya; Fukuda, Mitsunori; Nishimura, Daiki; Suzuki, Takeshi; Matsumoto, Takuma; Shimizu, Yoshifumi R.; Yahiro, Masanobu

We analyze recently measured total reaction cross sections (σR) for 24-38Mg incident on 12C targets at 240 MeV/nucleon by using the microscopic framework based on the double folding model and antisymmetrized molecular dynamics (AMD). The framework reproduces not only the measured σR but also other existing measured ground-state properties of Mg Isotopes (spin parity, total binding energy, one-neutron separation energy, and 2+ and 4+ excitation energies) quite well. AMD predicts large deformation from 31Mg19 to a drip-line nucleus 40Mg28, indicating that both the N = 20 and 28 magicities disappear.

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.

Structure of the Rigor Actin-Tropomyosin-Myosin Complex

PubMed Central

Behrmann, Elmar; Müller, Mirco; Penczek, Pawel A.; Mannherz, Hans Georg; Manstein, Dietmar J.; Raunser, Stefan

2014-01-01

The interaction of myosin with actin filaments is the central feature of muscle contraction and cargo movement along actin filaments of the cytoskeleton. Myosin converts the chemical energy stored in ATP into force and movement along actin filaments. Myosin binding to actin induces conformational changes that are coupled to the nucleotide-binding pocket and amplified by a specialized region of the motor domain for efficient force generation. Tropomyosin plays a key role in regulating the productive interaction between myosins and actin. Here, we report the 8 Å resolution structure of the actin-tropomyosin-myosin complex determined by cryo electron microscopy. The pseudo-atomic model of the complex obtained from fitting crystal structures into the map defines the large actin-myosin-tropomyosin interface and the molecular interactions between the proteins in detail and allows us to propose a structural model for tropomyosin dependent myosin binding to actin and actin-induced nucleotide release from myosin. PMID:22817895

Development of purely structure-based pharmacophores for the topoisomerase I-DNA-ligand binding pocket

NASA Astrophysics Data System (ADS)

Drwal, Malgorzata N.; Agama, Keli; Pommier, Yves; Griffith, Renate

2013-12-01

Purely structure-based pharmacophores (SBPs) are an alternative method to ligand-based approaches and have the advantage of describing the entire interaction capability of a binding pocket. Here, we present the development of SBPs for topoisomerase I, an anticancer target with an unusual ligand binding pocket consisting of protein and DNA atoms. Different approaches to cluster and select pharmacophore features are investigated, including hierarchical clustering and energy calculations. In addition, the performance of SBPs is evaluated retrospectively and compared to the performance of ligand- and complex-based pharmacophores. SBPs emerge as a valid method in virtual screening and a complementary approach to ligand-focussed methods. The study further reveals that the choice of pharmacophore feature clustering and selection methods has a large impact on the virtual screening hit lists. A prospective application of the SBPs in virtual screening reveals that they can be used successfully to identify novel topoisomerase inhibitors.

Alternative dimerization interfaces in the glucocorticoid receptor-α ligand binding domain.

PubMed

Bianchetti, Laurent; Wassmer, Bianca; Defosset, Audrey; Smertina, Anna; Tiberti, Marion L; Stote, Roland H; Dejaegere, Annick

2018-04-30

Nuclear hormone receptors (NRs) constitute a large family of multi-domain ligand-activated transcription factors. Dimerization is essential for their regulation, and both DNA binding domain (DBD) and ligand binding domain (LBD) are implicated in dimerization. Intriguingly, the glucocorticoid receptor-α (GRα) presents a DBD dimeric architecture similar to that of the homologous estrogen receptor-α (ERα), but an atypical dimeric architecture for the LBD. The physiological relevance of the proposed GRα LBD dimer is a subject of debate. We analyzed all GRα LBD homodimers observed in crystals using an energetic analysis based on the PISA and on the MM/PBSA methods and a sequence conservation analysis, using the ERα LBD dimer as a reference point. Several dimeric assemblies were observed for GRα LBD. The assembly generally taken to be physiologically relevant showed weak binding free energy and no significant residue conservation at the contact interface, while an alternative homodimer mediated by both helix 9 and C-terminal residues showed significant binding free energy and residue conservation. However, none of the GRα LBD assemblies found in crystals are as stable or conserved as the canonical ERα LBD dimer. GRα C-terminal sequence (F-domain) forms a steric obstacle to the canonical dimer assembly in all available structures. Our analysis calls for a re-examination of the currently accepted GRα homodimer structure and experimental investigations of the alternative architectures. This work questions the validity of the currently accepted architecture. This has implications for interpreting physiological data and for therapeutic design pertaining to glucocorticoid research. Copyright © 2018. Published by Elsevier B.V.

The origins of femtomolar protein-ligand binding: hydrogen-bond cooperativity and desolvation energetics in the biotin-(strept)avidin binding site.

PubMed

DeChancie, Jason; Houk, K N

2007-05-02

The unusually strong reversible binding of biotin by avidin and streptavidin has been investigated by density functional and MP2 ab initio quantum mechanical methods. The solvation of biotin by water has also been studied through QM/MM/MC calculations. The ureido moiety of biotin in the bound state hydrogen bonds to five residues, three to the carbonyl oxygen and one for each--NH group. These five hydrogen bonds act cooperatively, leading to stabilization that is larger than the sum of individual hydrogen-bonding energies. The charged aspartate is the key residue that provides the driving force for cooperativity in the hydrogen-bonding network for both avidin and streptavidin by greatly polarizing the urea of biotin. If the residue is removed, the network is disrupted, and the attenuation of the energetic contributions from the neighboring residues results in significant reduction of cooperative interactions. Aspartate is directly hydrogen-bonded with biotin in streptavidin and is one residue removed in avidin. The hydrogen-bonding groups in streptavidin are computed to give larger cooperative hydrogen-bonding effects than avidin. However, the net gain in electrostatic binding energy is predicted to favor the avidin-bicyclic urea complex due to the relatively large penalty for desolvation of the streptavidin binding site (specifically expulsion of bound water molecules). QM/MM/MC calculations involving biotin and the ureido moiety in aqueous solution, featuring PDDG/PM3, show that water interactions with the bicyclic urea are much weaker than (strept)avidin interactions due to relatively low polarization of the urea group in water.

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.

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.

Role of large thermal fluctuations and magnesium ions in t-RNA selectivity of the ribosome

PubMed Central

Guo, Zuojun; Gibson, Meghan; Sitha, Sanyasi; Chu, Steven; Mohanty, Udayan

2011-01-01

The fidelity of translation selection begins with the base pairing of codon-anticodon complex between the m-RNA and tRNAs. Binding of cognate and near-cognate tRNAs induces 30S subunit of the ribosome to wrap around the ternary complex, EF-Tu(GTP)aa-tRNA. We have proposed that large thermal fluctuations play a crucial role in the selection process. To test this conjecture, we have developed a theoretical technique to determine the probability that the ternary complex, as a result of large thermal fluctuations, forms contacts leading to stabilization of the GTPase activated state. We argue that the configurational searches for such processes are in the tail end of the probability distribution and show that the probability for this event is localized around the most likely configuration. Small variations in the repositioning of cognate relative to near-cognate complexes lead to rate enhancement of the cognate complex. The binding energies of over a dozen unique site-bound magnesium structural motifs are investigated and provide insights into the nature of interaction of divalent metal ions with the ribosome. PMID:21368154

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).

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.

Domain Formation Induced by the Adsorption of Charged Proteins on Mixed Lipid Membranes

PubMed Central

Mbamala, Emmanuel C.; Ben-Shaul, Avinoam; May, Sylvio

2005-01-01

Peripheral proteins can trigger the formation of domains in mixed fluid-like lipid membranes. We analyze the mechanism underlying this process for proteins that bind electrostatically onto a flat two-component membrane, composed of charged and neutral lipid species. Of particular interest are membranes in which the hydrocarbon lipid tails tend to segregate owing to nonideal chain mixing, but the (protein-free) lipid membrane is nevertheless stable due to the electrostatic repulsion between the charged lipid headgroups. The adsorption of charged, say basic, proteins onto a membrane containing anionic lipids induces local lipid demixing, whereby charged lipids migrate toward (or away from) the adsorption site, so as to minimize the electrostatic binding free energy. Apart from reducing lipid headgroup repulsion, this process creates a gradient in lipid composition around the adsorption zone, and hence a line energy whose magnitude depends on the protein's size and charge and the extent of lipid chain nonideality. Above a certain critical lipid nonideality, the line energy is large enough to induce domain formation, i.e., protein aggregation and, concomitantly, macroscopic lipid phase separation. We quantitatively analyze the thermodynamic stability of the dressed membrane based on nonlinear Poisson-Boltzmann theory, accounting for both the microscopic characteristics of the proteins and lipid composition modulations at and around the adsorption zone. Spinodal surfaces and critical points of the dressed membranes are calculated for several different model proteins of spherical and disk-like shapes. Among the models studied we find the most substantial protein-induced membrane destabilization for disk-like proteins whose charges are concentrated in the membrane-facing surface. If additional charges reside on the side faces of the proteins, direct protein-protein repulsion diminishes considerably the propensity for domain formation. Generally, a highly charged flat face of a macroion appears most efficient in inducing large compositional gradients, hence a large and unfavorable line energy and consequently lateral macroion aggregation and, concomitantly, macroscopic lipid phase separation. PMID:15626713

Dynamic coupling between the LID and NMP domain motions in the catalytic conversion of ATP and AMP to ADP by adenylate kinase

NASA Astrophysics Data System (ADS)

Jana, Biman; Adkar, Bharat V.; Biswas, Rajib; Bagchi, Biman

2011-01-01

The catalytic conversion of adenosine triphosphate (ATP) and adenosine monophosphate (AMP) to adenosine diphosphate (ADP) by adenylate kinase (ADK) involves large amplitude, ligand induced domain motions, involving the opening and the closing of ATP binding domain (LID) and AMP binding domain (NMP) domains, during the repeated catalytic cycle. We discover and analyze an interesting dynamical coupling between the motion of the two domains during the opening, using large scale atomistic molecular dynamics trajectory analysis, covariance analysis, and multidimensional free energy calculations with explicit water. Initially, the LID domain must open by a certain amount before the NMP domain can begin to open. Dynamical correlation map shows interesting cross-peak between LID and NMP domain which suggests the presence of correlated motion between them. This is also reflected in our calculated two-dimensional free energy surface contour diagram which has an interesting elliptic shape, revealing a strong correlation between the opening of the LID domain and that of the NMP domain. Our free energy surface of the LID domain motion is rugged due to interaction with water and the signature of ruggedness is evident in the observed root mean square deviation variation and its fluctuation time correlation functions. We develop a correlated dynamical disorder-type theoretical model to explain the observed dynamic coupling between the motion of the two domains in ADK. Our model correctly reproduces several features of the cross-correlation observed in simulations.

Evidence that Chemical Chaperone 4-Phenylbutyric Acid Binds to Human Serum Albumin at Fatty Acid Binding Sites

PubMed Central

James, Joel; Shihabudeen, Mohamed Sham; Kulshrestha, Shweta; Goel, Varun; Thirumurugan, Kavitha

2015-01-01

Endoplasmic reticulum stress elicits unfolded protein response to counteract the accumulating unfolded protein load inside a cell. The chemical chaperone, 4-Phenylbutyric acid (4-PBA) is a FDA approved drug that alleviates endoplasmic reticulum stress by assisting protein folding. It is found efficacious to augment pathological conditions like type 2 diabetes, obesity and neurodegeneration. This study explores the binding nature of 4-PBA with human serum albumin (HSA) through spectroscopic and molecular dynamics approaches, and the results show that 4-PBA has high binding specificity to Sudlow Site II (Fatty acid binding site 3, subdomain IIIA). Ligand displacement studies, RMSD stabilization profiles and MM-PBSA binding free energy calculation confirm the same. The binding constant as calculated from fluorescence spectroscopic studies was found to be kPBA = 2.69 x 105 M-1. Like long chain fatty acids, 4-PBA induces conformational changes on HSA as shown by circular dichroism, and it elicits stable binding at Sudlow Site II (fatty acid binding site 3) by forming strong hydrogen bonding and a salt bridge between domain II and III of HSA. This minimizes the fluctuation of HSA backbone as shown by limited conformational space occupancy in the principal component analysis. The overall hydrophobicity of W214 pocket (located at subdomain IIA), increases upon occupancy of 4-PBA at any FA site. Descriptors of this pocket formed by residues from other subdomains largely play a role in compensating the dynamic movement of W214. PMID:26181488

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.

Optimizing energy functions for protein-protein interface design.

PubMed

Sharabi, Oz; Yanover, Chen; Dekel, Ayelet; Shifman, Julia M

2011-01-15

Protein design methods have been originally developed for the design of monomeric proteins. When applied to the more challenging task of protein–protein complex design, these methods yield suboptimal results. In particular, they often fail to recapitulate favorable hydrogen bonds and electrostatic interactions across the interface. In this work, we aim to improve the energy function of the protein design program ORBIT to better account for binding interactions between proteins. By using the advanced machine learning framework of conditional random fields, we optimize the relative importance of all the terms in the energy function, attempting to reproduce the native side-chain conformations in protein–protein interfaces. We evaluate the performance of several optimized energy functions, each describes the van der Waals interactions using a different potential. In comparison with the original energy function, our best energy function (a) incorporates a much “softer” repulsive van der Waals potential, suitable for the discrete rotameric representation of amino acid side chains; (b) does not penalize burial of polar atoms, reflecting the frequent occurrence of polar buried residues in protein–protein interfaces; and (c) significantly up-weights the electrostatic term, attesting to the high importance of these interactions for protein–protein complex formation. Using this energy function considerably improves side chain placement accuracy for interface residues in a large test set of protein–protein complexes. Moreover, the optimized energy function recovers the native sequences of protein–protein interface at a higher rate than the default function and performs substantially better in predicting changes in free energy of binding due to mutations.

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

Protein-protein interfaces are vdW dominant with selective H-bonds and (or) electrostatics towards broad functional specificity.

PubMed

Nilofer, Christina; Sukhwal, Anshul; Mohanapriya, Arumugam; Kangueane, Pandjassarame

2017-01-01

Several catalysis, cellular regulation, immune function, cell wall assembly, transport, signaling and inhibition occur through Protein- Protein Interactions (PPI). This is possible with the formation of specific yet stable protein-protein interfaces. Therefore, it is of interest to understand its molecular principles using structural data in relation to known function. Several interface features have been documented using known X-ray structures of protein complexes since 1975. This has improved our understanding of the interface using structural features such as interface area, binding energy, hydrophobicity, relative hydrophobicity, salt bridges and hydrogen bonds. The strength of binding between two proteins is dependent on interface size (number of residues at the interface) and thus its corresponding interface area. It is known that large interfaces have high binding energy (sum of (van der Waals) vdW, H-bonds, electrostatics). However, the selective role played by each of these energy components and more especially that of vdW is not explicitly known. Therefore, it is important to document their individual role in known protein-protein structural complexes. It is of interest to relate interface size with vdW, H-bonds and electrostatic interactions at the interfaces of protein structural complexes with known function using statistical and multiple linear regression analysis methods to identify the prominent force. We used the manually curated non-redundant dataset of 278 hetero-dimeric protein structural complexes grouped using known functions by Sowmya et al. (2015) to gain additional insight to this phenomenon using a robust inter-atomic non-covalent interaction analyzing tool PPCheck (Anshul and Sowdhamini, 2015). This dataset consists of obligatory (enzymes, regulator, biological assembly), immune and nonobligatory (enzyme and regulator inhibitors) complexes. Results show that the total binding energy is more for large interfaces. However, this is not true for its individual energy factors. Analysis shows that vdW energies contribute to about 75% ± 11% on average among all complexes and it also increases with interface size (r2 ranging from 0.67 to 0.89 with p<0.01) at 95% confidence limit irrespective of molecular function. Thus, vdW is both dominant and proportional at the interface independent of molecular function. Nevertheless, H bond energy contributes to 15% ± 6.5% on average in these complexes. It also moderately increases with interface size (r2 ranging from 0.43 to 0.61 with p<0.01) only among obligatory and immune complexes. Moreover, there is about 11.3% ± 8.7% contribution by electrostatic energy. It increases with interface size specifically among non-obligatory regulator-inhibitors (r2 = 0.44). It is implied that both H-bonds and electrostatics are neither dominant nor proportional at the interface. Nonetheless, their presence cannot be ignored in binding. Therefore, H-bonds and (or) electrostatic energy having specific role for improved stability in complexes is implied. Thus, vdW is common at the interface stabilized further with selective H-bonds and (or) electrostatic interactions at an atomic level in almost all complexes. Comparison of this observation with residue level analysis of the interface is compelling. The role by H-bonds (14.83% ± 6.5% and r2 = 0.61 with p<0.01) among obligatory and electrostatic energy (8.8% ± 4.77% and r2 = 0.63 with p <0.01) among non-obligatory complexes within interfaces (class A) having more non-polar residues than surface is influencing our inference. However, interfaces (class B) having less non-polar residues than surface show 1.5 fold more electrostatic energy on average. The interpretation of the interface using inter-atomic (vdW, H-bonds, electrostatic) interactions combined with inter-residue predominance (class A and class B) in relation to known function is the key to reveal its molecular principles with new challenges.

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

Modeling protein-small molecule interactions: structure and thermodynamics of noble gases binding in a cavity in mutant phage T4 lysozyme L99A.

PubMed

Mann, G; Hermans, J

2000-09-29

The complexes of phage T4 lysozyme L99A with noble gases have been studied by molecular dynamics simulation. In a long simulation of the complex with one Xe atom, the structure was found to undergo global conformation change involving a reversible opening and closing of the entrance to the substrate-binding site, during which the conformations of the N and C-terminal domains varied little. The distributions of Xe positions sampled in dynamics simulations were refined in terms of anisotropic Gaussian distributions via least-squares minimization of the difference between Fourier transforms. In addition, molecular transformation simulations have been applied in order to calculate the binding free energies of Xe, Kr and Ar relative to a standard state at a pressure of 1 bar. A single bound Xe is found to assume an equilibrium distribution over three adjacent preferred sites, while in a two-Xe complex, the two Xe atoms preferentially occupy two of these. The positions of the three sites agree closely with the positions of bound Xe determined in the refined crystal structure of a complex formed at a pressure of 8 bar Xe, and the calculated affinities agree well with the observed partial occupancies. At a pressure of 8 bar, a mixture of one-Xe and two-Xe complexes is present, and similarly for complexes with Kr and Ar, with single occupancy relatively more prevalent with Kr and Ar. (Binding of a third Xe atom is found to be quite unfavorable.) A comparison with simulation results for the binding of benzene to the same site leads to the conclusion that binding of Xe within cavities in proteins is common because of several favorable factors: (1) Xe has a large atomic polarizability; (2) Xe can be applied at a relatively high pressure, i.e. high chemical potential; (3) an unfavorable entropic term related to the need to orient the ligand in the binding site is absent. Finally, it is found that the model's binding energy of a water molecule in the cavity is insufficient to overcome the unfavorable binding entropy. Copyright 2000 Academic Press.

Selective binding of pyrene in subdomain IB of human serum albumin: Combining energy transfer spectroscopy and molecular modelling to understand protein binding flexibility

NASA Astrophysics Data System (ADS)

Ling, Irene; Taha, Mohamed; Al-Sharji, Nada A.; Abou-Zied, Osama K.

2018-04-01

The ability of human serum albumin (HSA) to bind medium-sized hydrophobic molecules is important for the distribution, metabolism, and efficacy of many drugs. Herein, the interaction between pyrene, a hydrophobic fluorescent probe, and HSA was thoroughly investigated using steady-state and time-resolved fluorescence techniques, ligand docking, and molecular dynamics (MD) simulations. A slight quenching of the fluorescence signal from Trp214 (the sole tryptophan residue in the protein) in the presence of pyrene was used to determine the ligand binding site in the protein, using Förster's resonance energy transfer (FRET) theory. The estimated FRET apparent distance between pyrene and Trp214 was 27 Å, which was closely reproduced by the docking analysis (29 Å) and MD simulation (32 Å). The highest affinity site for pyrene was found to be in subdomain IB from the docking results. The calculated equilibrium structure of the complex using MD simulation shows that the ligand is largely stabilized by hydrophobic interaction with Phe165, Phe127, and the nonpolar moieties of Tyr138 and Tyr161. The fluorescence vibronic peak ratio I1/I3 of bound pyrene inside HSA indicates the presence of polar effect in the local environment of pyrene which is less than that of free pyrene in buffer. This was clarified by the MD simulation results in which an average of 5.7 water molecules were found within 0.5 nm of pyrene in the binding site. Comparing the fluorescence signals and lifetimes of pyrene inside HSA to that free in buffer, the high tendency of pyrene to form dimer was almost completely suppressed inside HSA, indicating a high selectivity of the binding pocket toward pyrene monomer. The current results emphasize the ability of HSA, as a major carrier of several drugs and ligands in blood, to bind hydrophobic molecules in cavities other than subdomain IIA which is known to bind most hydrophobic drugs. This ability stems from the nature of the amino acids forming the binding sites of the protein that can easily adapt their shape to accommodate a variety of molecular structures.

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.

Comparative Study of the Fatty Acid Binding Process of a New FABP from Cherax quadricarinatus by Fluorescence Intensity, Lifetime and Anisotropy

PubMed Central

Li, Jiayao; Henry, Etienne; Wang, Lanmei; Delelis, Olivier; Wang, Huan; Simon, Françoise; Tauc, Patrick; Brochon, Jean-Claude; Zhao, Yunlong; Deprez, Eric

2012-01-01

Fatty acid-binding proteins (FABPs) are small cytosolic proteins, largely distributed in invertebrates and vertebrates, which accomplish uptake and intracellular transport of hydrophobic ligands such as fatty acids. Although long chain fatty acids play multiple crucial roles in cellular functions (structural, energy metabolism, regulation of gene expression), the precise functions of FABPs, especially those of invertebrate species, remain elusive. Here, we have identified and characterized a novel FABP family member, Cq-FABP, from the hepatopancreas of red claw crayfish Cherax quadricarinatus. We report the characterization of fatty acid-binding affinity of Cq-FABP by four different competitive fluorescence-based assays. In the two first approaches, the fluorescent probe 8-Anilino-1-naphthalenesulfonate (ANS), a binder of internal cavities of protein, was used either by directly monitoring its fluorescence emission or by monitoring the fluorescence resonance energy transfer occurring between the single tryptophan residue of Cq-FABP and ANS. The third and the fourth approaches were based on the measurement of the fluorescence emission intensity of the naturally fluorescent cis-parinaric acid probe or the steady-state fluorescence anisotropy measurements of a fluorescently labeled fatty acid (BODIPY-C16), respectively. The four methodologies displayed consistent equilibrium constants for a given fatty acid but were not equivalent in terms of analysis. Indeed, the two first methods were complicated by the existence of non specific binding modes of ANS while BODIPY-C16 and cis-parinaric acid specifically targeted the fatty acid binding site. We found a relationship between the affinity and the length of the carbon chain, with the highest affinity obtained for the shortest fatty acid, suggesting that steric effects primarily influence the interaction of fatty acids in the binding cavity of Cq-FABP. Moreover, our results show that the binding affinities of several fatty acids closely parallel their prevalences in the hepatopancreas of C. quadricarinatus as measured under specific diet conditions. PMID:23284658

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.

Stepwise identification of HLA-A*0201-restricted CD8+ T-cell epitope peptides from herpes simplex virus type 1 genome boosted by a StepRank scheme.

PubMed

Bi, Jianjun; Song, Rengang; Yang, Huilan; Li, Bingling; Fan, Jianyong; Liu, Zhongrong; Long, Chaoqin

2011-01-01

Identification of immunodominant epitopes is the first step in the rational design of peptide vaccines aimed at T-cell immunity. To date, however, it is yet a great challenge for accurately predicting the potent epitope peptides from a pool of large-scale candidates with an efficient manner. In this study, a method that we named StepRank has been developed for the reliable and rapid prediction of binding capabilities/affinities between proteins and genome-wide peptides. In this procedure, instead of single strategy used in most traditional epitope identification algorithms, four steps with different purposes and thus different computational demands are employed in turn to screen the large-scale peptide candidates that are normally generated from, for example, pathogenic genome. The steps 1 and 2 aim at qualitative exclusion of typical nonbinders by using empirical rule and linear statistical approach, while the steps 3 and 4 focus on quantitative examination and prediction of the interaction energy profile and binding affinity of peptide to target protein via quantitative structure-activity relationship (QSAR) and structure-based free energy analysis. We exemplify this method through its application to binding predictions of the peptide segments derived from the 76 known open-reading frames (ORFs) of herpes simplex virus type 1 (HSV-1) genome with or without affinity to human major histocompatibility complex class I (MHC I) molecule HLA-A*0201, and find that the predictive results are well compatible with the classical anchor residue theory and perfectly match for the extended motif pattern of MHC I-binding peptides. The putative epitopes are further confirmed by comparisons with 11 experimentally measured HLA-A*0201-restrcited peptides from the HSV-1 glycoproteins D and K. We expect that this well-designed scheme can be applied in the computational screening of other viral genomes as well.

Three pillars for achieving quantum mechanical molecular dynamics simulations of huge systems: Divide-and-conquer, density-functional tight-binding, and massively parallel computation.

PubMed

Nishizawa, Hiroaki; Nishimura, Yoshifumi; Kobayashi, Masato; Irle, Stephan; Nakai, Hiromi

2016-08-05

The linear-scaling divide-and-conquer (DC) quantum chemical methodology is applied to the density-functional tight-binding (DFTB) theory to develop a massively parallel program that achieves on-the-fly molecular reaction dynamics simulations of huge systems from scratch. The functions to perform large scale geometry optimization and molecular dynamics with DC-DFTB potential energy surface are implemented to the program called DC-DFTB-K. A novel interpolation-based algorithm is developed for parallelizing the determination of the Fermi level in the DC method. The performance of the DC-DFTB-K program is assessed using a laboratory computer and the K computer. Numerical tests show the high efficiency of the DC-DFTB-K program, a single-point energy gradient calculation of a one-million-atom system is completed within 60 s using 7290 nodes of the K computer. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

DFT Insights into the Competitive Adsorption of Sulfur- and Nitrogen-Containing Compounds and Hydrocarbons on Co-Promoted Molybdenum Sulfide Catalysts

DOE PAGES

Rangarajan, Srinivas; Mavrikakis, Manos

2016-04-07

The adsorption of 20 nitrogen-/sulfur-containing and hydrocarbon compounds on the sulfur edge of cobalt-promoted molybdenum sulfide (CoMoS) catalyst was studied using density functional theory, accounting for van der Waals interactions, to elicit comparative structure–property trends across different classes of molecules relevant to hydrotreating. Unhindered organosulfur compounds preferentially adsorb on a “CUS-like” site formed by the dimerization of two neighboring sulfur atoms on the edge to create a vacancy. Nitrogen-containing compounds and 4,6-dimethyldibenzothiophene, however, prefer the brim sites. Binding energy trends indicate that nitrogen-containing compounds will inhibit hydrodesulfurization on the brim sites and, relatively weakly, on the CUS-like sites. Edge vacanciesmore » are,thus, likely to be essential for hydrodesulfurization of unhindered organosulfur compounds. Furthermore, van der Waals forces contribute significantly to the binding energy of compounds (up to 1.0 eV for large compounds such as alkyl-substituted acridines) on CoMoS.« less

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

Park, Jaehong; Reid, Obadiah G.; Blackburn, Jeffrey L.

The strong quantum confinement and low dielectric screening impart single-walled carbon nanotubes with exciton-binding energies substantially exceeding kBT at room temperature. Despite these large binding energies, reported photoluminescence quantum yields are typically low and some studies suggest that photoexcitation of carbon nanotube excitonic transitions can produce free charge carriers. Here we report the direct measurement of long-lived free-carrier generation in chirality-pure, single-walled carbon nanotubes in a low dielectric solvent. Time-resolved microwave conductivity enables contactless and quantitative measurement of the real and imaginary photoconductance of individually suspended nanotubes. We found that the conditions of the microwave conductivity measurement allow us tomore » avoid the complications of most previous measurements of nanotube free-carrier generation, including tube–tube/tube–electrode contact, dielectric screening by nearby excitons and many-body interactions. At low photon fluence (approximately 0.05 excitons per μm length of tubes), we directly observe free carriers on excitation of the first and second carbon nanotube exciton transitions.« less

Photodetachment spectroscopy and resonant photoelectron imaging of cryogenically-cooled deprotonated 2-hydroxypyrimidine anions

NASA Astrophysics Data System (ADS)

Huang, Dao-Ling; Zhu, Guo-Zhu; Liu, Yuan; Wang, Lai-Sheng

2017-02-01

We report a photodetachment and high-resolution photoelectron imaging study of cold deprotonated 2-hydroxypyrimidine anions, C4H3N2O-. Photodetachment spectroscopy reveals an excited dipole-bound state (DBS) of C4H3N2O- with a binding energy of 598 ± 5 cm-1 below the detachment threshold of 26,010 ± 5 cm-1. Twenty vibrational levels of the DBS are observed as resonances in the photodetachment spectrum, with three below the detachment threshold and seventeen above the threshold. By tuning the detachment laser to the above-threshold vibrational resonances, highly non-Franck-Condon photoelectron spectra are obtained. Nine fundamental vibrational frequencies are resolved, including six symmetry-forbidden modes. The 598 cm-1 binding energy for the DBS is quite high due to the large dipole moment of the C4H3N2Orad (>6 D). However, no evidence of a second DBS is observed below the detachment threshold.

Electronic structure of BaO/W cathode surfaces

NASA Technical Reports Server (NTRS)

Muller, Wolfgang

1989-01-01

The local electronic structure of the emissive layer of barium dispenser thermionic cathodes is investigated theoretically using the relativistic scattered-wave approach. The interaction of Ba and O with W, Os, and W-Os alloy surfaces is studied with atomic clusters modeling different absorption environments representative of B- and M-type cathodes. Ba is found to be strongly oxidized, while O and the metal substrate are in a reduced chemical state. The presence of O enhances the surface dipole and Ba binding energy relative to Ba on W. Model results for W-Os alloy substrates show only relatively small changes in Ba and O for identical geometries, but very large charge redistributions inside the substrate, which are attributed to the electronegativity difference between Os and W. If Os is present in the surface layer, the charge transfer from Ba to the substrate and the Ba binding energy increase relative to W. Explanations are offered for the improved electron emission from alloy surfaces and the different emission enhancement for different alloy substrates.

Photoinduced Spontaneous Free-Carrier Generation in Semiconducting Single-Walled Carbon Nanotubes

DOE PAGES

Park, Jaehong; Reid, Obadiah G.; Blackburn, Jeffrey L.; ...

2015-11-04

The strong quantum confinement and low dielectric screening impart single-walled carbon nanotubes with exciton-binding energies substantially exceeding kBT at room temperature. Despite these large binding energies, reported photoluminescence quantum yields are typically low and some studies suggest that photoexcitation of carbon nanotube excitonic transitions can produce free charge carriers. Here we report the direct measurement of long-lived free-carrier generation in chirality-pure, single-walled carbon nanotubes in a low dielectric solvent. Time-resolved microwave conductivity enables contactless and quantitative measurement of the real and imaginary photoconductance of individually suspended nanotubes. We found that the conditions of the microwave conductivity measurement allow us tomore » avoid the complications of most previous measurements of nanotube free-carrier generation, including tube–tube/tube–electrode contact, dielectric screening by nearby excitons and many-body interactions. At low photon fluence (approximately 0.05 excitons per μm length of tubes), we directly observe free carriers on excitation of the first and second carbon nanotube exciton transitions.« less

Structural Analysis on the Pathologic Mutant Glucocorticoid Receptor Ligand-Binding Domains.

PubMed

Hurt, Darrell E; Suzuki, Shigeru; Mayama, Takafumi; Charmandari, Evangelia; Kino, Tomoshige

2016-02-01

Glucocorticoid receptor (GR) gene mutations may cause familial or sporadic generalized glucocorticoid resistance syndrome. Most of the missense forms distribute in the ligand-binding domain and impair its ligand-binding activity and formation of the activation function (AF)-2 that binds LXXLL motif-containing coactivators. We performed molecular dynamics simulations to ligand-binding domain of pathologic GR mutants to reveal their structural defects. Several calculated parameters including interaction energy for dexamethasone or the LXXLL peptide indicate that destruction of ligand-binding pocket (LBP) is a primary character. Their LBP defects are driven primarily by loss/reduction of the electrostatic interaction formed by R611 and T739 of the receptor to dexamethasone and a subsequent conformational mismatch, which deacylcortivazol resolves with its large phenylpyrazole moiety and efficiently stimulates transcriptional activity of the mutant receptors with LBP defect. Reduced affinity of the LXXLL peptide to AF-2 is caused mainly by disruption of the electrostatic bonds to the noncore leucine residues of this peptide that determine the peptide's specificity to GR, as well as by reduced noncovalent interaction against core leucines and subsequent exposure of the AF-2 surface to solvent. The results reveal molecular defects of pathologic mutant receptors and provide important insights to the actions of wild-type GR.

Decorin Core Protein (Decoron) Shape Complements Collagen Fibril Surface Structure and Mediates Its Binding

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

Orgel, Joseph P.R.O.; Eid, Aya; Antipova, Olga

Decorin is the archetypal small leucine rich repeat proteoglycan of the vertebrate extracellular matrix (ECM). With its glycosaminoglycuronan chain, it is responsible for stabilizing inter-fibrillar organization. Type I collagen is the predominant member of the fibrillar collagen family, fulfilling both organizational and structural roles in animal ECMs. In this study, interactions between decoron (the decorin core protein) and binding sites in the d and e1 bands of the type I collagen fibril were investigated through molecular modeling of their respective X-ray diffraction structures. Previously, it was proposed that a model-based, highly curved concave decoron interacts with a single collagen molecule,more » which would form extensive van der Waals contacts and give rise to strong non-specific binding. However, the large well-ordered aggregate that is the collagen fibril places significant restraints on modes of ligand binding and necessitates multi-collagen molecular contacts. We present here a relatively high-resolution model of the decoron-fibril collagen complex. We find that the respective crystal structures complement each other well, although it is the monomeric form of decoron that shows the most appropriate shape complementarity with the fibril surface and favorable calculated energies of interaction. One molecule of decoron interacts with four to six collagen molecules, and the binding specificity relies on a large number of hydrogen bonds and electrostatic interactions, primarily with the collagen motifs KXGDRGE and AKGDRGE (d and e{sub 1} bands). This work helps us to understand collagen-decorin interactions and the molecular architecture of the fibrillar ECM in health and disease.« less

Decorin core protein (decoron) shape complements collagen fibril surface structure and mediates its binding.

PubMed

Orgel, Joseph P R O; Eid, Aya; Antipova, Olga; Bella, Jordi; Scott, John E

2009-09-15

Decorin is the archetypal small leucine rich repeat proteoglycan of the vertebrate extracellular matrix (ECM). With its glycosaminoglycuronan chain, it is responsible for stabilizing inter-fibrillar organization. Type I collagen is the predominant member of the fibrillar collagen family, fulfilling both organizational and structural roles in animal ECMs. In this study, interactions between decoron (the decorin core protein) and binding sites in the d and e(1) bands of the type I collagen fibril were investigated through molecular modeling of their respective X-ray diffraction structures. Previously, it was proposed that a model-based, highly curved concave decoron interacts with a single collagen molecule, which would form extensive van der Waals contacts and give rise to strong non-specific binding. However, the large well-ordered aggregate that is the collagen fibril places significant restraints on modes of ligand binding and necessitates multi-collagen molecular contacts. We present here a relatively high-resolution model of the decoron-fibril collagen complex. We find that the respective crystal structures complement each other well, although it is the monomeric form of decoron that shows the most appropriate shape complementarity with the fibril surface and favorable calculated energies of interaction. One molecule of decoron interacts with four to six collagen molecules, and the binding specificity relies on a large number of hydrogen bonds and electrostatic interactions, primarily with the collagen motifs KXGDRGE and AKGDRGE (d and e(1) bands). This work helps us to understand collagen-decorin interactions and the molecular architecture of the fibrillar ECM in health and disease.

A spin transition mechanism for cooperative adsorption in metal-organic frameworks

NASA Astrophysics Data System (ADS)

Reed, Douglas A.; Keitz, Benjamin K.; Oktawiec, Julia; Mason, Jarad A.; Runčevski, Tomče; Xiao, Dianne J.; Darago, Lucy E.; Crocellà, Valentina; Bordiga, Silvia; Long, Jeffrey R.

2017-10-01

Cooperative binding, whereby an initial binding event facilitates the uptake of additional substrate molecules, is common in biological systems such as haemoglobin. It was recently shown that porous solids that exhibit cooperative binding have substantial energetic benefits over traditional adsorbents, but few guidelines currently exist for the design of such materials. In principle, metal-organic frameworks that contain coordinatively unsaturated metal centres could act as both selective and cooperative adsorbents if guest binding at one site were to trigger an electronic transformation that subsequently altered the binding properties at neighbouring metal sites. Here we illustrate this concept through the selective adsorption of carbon monoxide (CO) in a series of metal-organic frameworks featuring coordinatively unsaturated iron(II) sites. Functioning via a mechanism by which neighbouring iron(II) sites undergo a spin-state transition above a threshold CO pressure, these materials exhibit large CO separation capacities with only small changes in temperature. The very low regeneration energies that result may enable more efficient Fischer-Tropsch conversions and extraction of CO from industrial waste feeds, which currently underutilize this versatile carbon synthon. The electronic basis for the cooperative adsorption demonstrated here could provide a general strategy for designing efficient and selective adsorbents suitable for various separations.

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.

Uncertainty Quantification in Alchemical Free Energy Methods.

PubMed

Bhati, Agastya P; Wan, Shunzhou; Hu, Yuan; Sherborne, Brad; Coveney, Peter V

2018-06-12

Alchemical free energy methods have gained much importance recently from several reports of improved ligand-protein binding affinity predictions based on their implementation using molecular dynamics simulations. A large number of variants of such methods implementing different accelerated sampling techniques and free energy estimators are available, each claimed to be better than the others in its own way. However, the key features of reproducibility and quantification of associated uncertainties in such methods have barely been discussed. Here, we apply a systematic protocol for uncertainty quantification to a number of popular alchemical free energy methods, covering both absolute and relative free energy predictions. We show that a reliable measure of error estimation is provided by ensemble simulation-an ensemble of independent MD simulations-which applies irrespective of the free energy method. The need to use ensemble methods is fundamental and holds regardless of the duration of time of the molecular dynamics simulations performed.

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.

Direct Observation of Electron-Phonon Coupling and Slow Vibrational Relaxation in Organic-Inorganic Hybrid Perovskites

NASA Astrophysics Data System (ADS)

Hurtado Parra, Sebastian; Straus, Daniel; Iotov, Natasha; Fichera, Bryan; Gebhardt, Julian; Rappe, Andrew; Subotnik, Joseph; Kikkawa, James; Kagan, Cherie

Quantum and dielectric confinement effects in Ruddlesden-Popper 2D hybrid perovskites create excitons with a binding energy exceeding 150 meV. We exploit the large exciton binding energy to study exciton and carrier dynamics as well as electron-phonon coupling (EPC) in hybrid perovskites using absorption and photoluminescence (PL) spectroscopies. At temperatures <75 K, we resolve splitting of the excitonic absorption and PL into multiple regularly spaced resonances every 40-46 meV, consistent with EPC to phonons located on the organic cation. We also resolve resonances with a 14 meV spacing, in accord with coupling to phonons with mixed organic and inorganic character. These assignments are supported by density-functional theory calculations. Hot exciton PL and time-resolved PL measurements show that vibrational relaxation occurs on a picosecond time scale competitive with that for PL. At temperatures >75 K, excitonic absorption and PL exhibit homogeneous broadening. While absorption remains homogeneous, PL becomes inhomogeneous at temperatures <75K, which we speculate is caused by the formation and subsequent dynamics of a polaronic exciton. This work is supported by the U.S. Department of Energy, Office of Basic Energy Sciences Grant DE-SC0002158 and the National Science Foundation Graduate Research Fellowship Grant DGE-1321851.

Low-temperature study of neutral and charged excitons in the large-area monolayer WS2

NASA Astrophysics Data System (ADS)

Gu, Hong; Chen, Le; Lu, Youming; Tian, Feifei; Zhang, Zhiqiang; Xu, Ke; Wu, Jing; Divakar Botcha, V.; Li, Kuilong; Liu, Xinke

2018-06-01

We present a low-temperature optical study of the large-area monolayer WS2 grown by chemical vapor deposition (CVD). Power-dependent photoluminescence (PL) measurements were conducted, and temperature-dependent PL spectra were measured in the range of 3 to 300 K. With the comparative PL bands obtained, a stronger trion emission in the edge region was detected to be the key difference. Sulfur vacancies (SVs) were observed to increase in density along the growth direction and found to be the main source of the large population of local charge carriers. The monolayer WS2 exhibited an upper bound for the trion binding energy of 18 meV in the edge region.

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.

Discovery of binding proteins for a protein target using protein-protein docking-based virtual screening.

PubMed

Zhang, Changsheng; Tang, Bo; Wang, Qian; Lai, Luhua

2014-10-01

Target structure-based virtual screening, which employs protein-small molecule docking to identify potential ligands, has been widely used in small-molecule drug discovery. In the present study, we used a protein-protein docking program to identify proteins that bind to a specific target protein. In the testing phase, an all-to-all protein-protein docking run on a large dataset was performed. The three-dimensional rigid docking program SDOCK was used to examine protein-protein docking on all protein pairs in the dataset. Both the binding affinity and features of the binding energy landscape were considered in the scoring function in order to distinguish positive binding pairs from negative binding pairs. Thus, the lowest docking score, the average Z-score, and convergency of the low-score solutions were incorporated in the analysis. The hybrid scoring function was optimized in the all-to-all docking test. The docking method and the hybrid scoring function were then used to screen for proteins that bind to tumor necrosis factor-α (TNFα), which is a well-known therapeutic target for rheumatoid arthritis and other autoimmune diseases. A protein library containing 677 proteins was used for the screen. Proteins with scores among the top 20% were further examined. Sixteen proteins from the top-ranking 67 proteins were selected for experimental study. Two of these proteins showed significant binding to TNFα in an in vitro binding study. The results of the present study demonstrate the power and potential application of protein-protein docking for the discovery of novel binding proteins for specific protein targets. © 2014 Wiley Periodicals, Inc.

A flexible docking scheme to explore the binding selectivity of PDZ domains.

PubMed

Gerek, Z Nevin; Ozkan, S Banu

2010-05-01

Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using ROSETTALIGAND, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 A. We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately.

A flexible docking scheme to explore the binding selectivity of PDZ domains

PubMed Central

Gerek, Z Nevin; Ozkan, S Banu

2010-01-01

Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using RosettaLigand, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 Å. We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately. PMID:20196074

Free-energy simulations reveal that both hydrophobic and polar interactions are important for influenza hemagglutinin antibody binding.

PubMed

Xia, Zhen; Huynh, Tien; Kang, Seung-gu; Zhou, Ruhong

2012-03-21

Antibodies binding to conserved epitopes can provide a broad range of neutralization to existing influenza subtypes and may also prevent the propagation of potential pandemic viruses by fighting against emerging strands. Here we propose a computational framework to study structural binding patterns and detailed molecular mechanisms of viral surface glycoprotein hemagglutinin (HA) binding with a broad spectrum of neutralizing monoclonal antibody fragments (Fab). We used rigorous free-energy perturbation (FEP) methods to calculate the antigen-antibody binding affinities, with an aggregate underlying molecular-dynamics simulation time of several microseconds (∼2 μs) using all-atom, explicit-solvent models. We achieved a high accuracy in the validation of our FEP protocol against a series of known binding affinities for this complex system, with <0.5 kcal/mol errors on average. We then introduced what to our knowledge are novel mutations into the interfacial region to further study the binding mechanism. We found that the stacking interaction between Trp-21 in HA2 and Phe-55 in the CDR-H2 of Fab is crucial to the antibody-antigen association. A single mutation of either W21A or F55A can cause a binding affinity decrease of ΔΔG > 4.0 kcal/mol (equivalent to an ∼1000-fold increase in the dissociation constant K(d)). Moreover, for group 1 HA subtypes (which include both the H1N1 swine flu and the H5N1 bird flu), the relative binding affinities change only slightly (< ±1 kcal/mol) when nonpolar residues at the αA helix of HA mutate to conservative amino acids of similar size, which explains the broad neutralization capability of antibodies such as F10 and CR6261. Finally, we found that the hydrogen-bonding network between His-38 (in HA1) and Ser-30/Gln-64 (in Fab) is important for preserving the strong binding of Fab against group 1 HAs, whereas the lack of such hydrogen bonds with Asn-38 in most group 2 HAs may be responsible for the escape of antibody neutralization. These large-scale simulations may provide new insight into the antigen-antibody binding mechanism at the atomic level, which could be essential for designing more-effective vaccines for influenza. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

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.

A computational docking study on the pH dependence of peptide binding to HLA-B27 sub-types differentially associated with ankylosing spondylitis

NASA Astrophysics Data System (ADS)

Serçinoğlu, Onur; Özcan, Gülin; Kabaş, Zeynep Kutlu; Ozbek, Pemra

2016-07-01

A single amino acid difference (Asp116His), having a key role in a pathogenesis pathway, distinguishes HLA-B*27:05 and HLA-B*27:09 sub-types as associated and non-associated with ankylosing spondylitis, respectively. In this study, molecular docking simulations were carried out with the aim of comprehending the differences in the binding behavior of both alleles at varying pH conditions. A library of modeled peptides was formed upon single point mutations aiming to address the effect of 20 naturally occurring amino acids at the binding core peptide positions. For both alleles, computational docking was applied using Autodock 4.2. Obtained free energies of binding (FEB) were compared within the peptide library and between the alleles at varying pH conditions. The amino acid preferences of each position were studied enlightening the role of each on binding. The preferred amino acids for each position of pVIPR were found to be harmonious with experimental studies. Our results indicate that, as the pH is lowered, the capacity of HLA-B*27:05 to bind peptides in the library is largely lost. Hydrogen bonding analysis suggests that the interaction between the main anchor positions of pVIPR and their respective binding pocket residues are affected from the pH the most, causing an overall shift in the FEB profiles.

A computational docking study on the pH dependence of peptide binding to HLA-B27 sub-types differentially associated with ankylosing spondylitis.

PubMed

Serçinoğlu, Onur; Özcan, Gülin; Kabaş, Zeynep Kutlu; Ozbek, Pemra

2016-07-01

A single amino acid difference (Asp116His), having a key role in a pathogenesis pathway, distinguishes HLA-B*27:05 and HLA-B*27:09 sub-types as associated and non-associated with ankylosing spondylitis, respectively. In this study, molecular docking simulations were carried out with the aim of comprehending the differences in the binding behavior of both alleles at varying pH conditions. A library of modeled peptides was formed upon single point mutations aiming to address the effect of 20 naturally occurring amino acids at the binding core peptide positions. For both alleles, computational docking was applied using Autodock 4.2. Obtained free energies of binding (FEB) were compared within the peptide library and between the alleles at varying pH conditions. The amino acid preferences of each position were studied enlightening the role of each on binding. The preferred amino acids for each position of pVIPR were found to be harmonious with experimental studies. Our results indicate that, as the pH is lowered, the capacity of HLA-B*27:05 to bind peptides in the library is largely lost. Hydrogen bonding analysis suggests that the interaction between the main anchor positions of pVIPR and their respective binding pocket residues are affected from the pH the most, causing an overall shift in the FEB profiles.

Evaluation of Several Two-Step Scoring Functions Based on Linear Interaction Energy, Effective Ligand Size, and Empirical Pair Potentials for Prediction of Protein-Ligand Binding Geometry and Free Energy

PubMed Central

Rahaman, Obaidur; Estrada, Trilce P.; Doren, Douglas J.; Taufer, Michela; Brooks, Charles L.; Armen, Roger S.

2011-01-01

The performance of several two-step scoring approaches for molecular docking were assessed for their ability to predict binding geometries and free energies. Two new scoring functions designed for “step 2 discrimination” were proposed and compared to our CHARMM implementation of the linear interaction energy (LIE) approach using the Generalized-Born with Molecular Volume (GBMV) implicit solvation model. A scoring function S1 was proposed by considering only “interacting” ligand atoms as the “effective size” of the ligand, and extended to an empirical regression-based pair potential S2. The S1 and S2 scoring schemes were trained and five-fold cross validated on a diverse set of 259 protein-ligand complexes from the Ligand Protein Database (LPDB). The regression-based parameters for S1 and S2 also demonstrated reasonable transferability in the CSARdock 2010 benchmark using a new dataset (NRC HiQ) of diverse protein-ligand complexes. The ability of the scoring functions to accurately predict ligand geometry was evaluated by calculating the discriminative power (DP) of the scoring functions to identify native poses. The parameters for the LIE scoring function with the optimal discriminative power (DP) for geometry (step 1 discrimination) were found to be very similar to the best-fit parameters for binding free energy over a large number of protein-ligand complexes (step 2 discrimination). Reasonable performance of the scoring functions in enrichment of active compounds in four different protein target classes established that the parameters for S1 and S2 provided reasonable accuracy and transferability. Additional analysis was performed to definitively separate scoring function performance from molecular weight effects. This analysis included the prediction of ligand binding efficiencies for a subset of the CSARdock NRC HiQ dataset where the number of ligand heavy atoms ranged from 17 to 35. This range of ligand heavy atoms is where improved accuracy of predicted ligand efficiencies is most relevant to real-world drug design efforts. PMID:21644546

Evaluation of several two-step scoring functions based on linear interaction energy, effective ligand size, and empirical pair potentials for prediction of protein-ligand binding geometry and free energy.

PubMed

Rahaman, Obaidur; Estrada, Trilce P; Doren, Douglas J; Taufer, Michela; Brooks, Charles L; Armen, Roger S

2011-09-26

The performances of several two-step scoring approaches for molecular docking were assessed for their ability to predict binding geometries and free energies. Two new scoring functions designed for "step 2 discrimination" were proposed and compared to our CHARMM implementation of the linear interaction energy (LIE) approach using the Generalized-Born with Molecular Volume (GBMV) implicit solvation model. A scoring function S1 was proposed by considering only "interacting" ligand atoms as the "effective size" of the ligand and extended to an empirical regression-based pair potential S2. The S1 and S2 scoring schemes were trained and 5-fold cross-validated on a diverse set of 259 protein-ligand complexes from the Ligand Protein Database (LPDB). The regression-based parameters for S1 and S2 also demonstrated reasonable transferability in the CSARdock 2010 benchmark using a new data set (NRC HiQ) of diverse protein-ligand complexes. The ability of the scoring functions to accurately predict ligand geometry was evaluated by calculating the discriminative power (DP) of the scoring functions to identify native poses. The parameters for the LIE scoring function with the optimal discriminative power (DP) for geometry (step 1 discrimination) were found to be very similar to the best-fit parameters for binding free energy over a large number of protein-ligand complexes (step 2 discrimination). Reasonable performance of the scoring functions in enrichment of active compounds in four different protein target classes established that the parameters for S1 and S2 provided reasonable accuracy and transferability. Additional analysis was performed to definitively separate scoring function performance from molecular weight effects. This analysis included the prediction of ligand binding efficiencies for a subset of the CSARdock NRC HiQ data set where the number of ligand heavy atoms ranged from 17 to 35. This range of ligand heavy atoms is where improved accuracy of predicted ligand efficiencies is most relevant to real-world drug design efforts.

Theoretical Studies of Hydrogen Storage Alloys.

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

Jonsson, Hannes

Theoretical calculations were carried out to search for lightweight alloys that can be used to reversibly store hydrogen in mobile applications, such as automobiles. Our primary focus was on magnesium based alloys. While MgH{sub 2} is in many respects a promising hydrogen storage material, there are two serious problems which need to be solved in order to make it useful: (i) the binding energy of the hydrogen atoms in the hydride is too large, causing the release temperature to be too high, and (ii) the diffusion of hydrogen through the hydride is so slow that loading of hydrogen into themore » metal takes much too long. In the first year of the project, we found that the addition of ca. 15% of aluminum decreases the binding energy to the hydrogen to the target value of 0.25 eV which corresponds to release of 1 bar hydrogen gas at 100 degrees C. Also, the addition of ca. 15% of transition metal atoms, such as Ti or V, reduces the formation energy of interstitial H-atoms making the diffusion of H-atoms through the hydride more than ten orders of magnitude faster at room temperature. In the second year of the project, several calculations of alloys of magnesium with various other transition metals were carried out and systematic trends in stability, hydrogen binding energy and diffusivity established. Some calculations of ternary alloys and their hydrides were also carried out, for example of Mg{sub 6}AlTiH{sub 16}. It was found that the binding energy reduction due to the addition of aluminum and increased diffusivity due to the addition of a transition metal are both effective at the same time. This material would in principle work well for hydrogen storage but it is, unfortunately, unstable with respect to phase separation. A search was made for a ternary alloy of this type where both the alloy and the corresponding hydride are stable. Promising results were obtained by including Zn in the alloy.« less

Enhanced conformational sampling to visualize a free-energy landscape of protein complex formation.

PubMed

Iida, Shinji; Nakamura, Haruki; Higo, Junichi

2016-06-15

We introduce various, recently developed, generalized ensemble methods, which are useful to sample various molecular configurations emerging in the process of protein-protein or protein-ligand binding. The methods introduced here are those that have been or will be applied to biomolecular binding, where the biomolecules are treated as flexible molecules expressed by an all-atom model in an explicit solvent. Sampling produces an ensemble of conformations (snapshots) that are thermodynamically probable at room temperature. Then, projection of those conformations to an abstract low-dimensional space generates a free-energy landscape. As an example, we show a landscape of homo-dimer formation of an endothelin-1-like molecule computed using a generalized ensemble method. The lowest free-energy cluster at room temperature coincided precisely with the experimentally determined complex structure. Two minor clusters were also found in the landscape, which were largely different from the native complex form. Although those clusters were isolated at room temperature, with rising temperature a pathway emerged linking the lowest and second-lowest free-energy clusters, and a further temperature increment connected all the clusters. This exemplifies that the generalized ensemble method is a powerful tool for computing the free-energy landscape, by which one can discuss the thermodynamic stability of clusters and the temperature dependence of the cluster networks. © 2016 The Author(s).

Systematic theoretical study of ethylene adsorption on δ-MoC(001), TiC(001), and ZrC(001) surfaces

DOE PAGES

Jimenez-Orozco, Carlos; Florez, Elizabeth; Moreno, Andres; ...

2016-05-31

A systematic study of ethylene adsorption over δ-MoC(001), TiC(001), and ZrC(001) surfaces was conducted by means of calculations based on periodic density functional theory. The structure and electronic properties of each carbide pristine surface had a strong influence in the bonding of ethylene. It was found that the metal and carbon sites of the carbide could participate in the adsorption process. As a consequence of this, very different bonding mechanisms were seen on δ-MoC(001) and TiC(001). The bonding of the molecule on the TMC(001) systems showed only minor similarities to the type of bonding found on a typical metal likemore » Pt(111). In general, the ethylene binding energy follow the trend in stability: ZrC(001) < TiC(001) < δ-MoC(001) < Pt(111). The van der Waals correction to the energy produces large binding energy values, modifies the stability orders and drives the ethylene closer to the surface but the adsorbate geometry parameters remain unchanged. Ethylene was activated on clearly defined binding geometries, changing its hybridization from sp 2 to sp 3 with an elongation (0.16–0.31 Å) of the C=C bond. As a result, on the basis of this theoretical study, δ-MoC(001) is proposed as a potential catalyst for the hydrogenation of olefins, whereas TiC(001) could be useful for their hydrogenolysis.« less

H{sub 2} Ortho-to-para Conversion on Grains: A Route to Fast Deuterium Fractionation in Dense Cloud Cores?

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

Bovino, S.; Grassi, T.; Schleicher, D. R. G.

Deuterium fractionation, i.e., the enhancement of deuterated species with respect to non-deuterated ones, is considered to be a reliable chemical clock of star-forming regions. This process is strongly affected by the ortho-to-para H{sub 2} ratio. In this Letter we explore the effect of the ortho–para (o–p) H{sub 2} conversion on grains on the deuteration timescale in fully-depleted dense cores, including the most relevant uncertainties that affect this complex process. We show that (i) the o–p H{sub 2} conversion on grains is not strongly influenced by the uncertainties on the conversion time and the sticking coefficient, and (ii) that the processmore » is controlled by the temperature and the residence time of ortho-H{sub 2} on the surface, i.e., by the binding energy. We find that for binding energies between 330 and 550 K, depending on the temperature, the o–p H{sub 2} conversion on grains can shorten the deuterium fractionation timescale by orders of magnitude, opening a new route for explaining the large observed deuteration fraction D {sub frac} in dense molecular cloud cores. Our results suggest that the star formation timescale, when estimated through the timescale to reach the observed deuteration fractions, might be shorter than previously proposed. However, more accurate measurements of the binding energy are needed in order to better assess the overall role of this process.« less

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.

Genome-wide inference of transcription factor-DNA binding specificity in cell regeneration using a combination strategy.

PubMed

Wang, Xiaofeng; Zhang, Aiqun; Ren, Weizheng; Chen, Caiyu; Dong, Jiahong

2012-11-01

The cell growth, development, and regeneration of tissue and organ are associated with a large number of gene regulation events, which are mediated in part by transcription factors (TFs) binding to cis-regulatory elements involved in the genome. Predicting the binding affinity and inferring the binding specificity of TF-DNA interactions at the genomic level would be fundamentally helpful for our understanding of the molecular mechanism and biological implication underlying sequence-specific TF-DNA recognition. In this study, we report the development of a combination method to characterize the interaction behavior of a 11-mer oligonucleotide segment and its mutations with the Gcn4p protein, a homodimeric, basic leucine zipper TF, and to predict the binding affinity and specificity of potential Gcn4p binders in the genome-wide scale. In this procedure, a position-mutated energy matrix is created based on molecular modeling analysis of native and mutated Gcn4p-DNA complex structures to describe the position-independent interaction energy profile of Gcn4p with different nucleotide types at each position of the oligonucleotide, and the energy terms extracted from the matrix and their interactives are then correlated with experimentally measured affinities of 19268 distinct oligonucleotides using statistical modeling methodology. Subsequently, the best one of built regression models is successfully applied to screen those of potential high-affinity Gcn4p binders from the complete genome. The findings arising from this study are briefly listed below: (i) The 11 positions of oligonucleotides are highly interactive and non-additive in contribution to Gcn4p-DNA binding affinity; (ii) Indirect conformational effects upon nucleotide mutations as well as associated subtle changes in interfacial atomic contacts, but not the direct nonbonded interactions, are primarily responsible for the sequence-specific recognition; (iii) The intrinsic synergistic effects among the sequence positions of oligonucleotides determine Gcn4p-DNA binding affinity and specificity; (iv) Linear regression models in conjunction with variable selection seem to perform fairly well in capturing the internal dependences hidden in the Gcn4p-DNA system, albeit ignoring nonlinear factors may lead the models to systematically underestimate and overestimate high- and low-affinity samples, respectively. © 2012 John Wiley & Sons A/S.

Nature of the water/aromatic parallel alignment interactions.

PubMed

Mitoraj, Mariusz P; Janjić, Goran V; Medaković, Vesna B; Veljković, Dušan Ž; Michalak, Artur; Zarić, Snežana D; Milčić, Miloš K

2015-01-30

The water/aromatic parallel alignment interactions are interactions where the water molecule or one of its O-H bonds is parallel to the aromatic ring plane. The calculated energies of the interactions are significant, up to ΔE(CCSD)(T)(limit) = -2.45 kcal mol(-1) at large horizontal displacement, out of benzene ring and CH bond region. These interactions are stronger than CH···O water/benzene interactions, but weaker than OH···π interactions. To investigate the nature of water/aromatic parallel alignment interactions, energy decomposition methods, symmetry-adapted perturbation theory, and extended transition state-natural orbitals for chemical valence (NOCV), were used. The calculations have shown that, for the complexes at large horizontal displacements, major contribution to interaction energy comes from electrostatic interactions between monomers, and for the complexes at small horizontal displacements, dispersion interactions are dominant binding force. The NOCV-based analysis has shown that in structures with strong interaction energies charge transfer of the type π → σ*(O-H) between the monomers also exists. © 2014 Wiley Periodicals, Inc.

Truncation of the Binary Distribution Function in Globular Cluster Formation

NASA Astrophysics Data System (ADS)

Vesperini, E.; Chernoff, David F.

1996-02-01

We investigate a population of primordial binaries during the initial stage of evolution of a star cluster. For our calculations we assume that equal-mass stars form rapidly in a tidally truncated gas cloud, that ˜10% of the stars are in binaries, and that the resulting star cluster undergoes an epoch of violent relaxation. We study the collisional interaction of the binaries and single stars, in particular, the ionization of the binaries and the energy exchange between binaries and single stars. We find that for large N systems (N > 1000), even the most violent beginning leaves the binary distribution function largely intact. Hence, the binding energy originally tied up in the cloud's protostellar pairs is preserved during the relaxation process, and the binaries are available to interact at later times within the virialized cluster.

Ultrafast Structural Dynamics in Combustion Relevant Model Systems

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

Weber, Peter M.

2014-03-31

The research project explored the time resolved structural dynamics of important model reaction system using an array of novel methods that were developed specifically for this purpose. They include time resolved electron diffraction, time resolved relativistic electron diffraction, and time resolved Rydberg fingerprint spectroscopy. Toward the end of the funding period, we also developed time-resolved x-ray diffraction, which uses ultrafast x-ray pulses at LCLS. Those experiments are just now blossoming, as the funding period expired. In the following, the time resolved Rydberg Fingerprint Spectroscopy is discussed in some detail, as it has been a very productive method. The binding energymore » of an electron in a Rydberg state, that is, the energy difference between the Rydberg level and the ground state of the molecular ion, has been found to be a uniquely powerful tool to characterize the molecular structure. To rationalize the structure sensitivity we invoke a picture from electron diffraction: when it passes the molecular ion core, the Rydberg electron experiences a phase shift compared to an electron in a hydrogen atom. This phase shift requires an adjustment of the binding energy of the electron, which is measurable. As in electron diffraction, the phase shift depends on the molecular, geometrical structure, so that a measurement of the electron binding energy can be interpreted as a measurement of the molecule’s structure. Building on this insight, we have developed a structurally sensitive spectroscopy: the molecule is first elevated to the Rydberg state, and the binding energy is then measured using photoelectron spectroscopy. The molecule’s structure is read out as the binding energy spectrum. Since the photoionization can be done with ultrafast laser pulses, the technique is inherently capable of a time resolution in the femtosecond regime. For the purpose of identifying the structures of molecules during chemical reactions, and for the analysis of molecular species in the hot environments of combustion processes, there are several features that make the Rydberg ionization spectroscopy uniquely useful. First, the Rydberg electron’s orbit is quite large and covers the entire molecule for most molecular structures of combustion interest. Secondly, the ionization does not change vibrational quantum numbers, so that even complicated and large molecules can be observed with fairly well resolved spectra. In fact, the spectroscopy is blind to vibrational excitation of the molecule. This has the interesting consequence for the study of chemical dynamics, where the molecules are invariably very energetic, that the molecular structures are observed unobstructed by the vibrational congestion that dominates other spectroscopies. This implies also that, as a tool to probe the time-dependent structural dynamics of chemically interesting molecules, Rydberg spectroscopy may well be better suited than electron or x-ray diffraction. With recent progress in calculating Rydberg binding energy spectra, we are approaching the point where the method can be evolved into a structure determination method. To implement the Rydberg ionization spectroscopy we use a molecular beam based, time-resolved pump-probe multi-photon ionization/photoelectron scheme in which a first laser pulse excites the molecule to a Rydberg state, and a probe pulse ionizes the molecule. A time-of-flight detector measures the kinetic energy spectrum of the photoelectrons. The photoelectron spectrum directly provides the binding energy of the electron, and thereby reveals the molecule’s time-dependent structural fingerprint. Only the duration of the laser pulses limits the time resolution. With a new laser system, we have now reached time resolutions better than 100 fs, although very deep UV wavelengths (down to 190 nm) have slightly longer instrument functions. The structural dynamics of molecules in Rydberg-excited states is obtained by delaying the probe ionization photon from the pump photon; the structural dynamics of molecules in their ground state or excited valence states is measured by inducing the dynamics using a near UV laser pulse, and employing a multi-photon ionization scheme via the Rydberg states as a probe process. Thus, the technique is capable of measuring the reaction dynamics in any electronic state of neutral molecules.« less

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.

Constrained Surface Complexation Modeling: Rutile in RbCl, NaCl, and NaCF 3SO 3 Media to 250 °C

DOE PAGES

Machesky, Michael L.; Předota, Milan; Ridley, Moira K.; ...

2015-06-01

In this paper, a comprehensive set of molecular-level results, primarily from classical molecular dynamics (CMD) simulations, are used to constrain CD-MUSIC surface complexation model (SCM) parameters describing rutile powder titrations conducted in RbCl, NaCl, and NaTr (Tr = triflate, CF 3SO 3 –) electrolyte media from 25 to 250 °C. Rb + primarily occupies the innermost tetradentate binding site on the rutile (110) surface at all temperatures (25, 150, 250 °C) and negative charge conditions (-0.1 and -0.2 C/m 2) probed via CMD simulations, reflecting the small hydration energy of this large, monovalent cation. Consequently, variable SCM parameters (Stern-layer capacitancemore » values and intrinsic Rb + binding constants) were adjusted relatively easily to satisfactorily match the CMD and titration data. The larger hydration energy of Na + results in a more complex inner-sphere distribution, which shifts from bidentate to tetradentate binding with increasing negative charge and temperature, and this distribution was not matched well for both negative charge conditions, which may reflect limitations in the CMD and/or SCM approaches. Finally, in particular, the CMD axial density profiles for Rb + and Na + reveal that peak binding distances shift toward the surface with increasing negative charge, suggesting that the CD-MUSIC framework may be improved by incorporating CD or Stern-layer capacitance values that vary with charge.« less

Constrained Surface Complexation Modeling: Rutile in RbCl, NaCl, and NaCF 3SO 3 Media to 250 °C

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

Machesky, Michael L.; Předota, Milan; Ridley, Moira K.

In this paper, a comprehensive set of molecular-level results, primarily from classical molecular dynamics (CMD) simulations, are used to constrain CD-MUSIC surface complexation model (SCM) parameters describing rutile powder titrations conducted in RbCl, NaCl, and NaTr (Tr = triflate, CF 3SO 3 –) electrolyte media from 25 to 250 °C. Rb + primarily occupies the innermost tetradentate binding site on the rutile (110) surface at all temperatures (25, 150, 250 °C) and negative charge conditions (-0.1 and -0.2 C/m 2) probed via CMD simulations, reflecting the small hydration energy of this large, monovalent cation. Consequently, variable SCM parameters (Stern-layer capacitancemore » values and intrinsic Rb + binding constants) were adjusted relatively easily to satisfactorily match the CMD and titration data. The larger hydration energy of Na + results in a more complex inner-sphere distribution, which shifts from bidentate to tetradentate binding with increasing negative charge and temperature, and this distribution was not matched well for both negative charge conditions, which may reflect limitations in the CMD and/or SCM approaches. Finally, in particular, the CMD axial density profiles for Rb + and Na + reveal that peak binding distances shift toward the surface with increasing negative charge, suggesting that the CD-MUSIC framework may be improved by incorporating CD or Stern-layer capacitance values that vary with charge.« less

Do Halogen–Hydrogen Bond Donor Interactions Dominate the Favorable Contribution of Halogens to Ligand–Protein Binding?

PubMed Central

2017-01-01

Halogens are present in a significant number of drugs, contributing favorably to ligand–protein binding. Currently, the contribution of halogens, most notably chlorine and bromine, is largely attributed to halogen bonds involving favorable interactions with hydrogen bond acceptors. However, we show that halogens acting as hydrogen bond acceptors potentially make a more favorable contribution to ligand binding than halogen bonds based on quantum mechanical calculations. In addition, bioinformatics analysis of ligand–protein crystal structures shows the presence of significant numbers of such interactions. It is shown that interactions between halogens and hydrogen bond donors (HBDs) are dominated by perpendicular C–X···HBD orientations. Notably, the orientation dependence of the halogen–HBD (X–HBD) interactions is minimal over greater than 100° with favorable interaction energies ranging from −2 to −14 kcal/mol. This contrasts halogen bonds in that X–HBD interactions are substantially more favorable, being comparable to canonical hydrogen bonds, with a smaller orientation dependence, such that they make significant, favorable contributions to ligand–protein binding and, therefore, should be actively considered during rational ligand design. PMID:28657759

Theoretical Study on the Complexes of Benzene with Isoelectronic Nitrogen-Containing Heterocycles

PubMed Central

Wang, Weizhou; Hobza, Pavel

2008-01-01

The π–π interactions between benzene and the aromatic nitrogen heterocycles pyridine, pyrimidine, 1,3,5-triazine, 1,2,3-triazine, 1,2,4,5-tetrazine, and 1,2,3,4,5-pentazine are systematically investigated. The T-shaped structures of all complexes studied exhibit a contraction of the C—H bond accompanied by a rather large blue shift (40–52 cm−1) of its stretching frequency, and they are almost isoenergetic with the corresponding displaced-parallel structures at reliable levels of theory. With increasing number of nitrogen atoms in the heterocycle, the geometries, frequencies, energies, percentage of s character at C, and the electron density in the C—H σ antibonding orbital of the complexes all increase or decrease systematically. Decomposition analysis of the total binding energy showed that for all the complexes, the dispersion energy is the dominant attractive contribution, and a rather large attraction originating from electrostatic contribution is compensated by its exchange counterpart. PMID:18389512

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.

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

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

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

The structure of neuronal calcium sensor-1 in solution revealed by molecular dynamics simulations.

PubMed

Bellucci, Luca; Corni, Stefano; Di Felice, Rosa; Paci, Emanuele

2013-01-01

Neuronal calcium sensor-1 (NCS-1) is a protein able to trigger signal transduction processes by binding a large number of substrates and re-shaping its structure depending on the environmental conditions. The X-ray crystal structure of the unmyristoilated NCS-1 shows a large solvent-exposed hydrophobic crevice (HC); this HC is partially occupied by the C-terminal tail and thus elusive to the surrounding solvent. We studied the native state of NCS-1 by performing room temperature molecular dynamics (MD) simulations starting from the crystal and the solution structures. We observe relaxation to a state independent of the initial structure, in which the C-terminal tail occupies the HC. We suggest that the C-terminal tail shields the HC binding pocket and modulates the affinity of NCS-1 for its natural targets. By analyzing the topology and nature of the inter-residue potential energy, we provide a compelling description of the interaction network that determines the three-dimensional organization of NCS-1.

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.

Proposal for novel curcumin derivatives as potent inhibitors against Alzheimer's disease: Ab initio molecular simulations on the specific interactions between amyloid-beta peptide and curcumin

NASA Astrophysics Data System (ADS)

Ota, Shintaro; Fujimori, Mitsuki; Ishimura, Hiromi; Shulga, Sergiy; Kurita, Noriyuki

2017-10-01

Accumulation of amyloid-β (Aβ) peptides in a brain is closely related with the pathogenesis of Alzheimer's disease. To suppress the production of Aβ peptides, we propose novel curcumin derivatives and investigate their binding properties with the amyloid precursor protein (APP), using protein-ligand docking as well as ab initio molecular simulations. Our proposed derivative (curcumin XIV) is found to have a large binding energy with APP and interacts strongly with the cleavage site Ala19 by secretase. It is thus expected that curcumin XIV can protect APP from the secretase attack and be a potent inhibitor against the production of Aβ peptides.

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

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

Hsu, Hao-Chi; Tong, Simon; Zhou, Yuchen

Human FABP5 and FABP7 are intracellular endocannabinoid transporters. SBFI-26 is an α-truxillic acid 1-naphthyl monoester that competitively inhibits the activities of FABP5 and FABP7 and produces antinociceptive and anti-inflammatory effects in mice. The synthesis of SBFI-26 yields several stereoisomers, and it is not known how the inhibitor binds the transporters. Here we report co-crystal structures of SBFI-26 in complex with human FABP5 and FABP7 at 2.2 and 1.9 Å resolution, respectively. We found that only (S)-SBFI-26 was present in the crystal structures. The inhibitor largely mimics the fatty acid binding pattern, but it also has several unique interactions. Notably, themore » FABP7 complex corroborates key aspects of the ligand binding pose at the canonical site previously predicted by virtual screening. In FABP5, SBFI-26 was unexpectedly found to bind at the substrate entry portal region in addition to binding at the canonical ligand-binding pocket. Our structural and binding energy analyses indicate that both R and S forms appear to bind the transporter equally well. We suggest that the S enantiomer observed in the crystal structures may be a result of the crystallization process selectively incorporating the (S)-SBFI-26–FABP complexes into the growing lattice, or that the S enantiomer may bind to the portal site more rapidly than to the canonical site, leading to an increased local concentration of the S enantiomer for binding to the canonical site. Our work reveals two binding poses of SBFI-26 in its target transporters. This knowledge will guide the development of more potent FABP inhibitors based upon the SBFI-26 scaffold.« less

Substituent Effects on Thermal Decolorization Rates of Bisbenzospiropyrans

PubMed Central

Lu, Nina T.; Nguyen, Vi N.; Kumar, Satish; McCurdy, Alison

2009-01-01

A novel application of photochromic molecules is to mimic physiological oscillatory calcium signals by reversibly binding and releasing calcium ions in response to light. Substituent changes on the largely unexplored photochromic bisbenzospiropyran scaffold led to significant changes in thermal fading rates in several organic solvents. Excellent correlations have been found between fading rates and empirical Hammett constants as well as calculated ground-state energies. These correlations can be used to improve scaffold design. PMID:16238356

Mixtures of latex particles and the surfactant of opposite charge used as interface stabilizers--influence of particle contact angle, zeta potential, flocculation and shear energy.

PubMed

Deleurence, Rémi; Parneix, Caroline; Monteux, Cécile

2014-09-28

We investigate the stabilization of air-water interfaces by mixtures of negatively charged latex particles (sulfate polystyrene) and cationic surfactants (alkyl trimethylammonium bromides). First we report results concerning the binding of surfactant molecules to the latex particles. As the surfactant concentration increases, the charge of the particles reverses, from negative to positive, because CnTAB first binds electrostatically to the latex particles and then through hydrophobic interaction with the monolayer already adsorbed on the particles as well as directly with the hydrophobic surface of the latex. Over a large range of surfactant concentrations around the charge inversion, a strong flocculation is observed and 100 μm large aggregates form in the suspension. Unlike previous studies published on mixtures of inorganic particles with oppositely charged surfactants, we show that we can vary the sign of the zeta potential of the particles without changing the contact angle of the particles over a large range of surfactant concentrations. Indeed, the latex particles that we study are more hydrophobic than inorganic particles, hence adding moderate concentrations of the surfactant results in a weak variation of the contact angle while the charge of the particles can be reversed. This enables decoupling of the effect of zeta potential and contact angle on the interfacial properties of the mixtures. Our study shows that the contact angle and the charge of the particles are not sufficient parameters to control the foam properties, and the key-parameters are the flocculation state and the shear energy applied to produce the foam. Indeed, flocculated samples, whatever the sign of the zeta potential, enable production of a stable armour at the interface. The large aggregates do not adsorb spontaneously at the interface because of their large size, however when a large shear energy is used to produce the foam very stable foam is obtained, where particles are trapped at interfaces. We suggest that the large aggregates may be broken during shear and may reform at the interface to form a solid armour. A simple calculation taking into account the adsorption dynamics of the aggregates as a function of their size is consistent with this hypothesis.

Exploring movement and energy in human P-glycoprotein conformational rearrangement.

PubMed

Zhang, Yue; Gong, Weikang; Wang, Yan; Liu, Yang; Li, Chunhua

2018-04-24

Human P-glycoprotein (P-gp), a kind of ATP-Binding Cassette transporter, can export a diverse variety of anti-cancer drugs out of the tumor cell. Its overexpression is one of the main reasons for the multidrug resistance (MDR) of tumor cells. It has been confirmed that during the substrate transport process, P-gp experiences a large-scale structural rearrangement from the inward- to outward-facing states. However, the mechanism of how the nucleotide-binding domains (NBDs) control the transmembrane domains (TMDs) to open towards the periplasm in the outward-facing state has not yet been fully characterized. Herein, targeted molecular dynamics simulations were performed to explore the conformational rearrangement of human P-gp. The results show that the allosteric process proceeds in a coupled way, and first the transition is driven by the NBDs, and then transmitted to the cytoplasmic parts of TMDs, finally to the periplasmic parts. The trajectories show that besides the translational motions, the NBDs undergo a rotation movement, which mainly occurs in xy plane and ensures the formation of the correct ATP-binding pockets. The analyses on the interaction energies between the six structure segments (cICLs) from the TMDs and NBDs reveal that their subtle energy differences play an important role in causing the periplasmic parts of the transmembrane helices to separate from each other in the established directions and in appropriate amplitudes. This conclusion can explain the two experimental phenomena about human P-gp in some extent. These studies have provided a detailed exploration into human P-gp rearrangement process and given an energy insight into the TMD reorientation during P-gp transition.

From Aβ Filament to Fibril: Molecular Mechanism of Surface-Activated Secondary Nucleation from All-Atom MD Simulations.

PubMed

Schwierz, Nadine; Frost, Christina V; Geissler, Phillip L; Zacharias, Martin

2017-02-02

Secondary nucleation pathways in which existing amyloid fibrils catalyze the formation of new aggregates and neurotoxic oligomers are of immediate importance for the onset and progression of Alzheimer's disease. Here, we apply extensive all-atom molecular dynamics simulations in explicit water to study surface-activated secondary nucleation pathways at the extended lateral β-sheet surface of a preformed Aβ 9-40 filament. Calculation of free-energy profiles allows us to determine binding free energies and conformational intermediates for nucleation complexes consisting of 1-4 Aβ peptides. In addition, we combine the free-energy profiles with position-dependent diffusion profiles to extract complementary kinetic information and macroscopic growth rates. Single monomers bind to the β-sheet surface in a disordered, hydrophobically collapsed conformation, whereas dimers and larger oligomers can retain a cross-β conformation resembling a more ordered fibril structure. The association processes during secondary nucleation follow a dock/lock mechanism consisting of a fast initial encounter phase (docking) and a slow structural rearrangement phase (locking). The major driving forces for surface-activated secondary nucleation are the release of a large number of hydration water molecules and the formation of hydrophobic interface contacts, the latter being in contrast to the elongation process at filament tips, which is dominated by the formation of stable and highly specific interface hydrogen bonds. The calculated binding free energies and the association rates for the attachment of Aβ monomers and oligomers to the extended lateral β-sheet surface of the filament seed are higher compared to those for elongation at the filament tips, indicating that secondary nucleation pathways can become important once a critical concentration of filaments has formed.

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.

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.

Regulation of Polycystin-1 Function by Calmodulin Binding

PubMed Central

Doerr, Nicholas; Wang, Yidi; Kipp, Kevin R.; Liu, Guangyi; Benza, Jesse J.; Pletnev, Vladimir; Pavlov, Tengis S.; Staruschenko, Alexander; Mohieldin, Ashraf M.; Takahashi, Maki; Nauli, Surya M.; Weimbs, Thomas

2016-01-01

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common genetic disease that leads to progressive renal cyst growth and loss of renal function, and is caused by mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. The PC1/PC2 complex localizes to primary cilia and can act as a flow-dependent calcium channel in addition to numerous other signaling functions. The exact functions of the polycystins, their regulation and the purpose of the PC1/PC2 channel are still poorly understood. PC1 is an integral membrane protein with a large extracytoplasmic N-terminal domain and a short, ~200 amino acid C-terminal cytoplasmic tail. Most proteins that interact with PC1 have been found to bind via the cytoplasmic tail. Here we report that the PC1 tail has homology to the regulatory domain of myosin heavy chain including a conserved calmodulin-binding motif. This motif binds to CaM in a calcium-dependent manner. Disruption of the CaM-binding motif in PC1 does not affect PC2 binding, cilia targeting, or signaling via heterotrimeric G-proteins or STAT3. However, disruption of CaM binding inhibits the PC1/PC2 calcium channel activity and the flow-dependent calcium response in kidney epithelial cells. Furthermore, expression of CaM-binding mutant PC1 disrupts cellular energy metabolism. These results suggest that critical functions of PC1 are regulated by its ability to sense cytosolic calcium levels via binding to CaM. PMID:27560828

Qgui: A high-throughput interface for automated setup and analysis of free energy calculations and empirical valence bond simulations in biological systems.

PubMed

Isaksen, Geir Villy; Andberg, Tor Arne Heim; Åqvist, Johan; Brandsdal, Bjørn Olav

2015-07-01

Structural information and activity data has increased rapidly for many protein targets during the last decades. In this paper, we present a high-throughput interface (Qgui) for automated free energy and empirical valence bond (EVB) calculations that use molecular dynamics (MD) simulations for conformational sampling. Applications to ligand binding using both the linear interaction energy (LIE) method and the free energy perturbation (FEP) technique are given using the estrogen receptor (ERα) as a model system. Examples of free energy profiles obtained using the EVB method for the rate-limiting step of the enzymatic reaction catalyzed by trypsin are also shown. In addition, we present calculation of high-precision Arrhenius plots to obtain the thermodynamic activation enthalpy and entropy with Qgui from running a large number of EVB simulations. Copyright © 2015 Elsevier Inc. All rights reserved.

The Impact of a Ligand Binding on Strand Migration in the SAM-I Riboswitch

PubMed Central

Huang, Wei; Kim, Joohyun; Jha, Shantenu; Aboul-ela, Fareed

2013-01-01

Riboswitches sense cellular concentrations of small molecules and use this information to adjust synthesis rates of related metabolites. Riboswitches include an aptamer domain to detect the ligand and an expression platform to control gene expression. Previous structural studies of riboswitches largely focused on aptamers, truncating the expression domain to suppress conformational switching. To link ligand/aptamer binding to conformational switching, we constructed models of an S-adenosyl methionine (SAM)-I riboswitch RNA segment incorporating elements of the expression platform, allowing formation of an antiterminator (AT) helix. Using Anton, a computer specially developed for long timescale Molecular Dynamics (MD), we simulated an extended (three microseconds) MD trajectory with SAM bound to a modeled riboswitch RNA segment. Remarkably, we observed a strand migration, converting three base pairs from an antiterminator (AT) helix, characteristic of the transcription ON state, to a P1 helix, characteristic of the OFF state. This conformational switching towards the OFF state is observed only in the presence of SAM. Among seven extended trajectories with three starting structures, the presence of SAM enhances the trend towards the OFF state for two out of three starting structures tested. Our simulation provides a visual demonstration of how a small molecule (<500 MW) binding to a limited surface can trigger a large scale conformational rearrangement in a 40 kDa RNA by perturbing the Free Energy Landscape. Such a mechanism can explain minimal requirements for SAM binding and transcription termination for SAM-I riboswitches previously reported experimentally. PMID:23704854

Molecular Dynamics of CYP2D6 Polymorphisms in the Absence and Presence of a Mechanism-Based Inactivator Reveals Changes in Local Flexibility and Dominant Substrate Access Channels

PubMed Central

de Waal, Parker W.; Sunden, Kyle F.; Furge, Laura Lowe

2014-01-01

Cytochrome P450 enzymes (CYPs) represent an important enzyme superfamily involved in metabolism of many endogenous and exogenous small molecules. CYP2D6 is responsible for ∼15% of CYP-mediated drug metabolism and exhibits large phenotypic diversity within CYPs with over 100 different allelic variants. Many of these variants lead to functional changes in enzyme activity and substrate selectivity. Herein, a molecular dynamics comparative analysis of four different variants of CYP2D6 was performed. The comparative analysis included simulations with and without SCH 66712, a ligand that is also a mechanism-based inactivator, in order to investigate the possible structural basis of CYP2D6 inactivation. Analysis of protein stability highlighted significantly altered flexibility in both proximal and distal residues from the variant residues. In the absence of SCH 66712, *34, *17-2, and *17-3 displayed more flexibility than *1, and *53 displayed more rigidity. SCH 66712 binding reversed flexibility in *17-2 and *17-3, through *53 remained largely rigid. Throughout simulations with docked SCH 66712, ligand orientation within the heme-binding pocket was consistent with previously identified sites of metabolism and measured binding energies. Subsequent tunnel analysis of substrate access, egress, and solvent channels displayed varied bottle-neck radii. Taken together, our results indicate that SCH 66712 should inactivate these allelic variants, although varied flexibility and substrate binding-pocket accessibility may alter its interaction abilities. PMID:25286176

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

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.

Global Energy and Aviation Concerns

NASA Technical Reports Server (NTRS)

Hendricks, Robert C.; Daggett, Dave; Anast, Peter; Lowery, Nathan

2006-01-01

Renewable energy sources are usually diffuse and require large facilities. Biofuels work better, are more economical to produce for ground transportation, but sharply increase competition for food croplands. Noble laureate Richard Smalley (deceased-2005) conceptual 20 TWe power generation covers hundreds x hundreds of miles. Combined with Fuller s superconducting power grid system would enable renewable planetary energy. A solar-wind project in Australia will have a 7km diameter collector interfacing with a 1 km tower to extract 200 MW from wind turbines mounted at the base. GE Energy s 3.5MW Wind Turbine is large and placing this in perspective, it is as if one were rotating a Boeing 747-200; the blade diameter is that large. Wind turbines are rapidly gaining popularity in Europe and photovoltaic (PV) is expected to also expand rapidly. It becomes clear that we need (and still have time) to develop new sources of energy. Hf 178 bombarded by X-rays produces Gamma-rays for heating. The reaction stops when the X-rays stop; the half life is about 30 years and seems manageable vs 30 000 years. Water splitting needs to be perused as do ultra fast ultra intense laser applications in terms of fusion and new materials developments including new ways to strip and re-bind hydrogen into fuels. New methods and tools for development are being found in quantum mechanical applications to macro-systems and need to be developed into a set of new tool boxes for development of these new energy sources.

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.

A dipole-bound dianion

NASA Astrophysics Data System (ADS)

Skurski, Piotr; Simons, Jack

2000-04-01

The possibility of binding two electrons by the dipole potential of a molecule was examined earlier by us using model potentials. That study suggested that large dipole moments μ=qR and large charge separation distances R (or equivalently large charges q) would be required to achieve binding two electrons. For example, even with a charge q=1.5 a.u. which might be achieved using di- or tri-valent cations, a dipole moment exceeding 15.922 D is needed. The presence of inner-shell electrons even further increases the value of μ that is required because the dipole-bound electrons' orbital must be orthogonal to and excluded from such inner shells. In the present work, we discuss our efforts to find a real molecule that can actually bind two electrons to a single dipole site. Numerical results are presented for the mono- and dianions of a double 5-member carbon ring system substituted with a Ca atom and three superhalogen -PF5 groups. The dianion of this molecule is found to be geometrically stable and to have a vertical electron detachment energy of ca. 0.8 eV. Its two excess electrons occupy the same fully symmetric a1 molecular orbital localized at the electropositive Ca end of the neutral system as is routinely observed in dipole-bound monoanions. Although our final candidate is chemically unusual, it is hoped that our predictions about it will encourage others to search for more synthetically tractable alternatives.

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

Adlayer structure dependent ultrafast desorption dynamics in carbon monoxide adsorbed on Pd (111)

NASA Astrophysics Data System (ADS)

Hong, Sung-Young; Xu, Pan; Camillone, Nina R.; White, Michael G.; Camillone, Nicholas

2016-07-01

We report our ultrafast photoinduced desorption investigation of the coverage dependence of substrate-adsorbate energy transfer in carbon monoxide adlayers on the (111) surface of palladium. As the CO coverage is increased, the adsorption site population shifts from all threefold hollows (up to 0.33 ML), to bridge and near bridge (>0.5 to 0.6 ML) and finally to mixed threefold hollow plus top site (at saturation at 0.75 ML). We show that between 0.24 and 0.75 ML this progression of binding site motifs is accompanied by two remarkable features in the ultrafast photoinduced desorption of the adsorbates: (i) the desorption probability increases roughly two orders magnitude, and (ii) the adsorbate-substrate energy transfer rate observed in two-pulse correlation experiments varies nonmonotonically, having a minimum at intermediate coverages. Simulations using a phenomenological model to describe the adsorbate-substrate energy transfer in terms of frictional coupling indicate that these features are consistent with an adsorption-site dependent electron-mediated energy coupling strength, ηel, that decreases with binding site in the order: three-fold hollow > bridge and near bridge > top site. This weakening of ηel largely counterbalances the decrease in the desorption activation energy that accompanies this progression of adsorption site motifs, moderating what would otherwise be a rise of several orders of magnitude in the desorption probability. Within this framework, the observed energy transfer rate enhancement at saturation coverage is due to interadsorbate energy transfer from the copopulation of molecules bound in three-fold hollows to their top-site neighbors.

Adlayer structure dependent ultrafast desorption dynamics in carbon monoxide adsorbed on Pd (111)

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

Hong, Sung -Young; Xu, Pan; Camillone, Nina R.

Here, we report our ultrafast photoinduced desorption investigation of the coverage dependence of substrate–adsorbate energy transfer in carbon monoxide adlayers on the (111) surface of palladium. As the CO coverage is increased, the adsorption site population shifts from all threefold hollows (up to 0.33 ML), to bridge and near bridge (>0.5 to 0.6 ML) and finally to mixed threefold hollow plus top site (at saturation at 0.75 ML). We show that between 0.24 and 0.75 ML this progression of binding site motifs is accompanied by two remarkable features in the ultrafast photoinduced desorption of the adsorbates: (i) the desorption probabilitymore » increases roughly two orders magnitude, and (ii) the adsorbate–substrate energy transfer rate observed in two-pulse correlation experiments varies nonmonotonically, having a minimum at intermediate coverages. Simulations using a phenomenological model to describe the adsorbate–substrate energy transfer in terms of frictional coupling indicate that these features are consistent with an adsorption-site dependent electron-mediated energy coupling strength, η el, that decreases with binding site in the order: three-fold hollow > bridge and near bridge > top site. This weakening of η el largely counterbalances the decrease in the desorption activation energy that accompanies this progression of adsorption site motifs, moderating what would otherwise be a rise of several orders of magnitude in the desorption probability. Within this framework, the observed energy transfer rate enhancement at saturation coverage is due to interadsorbate energy transfer from the copopulation of molecules bound in three-fold hollows to their top-site neighbors.« less

Adlayer structure dependent ultrafast desorption dynamics in carbon monoxide adsorbed on Pd (111)

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

Hong, Sung-Young; Camillone, Nina R.; Camillone, Nicholas, E-mail: nicholas@bnl.gov

We report our ultrafast photoinduced desorption investigation of the coverage dependence of substrate–adsorbate energy transfer in carbon monoxide adlayers on the (111) surface of palladium. As the CO coverage is increased, the adsorption site population shifts from all threefold hollows (up to 0.33 ML), to bridge and near bridge (>0.5 to 0.6 ML) and finally to mixed threefold hollow plus top site (at saturation at 0.75 ML). We show that between 0.24 and 0.75 ML this progression of binding site motifs is accompanied by two remarkable features in the ultrafast photoinduced desorption of the adsorbates: (i) the desorption probability increasesmore » roughly two orders magnitude, and (ii) the adsorbate–substrate energy transfer rate observed in two-pulse correlation experiments varies nonmonotonically, having a minimum at intermediate coverages. Simulations using a phenomenological model to describe the adsorbate–substrate energy transfer in terms of frictional coupling indicate that these features are consistent with an adsorption-site dependent electron-mediated energy coupling strength, η{sub el}, that decreases with binding site in the order: three-fold hollow > bridge and near bridge > top site. This weakening of η{sub el} largely counterbalances the decrease in the desorption activation energy that accompanies this progression of adsorption site motifs, moderating what would otherwise be a rise of several orders of magnitude in the desorption probability. Within this framework, the observed energy transfer rate enhancement at saturation coverage is due to interadsorbate energy transfer from the copopulation of molecules bound in three-fold hollows to their top-site neighbors.« less

Adlayer structure dependent ultrafast desorption dynamics in carbon monoxide adsorbed on Pd (111)

DOE PAGES

Hong, Sung -Young; Xu, Pan; Camillone, Nina R.; ...

2016-07-01

Here, we report our ultrafast photoinduced desorption investigation of the coverage dependence of substrate–adsorbate energy transfer in carbon monoxide adlayers on the (111) surface of palladium. As the CO coverage is increased, the adsorption site population shifts from all threefold hollows (up to 0.33 ML), to bridge and near bridge (>0.5 to 0.6 ML) and finally to mixed threefold hollow plus top site (at saturation at 0.75 ML). We show that between 0.24 and 0.75 ML this progression of binding site motifs is accompanied by two remarkable features in the ultrafast photoinduced desorption of the adsorbates: (i) the desorption probabilitymore » increases roughly two orders magnitude, and (ii) the adsorbate–substrate energy transfer rate observed in two-pulse correlation experiments varies nonmonotonically, having a minimum at intermediate coverages. Simulations using a phenomenological model to describe the adsorbate–substrate energy transfer in terms of frictional coupling indicate that these features are consistent with an adsorption-site dependent electron-mediated energy coupling strength, η el, that decreases with binding site in the order: three-fold hollow > bridge and near bridge > top site. This weakening of η el largely counterbalances the decrease in the desorption activation energy that accompanies this progression of adsorption site motifs, moderating what would otherwise be a rise of several orders of magnitude in the desorption probability. Within this framework, the observed energy transfer rate enhancement at saturation coverage is due to interadsorbate energy transfer from the copopulation of molecules bound in three-fold hollows to their top-site neighbors.« less

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.

Identification of key residues for protein conformational transition using elastic network model.

PubMed

Su, Ji Guo; Xu, Xian Jin; Li, Chun Hua; Chen, Wei Zu; Wang, Cun Xin

2011-11-07

Proteins usually undergo conformational transitions between structurally disparate states to fulfill their functions. The large-scale allosteric conformational transitions are believed to involve some key residues that mediate the conformational movements between different regions of the protein. In the present work, a thermodynamic method based on the elastic network model is proposed to predict the key residues involved in protein conformational transitions. In our method, the key functional sites are identified as the residues whose perturbations largely influence the free energy difference between the protein states before and after transition. Two proteins, nucleotide binding domain of the heat shock protein 70 and human/rat DNA polymerase β, are used as case studies to identify the critical residues responsible for their open-closed conformational transitions. The results show that the functionally important residues mainly locate at the following regions for these two proteins: (1) the bridging point at the interface between the subdomains that control the opening and closure of the binding cleft; (2) the hinge region between different subdomains, which mediates the cooperative motions between the corresponding subdomains; and (3) the substrate binding sites. The similarity in the positions of the key residues for these two proteins may indicate a common mechanism in their conformational transitions.

Energetics of subdomain movements and fluorescence probe solvation environment change in ATP-bound myosin.

PubMed

Harris, Michael J; Woo, Hyung-June

2008-11-01

Energetics of conformational changes experienced by an ATP-bound myosin head detached from actin was studied by all-atom explicit water umbrella sampling simulations. The statistics of coupling between large scale domain movements and smaller scale structural features were examined, including the closing of the ATP binding pocket, and a number of key hydrogen bond formations shown to play roles in structural and biochemical studies. The statistics for the ATP binding pocket open/close transition show an evolution of the relative stability from the open state in the early stages of the recovery stroke to the stable closed state after the stroke. The change in solvation environment of the fluorescence probe Trp507 (scallop numbering; 501 in Dictyostelium discoideum) indicates that the probe faithfully reflects the closing of the binding pocket as previously shown in experimental studies, while being directly coupled to roughly the early half of the overall large scale conformational change of the converter domain rotation. The free energy change of this solvation environment change, in particular, is -1.3 kcal/mol, in close agreement with experimental estimates. In addition, our results provide direct molecular level data allowing for interpretations of the fluorescence experiments of myosin conformational change in terms of the de-solvation of Trp side chain.

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.

Measuring the Influence of Dielectric Environment on 2D Excitons in Monolayer Semiconductors: Insight from High Magnetic Fields1

NASA Astrophysics Data System (ADS)

Stier, Andreas

The relatively heavy electrons and holes in monolayer semiconductors such as MoS2 form tightly-bound excitons with large binding energies, thus motivating magneto-optical studies in high magnetic fields. Because 2D excitons in these materials necessarily lie close to a surface, their properties are expected to be strongly influenced by the surrounding dielectric environment. However, systematic studies exploring this role are challenging, in part because the most readily accessible exciton parameter - the exciton's optical transition energy - is largely unaffected by the surrounding medium. Here we show that the role of the dielectric environment can be revealed through its systematic influence on the size of the exciton, which can be directly measured via the diamagnetic shift of the exciton transition in high magnetic fields. Using exfoliated WSe2 monolayers affixed to single-mode optical fibers, we tune the surrounding dielectric environment by encapsulating the monolayers with different materials, and perform polarization resolved low-temperature magneto-absorption studies to 65 tesla. The systematic increase of the exciton's size with dielectric screening, and concurrent two-fold reduction in binding energy (also inferred from these measurements), is quantitatively compared with leading theoretical models based on the Keldysh potential. These results demonstrate how exciton properties can be tuned in future 2D devices and van der Waals heterostructures. 1In collaboration with S.A. Crooker (NHMFL); J. Kono (Rice University); K.M. McCreary, B.T. Jonker (Naval Research Lab); N.P. Wilson, G. Clark, X. Xu (University of Washington).

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.

Cisplatin Radiosensitization of DNA Irradiated with 2-20 eV Electrons: Role of Transient Anions.

PubMed

Bao, Qianhong; Chen, Yunfeng; Zheng, Yi; Sanche, Léon

2014-06-20

Platinum chemotherapeutic agents, such as cisplatin ( cis -diamminedichloroplatinum(II)), can act as radiosensitizers when bound covalently to nuclear DNA in cancer cells. This radiosensitization is largely due to an increase in DNA damage induced by low-energy secondary electrons, produced in large quantities by high-energy radiation. We report the yields of single- and double-strand breaks (SSB and DSB) and interduplex cross-links (CL) induced by electrons of 1.6-19.6 eV (i.e., the yield functions) incident on 5 monolayer (ML) films of cisplatin-DNA complexes. These yield functions are compared with those previously recorded with 5 ML films of unmodified plasmid DNA. Binding of five cisplatin molecules to plasmid DNA (3197 base pairs) enhances SSB, DSB, and CL by factors varying, from 1.2 to 2.8, 1.4 to 3.5, and 1.2 to 2.7, respectively, depending on electron energy. All yield functions exhibit structures around 5 and 10 eV that can be attributed to enhancement of bond scission, via the initial formation of core-excited resonances associated with π → π * transitions of the bases. This increase in damage is interpreted as arising from a modification of the parameters of the corresponding transient anions already present in nonmodified DNA, particularly those influencing molecular dissociation. Two additional resonances, specific to cisplatin-modified DNA, are formed at 13.6 and 17.6 eV in the yield function of SSB. Furthermore, cisplatin binding causes the induction of DSB by electrons of 1.6-3.6 eV, i.e., in an energy region where a DSB cannot be produced by a single electron in pure DNA. Breaking two bonds with a subexcitation-energy electron is tentatively explained by a charge delocalization mechanism, where a single electron occupies simultaneously two σ * bonds linking the Pt atom to guanine bases on opposite strands.

Cisplatin Radiosensitization of DNA Irradiated with 2–20 eV Electrons: Role of Transient Anions

PubMed Central

Bao, Qianhong; Chen, Yunfeng; Zheng, Yi; Sanche, Léon

2015-01-01

Platinum chemotherapeutic agents, such as cisplatin (cis-diamminedichloroplatinum(II)), can act as radiosensitizers when bound covalently to nuclear DNA in cancer cells. This radiosensitization is largely due to an increase in DNA damage induced by low-energy secondary electrons, produced in large quantities by high-energy radiation. We report the yields of single- and double-strand breaks (SSB and DSB) and interduplex cross-links (CL) induced by electrons of 1.6–19.6 eV (i.e., the yield functions) incident on 5 monolayer (ML) films of cisplatin–DNA complexes. These yield functions are compared with those previously recorded with 5 ML films of unmodified plasmid DNA. Binding of five cisplatin molecules to plasmid DNA (3197 base pairs) enhances SSB, DSB, and CL by factors varying, from 1.2 to 2.8, 1.4 to 3.5, and 1.2 to 2.7, respectively, depending on electron energy. All yield functions exhibit structures around 5 and 10 eV that can be attributed to enhancement of bond scission, via the initial formation of core-excited resonances associated with π → π* transitions of the bases. This increase in damage is interpreted as arising from a modification of the parameters of the corresponding transient anions already present in nonmodified DNA, particularly those influencing molecular dissociation. Two additional resonances, specific to cisplatin-modified DNA, are formed at 13.6 and 17.6 eV in the yield function of SSB. Furthermore, cisplatin binding causes the induction of DSB by electrons of 1.6–3.6 eV, i.e., in an energy region where a DSB cannot be produced by a single electron in pure DNA. Breaking two bonds with a subexcitation-energy electron is tentatively explained by a charge delocalization mechanism, where a single electron occupies simultaneously two σ* bonds linking the Pt atom to guanine bases on opposite strands. PMID:26793285

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.

Drug Resistance Mechanism of L10F, L10F/N88S and L90M mutations in CRF01_AE HIV-1 protease: Molecular dynamics simulations and binding free energy calculations.

PubMed

Vasavi, C S; Tamizhselvi, Ramasamy; Munusami, Punnagai

2017-08-01

HIV-1 protease plays a crucial role in viral replication and maturation, which makes it one of the most attractive targets for anti-retroviral therapy. The majority of HIV infections in developing countries are due to non-B subtype. Subtype AE is spreading rapidly and infecting huge population worldwide. The mutations in the active site of subtype AE directly impair the interactions with the inhibitor. The non-active site mutations influence the binding of the inhibitor indirectly and their resistance mechanism is not well understood. It is important to design new effective inhibitors that combat drug resistance in subtype AE protease. In this work, we examined the effect of non active site mutations L10F, L10F/N88S and L90M with nelfinavir using molecular dynamics simulation and binding free energy calculations. The simulations suggested that the L10F and L10F/N88S mutants decrease the binding affinity of nelfinavir, whereas the L90M mutant increases the binding affinity. The formation of hydrogen bonds between nelfinavir and Asp30 is crucial for effective binding. The benzamide moiety of nelfinavir shows large positional deviation in L10F and L10F/N88S complexes and the L10F/N88S mutation changes the hydrogen bond between the side chain atoms of 30th residue and the 88th residue. Consequently the hydrogen bond interaction between Asp30 and nelfinavir are destroyed leading to drug resistance. Our present study shed light on the resistance mechanism of the strongly linked mutation L10F/N88S observed experimentally in AE subtype. Copyright © 2017 Elsevier Inc. All rights reserved.

Free energy simulations reveal a double mutant avian H5N1 virus hemagglutinin with altered receptor binding specificity.

PubMed

Das, Payel; Li, Jingyuan; Royyuru, Ajay K; Zhou, Ruhong

2009-08-01

Historically, influenza pandemics have been triggered when an avian influenza virus or a human/avian reassorted virus acquires the ability to replicate efficiently and become transmissible in the human population. Most critically, the major surface glycoprotein hemagglutinin (HA) must adapt to the usage of human-like (alpha-2,6-linked) sialylated glycan receptors. Therefore, identification of mutations that can switch the currently circulating H5N1 HA receptor binding specificity from avian to human might provide leads to the emergence of pandemic H5N1 viruses. To define such mutations in the H5 subtype, here we provide a computational framework that combines molecular modeling with extensive free energy simulations. Our results show that the simulated binding affinities are in good agreement with currently available experimental data. Moreover, we predict that one double mutation (V135S and A138S) in HA significantly enhances alpha-2,6-linked receptor recognition by the H5 subtype. Our simulations indicate that this double mutation in H5N1 HA increases the binding affinity to alpha-2,6-linked sialic acid receptors by 2.6 +/- 0.7 kcal/mol per HA monomer that primarily arises from the electrostatic interactions. Further analyses reveal that introduction of this double mutation results in a conformational change in the receptor binding pocket of H5N1 HA. As a result, a major rearrangement occurs in the hydrogen-bonding network of HA with the human receptor, making the human receptor binding pattern of double mutant H5N1 HA surprisingly similar to that observed in human H1N1 HA. These large scale molecular simulations on single and double mutants thus provide new insights into our understanding toward human adaptation of the avian H5N1 virus. 2009 Wiley Periodicals, Inc.

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)

Balanced Branching in Transcription Termination

NASA Technical Reports Server (NTRS)

Harrington, K. J.; Laughlin, R. B.; Liang, S.

2001-01-01

The theory of stochastic transcription termination based on free-energy competition requires two or more reaction rates to be delicately balanced over a wide range of physical conditions. A large body of work on glasses and large molecules suggests that this should be impossible in such a large system in the absence of a new organizing principle of matter. We review the experimental literature of termination and find no evidence for such a principle but many troubling inconsistencies, most notably anomalous memory effects. These suggest that termination has a deterministic component and may conceivably be not stochastic at all. We find that a key experiment by Wilson and von Hippel allegedly refuting deterministic termination was an incorrectly analyzed regulatory effect of Mg(2+) binding.

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.

A calorimetric investigation of the interaction of the lac repressor with inducer.

PubMed

Donnér, J; Caruthers, M H; Gill, S J

1982-12-25

A calorimetric study has been made of the interaction between the lac repressor and isopropyl-1-thio-beta-D-galactopyranoside (IPTG). The buffer-corrected enthalpy of reaction at 25 degrees C was found to be -15.6, -24.7, -4.6 kJ/mol of bound IPTG at pH 7.0, pH 8.1, and pH 9.0, respectively. This large range of enthalpy values is in contrast to a maximum difference in the free energy of the reaction of only 1.5 kJ/mol of bound IPTG between these pH values. The reaction was found by calorimetric measurements in different buffers to be accompanied by an uptake of 0.29 mol of protons/mol of bound IPTG at pH 8.1. The pH dependency of the reaction enthalpy suggests differences in the extent of protonation of the binding site and the involvement of H bonding with IPTG. The lack of strong hydrophobic contributions in the IPTG binding process is revealed by the absence of any determinable heat capacity change for the reaction at pH 7.0. The presence of phosphate buffer significantly alters the enthalpy of IPTG binding at higher pH values, but has little effect upon the binding constant. This implies that highly negative phosphate species change the nature of the IPTG binding site without any displacement of phosphate upon IPTG binding.

In vitro and in silico assessment of the structure-dependent binding of bisphenol analogues to glucocorticoid receptor.

PubMed

Zhang, Jie; Zhang, Tiehua; Guan, Tianzhu; Yu, Hansong; Li, Tiezhu

2017-03-01

Widespread use of bisphenol A (BPA) and other bisphenol analogues has attracted increasing attention for their potential adverse effects. As environmental endocrine-disrupting compounds (EDCs), bisphenols (BPs) may activate a variety of nuclear receptors, including glucocorticoid receptor (GR). In this work, the binding of 11 BPs to GR was investigated by fluorescence polarization (FP) assay in combination with molecular dynamics simulations. The human glucocorticoid receptor was prepared as a soluble recombinant protein. A fluorescein-labeled dexamethasone derivative (Dex-fl) was employed as tracer. Competitive displacement of Dex-fl from GR by BPs showed that the binding affinities of bisphenol analogues were largely dependent on their characteristic functional groups. In order to further understand the relationship between BPs structures and their GR-mediated activities, molecular docking was utilized to explore the binding modes at the atomic level. The results confirmed that structural variations of bisphenol analogues contributed to different interactions of BPs with GR, potentially causing distinct toxic effects. Comparison of the calculated binding energies vs. experimental binding affinities yielded a good correlation (R 2  = 0.8266), which might be helpful for the design of environmentally benign materials with reduced toxicities. In addition, the established FP assay based on GR exhibited the potential to offer an alternative to traditional methods for the detection of bisphenols.

Self-assembly kinetics of DNA functionalised liposomes

NASA Astrophysics Data System (ADS)

Mognetti, B. M.; Bachmann, S. J.; Kotar, J.; Parolini, L.; Petitzon, M.; Cicuta, P.; di Michele, L.

DNA has been largely used to program state-dependent interactions between functionalised Brownian units resulting in responsive systems featuring complex phase behaviours. In this talk I will show how DNA can also be used to control aggregation kinetics in systems of liposomes functionalised by three types of linkers that can simultaneously bind. In doing so, I will present a general coarse-graining strategy that allows calculating the adhesion free energy between pairs of compliant units functionalised by mobile binders. I will highlight the important role played by bilayer deformability and will calculate the free energy contribution due to the presence of complexes made by more than two binders. Finally we will demonstrate the importance of explicitly accounting for the kinetics underlying ligand-receptor reactions when studying large-scale self-assembly. We acknowledge support from ULB, the Oppenheimer Fund, and the EPSRC Programme Grant CAPITALS No. EP/J017566/1.

Functional importance of short-range binding and long-range solvent interactions in helical antifreeze peptides.

PubMed

Ebbinghaus, Simon; Meister, Konrad; Prigozhin, Maxim B; Devries, Arthur L; Havenith, Martina; Dzubiella, Joachim; Gruebele, Martin

2012-07-18

Short-range ice binding and long-range solvent perturbation both have been implicated in the activity of antifreeze proteins and antifreeze glycoproteins. We study these two mechanisms for activity of winter flounder antifreeze peptide. Four mutants are characterized by freezing point hysteresis (activity), circular dichroism (secondary structure), Förster resonance energy transfer (end-to-end rigidity), molecular dynamics simulation (structure), and terahertz spectroscopy (long-range solvent perturbation). Our results show that the short-range model is sufficient to explain the activity of our mutants, but the long-range model provides a necessary condition for activity: the most active peptides in our data set all have an extended dynamical hydration shell. It appears that antifreeze proteins and antifreeze glycoproteins have reached different evolutionary solutions to the antifreeze problem, utilizing either a few precisely positioned OH groups or a large quantity of OH groups for ice binding, assisted by long-range solvent perturbation. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

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

PubMed

Mucs, Daniel; Bryce, Richard A

2013-03-01

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

A Hot-Spot Motif Characterizes the Interface between a Designed Ankyrin-Repeat Protein and Its Target Ligand

PubMed Central

Cheung, Luthur Siu-Lun; Kanwar, Manu; Ostermeier, Marc; Konstantopoulos, Konstantinos

2012-01-01

Nonantibody scaffolds such as designed ankyrin repeat proteins (DARPins) can be rapidly engineered to detect diverse target proteins with high specificity and offer an attractive alternative to antibodies. Using molecular simulations, we predicted that the binding interface between DARPin off7 and its ligand (maltose binding protein; MBP) is characterized by a hot-spot motif in which binding energy is largely concentrated on a few amino acids. To experimentally test this prediction, we fused MBP to a transmembrane domain to properly orient the protein into a polymer-cushioned lipid bilayer, and characterized its interaction with off7 using force spectroscopy. Using this, to our knowledge, novel technique along with surface plasmon resonance, we validated the simulation predictions and characterized the effects of select mutations on the kinetics of the off7-MBP interaction. Our integrated approach offers scientific insights on how the engineered protein interacts with the target molecule. PMID:22325262

Theoretical studies of alkyl radicals in the NaY and HY zeolites.

PubMed

Ghandi, Khashayar; Zahariev, Federico E; Wang, Yan Alexander

2005-08-18

Interplay of quantum mechanical calculations and experimental data on hyperfine coupling constants of ethyl radical in zeolites at several temperatures was engaged to study the geometries and binding energies and to predict the temperature dependence of hyperfine splitting of a series of alkyl radicals in zeolites for the first time. The main focus is on the hyperfine interaction of alkyl radicals in the NaY and HY zeolites. The hyperfine splitting for neutral free radicals and free radical cations is predicted for different zeolite environments. This information can be used to establish the nature of the muoniated alkyl radicals in the NaY and HY zeolites via muSR experiments. The muon hyperfine coupling constants of the ethane radical cation in these zeolites are very large with relatively little dependence on temperature. It was found that the intramolecular dynamics of alkyl free radicals are only weakly affected by their strong binding to zeolites. In contrast, the substrate binding has a significant effect on their intermolecular dynamics.

The force-dependent mechanism of DnaK-mediated mechanical folding

PubMed Central

Perales-Calvo, Judit; Giganti, David; Stirnemann, Guillaume; Garcia-Manyes, Sergi

2018-01-01

It is well established that chaperones modulate the protein folding free-energy landscape. However, the molecular determinants underlying chaperone-mediated mechanical folding remain largely elusive, primarily because the force-extended unfolded conformation fundamentally differs from that characterized in biochemistry experiments. We use single-molecule force-clamp spectroscopy, combined with molecular dynamics simulations, to study the effect that the Hsp70 system has on the mechanical folding of three mechanically stiff model proteins. Our results demonstrate that, when working independently, DnaJ (Hsp40) and DnaK (Hsp70) work as holdases, blocking refolding by binding to distinct substrate conformations. Whereas DnaK binds to molten globule–like forms, DnaJ recognizes a cryptic sequence in the extended state in an unanticipated force-dependent manner. By contrast, the synergetic coupling of the Hsp70 system exhibits a marked foldase behavior. Our results offer unprecedented molecular and kinetic insights into the mechanisms by which mechanical force finely regulates chaperone binding, directly affecting protein elasticity. PMID:29487911

Can HN[double bond, length as m-dash]NH, FN[double bond, length as m-dash]NH, or HN[double bond, length as m-dash]CHOH bridge the σ-hole and the lone pair at P in binary complexes with H2XP, for X = F, Cl, NC, OH, CN, CCH, CH3, and H?

PubMed

Del Bene, Janet E; Alkorta, Ibon; Elguero, José

2015-11-11

Ab initio MP2/aug'-cc-pVTZ calculations have been carried out to investigate the properties of complexes formed between H2XP, for X = F, Cl, NC, OH, CN, CCH, CH3, and H, and the possible bridging molecules HN[double bond, length as m-dash]NH, FN[double bond, length as m-dash]NH, and HN[double bond, length as m-dash]CHOH. H2XP:HNNH and H2XP:FNNH complexes are stabilized by PN pnicogen bonds, except for H2(CH3)P:FNNH and H3P:FNNH which are stabilized by N-HP hydrogen bonds. H2XP:HNCHOH complexes are stabilized by PN pnicogen bonds and nonlinear O-HP hydrogen bonds. For a fixed H2XP molecule, binding energies decrease in the order HNCHOH > HNNH > FNNH, except for the binding energies of H2(CH3)P and H3P with HNNH and FNNH. Binding energies of complexes with HNCHOH and HNNH increase as the P-N1 distance decreases, but binding energies of complexes with FNNH show little dependence on this distance. The large binding energies of H2XP:HNCHOH complexes arise from a cooperative effect involving electron-pair acceptance by P to form a pnicogen bond, and electron-pair donation by P to form a hydrogen bond. The dominant charge-transfer interaction in these complexes involves electron-pair donation by N across the pnicogen bond, except for complexes in which X is one of the more electropositive substituents, CCH, CH3, and H. For these, lone-pair donation by P across the hydrogen bond dominates. AIM and NBO data for these complexes are consistent with their bonding characteristics, showing molecular graphs with bond critical points and charge-transfer interactions associated with hydrogen and pnicogen bonds. EOM-CCSD spin-spin coupling constants (1p)J(P-N) across the pnicogen bond for each series of complexes correlate with the P-N distance. In contrast, (2h)J(O-P) values for complexes H2XP:HNCHOH do not correlate with the O-P distance, a consequence of the nonlinearity of these hydrogen bonds.

On the applicability of one- and many-electron quantum chemistry models for hydrated electron clusters

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

Turi, László, E-mail: turi@chem.elte.hu

2016-04-21

We evaluate the applicability of a hierarchy of quantum models in characterizing the binding energy of excess electrons to water clusters. In particular, we calculate the vertical detachment energy of an excess electron from water cluster anions with methods that include one-electron pseudopotential calculations, density functional theory (DFT) based calculations, and ab initio quantum chemistry using MP2 and eom-EA-CCSD levels of theory. The examined clusters range from the smallest cluster size (n = 2) up to nearly nanosize clusters with n = 1000 molecules. The examined cluster configurations are extracted from mixed quantum-classical molecular dynamics trajectories of cluster anions withmore » n = 1000 water molecules using two different one-electron pseudopotenial models. We find that while MP2 calculations with large diffuse basis set provide a reasonable description for the hydrated electron system, DFT methods should be used with precaution and only after careful benchmarking. Strictly tested one-electron psudopotentials can still be considered as reasonable alternatives to DFT methods, especially in large systems. The results of quantum chemistry calculations performed on configurations, that represent possible excess electron binding motifs in the clusters, appear to be consistent with the results using a cavity structure preferring one-electron pseudopotential for the hydrated electron, while they are in sharp disagreement with the structural predictions of a non-cavity model.« less

On the applicability of one- and many-electron quantum chemistry models for hydrated electron clusters

NASA Astrophysics Data System (ADS)

Turi, László

2016-04-01

We evaluate the applicability of a hierarchy of quantum models in characterizing the binding energy of excess electrons to water clusters. In particular, we calculate the vertical detachment energy of an excess electron from water cluster anions with methods that include one-electron pseudopotential calculations, density functional theory (DFT) based calculations, and ab initio quantum chemistry using MP2 and eom-EA-CCSD levels of theory. The examined clusters range from the smallest cluster size (n = 2) up to nearly nanosize clusters with n = 1000 molecules. The examined cluster configurations are extracted from mixed quantum-classical molecular dynamics trajectories of cluster anions with n = 1000 water molecules using two different one-electron pseudopotenial models. We find that while MP2 calculations with large diffuse basis set provide a reasonable description for the hydrated electron system, DFT methods should be used with precaution and only after careful benchmarking. Strictly tested one-electron psudopotentials can still be considered as reasonable alternatives to DFT methods, especially in large systems. The results of quantum chemistry calculations performed on configurations, that represent possible excess electron binding motifs in the clusters, appear to be consistent with the results using a cavity structure preferring one-electron pseudopotential for the hydrated electron, while they are in sharp disagreement with the structural predictions of a non-cavity model.

A Direct Comparison of the MM-GB/SA Scoring Procedure and Free-Energy Perturbation Calculations Using Carbonic Anhydrase as a Test Case: Strengths and Pitfalls of Each Approach.

PubMed

Guimarães, Cristiano R W

2011-07-12

MM-GB/SA scoring and free energy perturbation (FEP) calculations have emerged as reliable methodologies to understand structural and energetic relationships to binding. In spite of successful applications to elucidate the structure-activity relationships for few pairs of ligands, the reality is that the performance of FEP calculations has rarely been tested for more than a handful of compounds. In this work, a series of 13 benzene sulfonamide inhibitors of carbonic anhydrase with binding free energies determined by isothermal titration calorimetry was selected as a test case. R(2) values of 0.70, 0.71, and 0.49 with the experiment were obtained with MM-GB/SA and FEP simulations run with MCPRO+ and Desmond, respectively. All methods work well, but the results obtained with Desmond are inferior to MM-GB/SA and MCPRO+. The main contrast between the methods is the level of sampling, ranging from full to restricted flexibility to single conformation for the complexes in Desmond, MCPRO+, and MM-GB/SA, respectively. The current and historical results obtained with MM-GB/SA qualify this approach as a more attractive alternative for rank-ordering; it can achieve equivalent or superior predictive accuracy and handle more structurally dissimilar ligands at a fraction of the computational cost of the rigorous free-energy methods. As for the large theoretical dynamic range for the binding energies, that seems to be a direct result of the degree of sampling in the simulations since MCPRO+ as well as MM-GB/SA are plagued by this. Van't Hoff analysis for selected pairs of ligands suggests that the wider scoring spread is not only affected by missing entropic contributions due to restricted sampling but also exaggerated enthalpic separation between the weak and potent compounds caused by diminished shielding of electrostatic interactions, thermal effects, and protein relaxation/strain.

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-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

Sampling protein motion and solvent effect during ligand binding

PubMed Central

Limongelli, Vittorio; Marinelli, Luciana; Cosconati, Sandro; La Motta, Concettina; Sartini, Stefania; Mugnaini, Laura; Da Settimo, Federico; Novellino, Ettore; Parrinello, Michele

2012-01-01

An exhaustive description of the molecular recognition mechanism between a ligand and its biological target is of great value because it provides the opportunity for an exogenous control of the related process. Very often this aim can be pursued using high resolution structures of the complex in combination with inexpensive computational protocols such as docking algorithms. Unfortunately, in many other cases a number of factors, like protein flexibility or solvent effects, increase the degree of complexity of ligand/protein interaction and these standard techniques are no longer sufficient to describe the binding event. We have experienced and tested these limits in the present study in which we have developed and revealed the mechanism of binding of a new series of potent inhibitors of Adenosine Deaminase. We have first performed a large number of docking calculations, which unfortunately failed to yield reliable results due to the dynamical character of the enzyme and the complex role of the solvent. Thus, we have stepped up the computational strategy using a protocol based on metadynamics. Our approach has allowed dealing with protein motion and solvation during ligand binding and finally identifying the lowest energy binding modes of the most potent compound of the series, 4-decyl-pyrazolo[1,5-a]pyrimidin-7-one. PMID:22238423

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.

Leptin does not mediate short-term fasting-induced changes in growth hormone pulsatility but increases IGF-I in leptin deficiency states.

PubMed

Chan, Jean L; Williams, Catherine J; Raciti, Patricia; Blakeman, Jennifer; Kelesidis, Theodore; Kelesidis, Iosif; Johnson, Michael L; Thorner, Michael O; Mantzoros, Christos S

2008-07-01

States of acute and chronic energy deficit are characterized by increased GH secretion and decreased IGF-I levels. The objective of the study was to determine whether changes in levels of leptin, a key mediator of the adaptation to starvation, regulate the GH-IGF system during energy deficit. We studied 14 healthy normal-weight men and women during three conditions: baseline fed and 72-h fasting (to induce hypoleptinemia) with administration of placebo or recombinant methionyl human leptin (r-metHuLeptin) (to reverse the fasting associated hypoleptinemia). We also studied eight normal-weight women with exercise-induced chronic energy deficit and hypothalamic amenorrhea at baseline and during 2-3 months of r-metHuLeptin treatment. GH pulsatility, IGF levels, IGF and GH binding protein (GHBP) levels were measured. During short-term energy deficit, measures of GH pulsatility and disorderliness and levels of IGF binding protein (IGFBP)-1 increased, whereas leptin, insulin, IGF-I (total and free), IGFBP-4, IGFBP-6, and GHBP decreased; r-metHuLeptin administration blunted the starvation-associated decrease of IGF-I. In chronic energy deficit, total and free IGF-I, IGFBP-6, and GHBP levels were lower, compared with euleptinemic controls; r-metHuLeptin administration had no major effect on GH pulsatility after 2 wk but increased total IGF-I levels and tended to increase free IGF-I and IGFBP-3 after 1 month. The GH/IGF system changes associated with energy deficit are largely independent of leptin deficiency. During acute energy deficit, r-metHuLeptin administration in replacement doses blunts the starvation-induced decrease of IGF-I, but during chronic energy deficit, r-metHuLeptin administration increases IGF-I and tends to increase free IGF-I and IGFBP-3.

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.

Accurate and reliable prediction of relative ligand binding potency in prospective drug discovery by way of a modern free-energy calculation protocol and force field.

PubMed

Wang, Lingle; Wu, Yujie; Deng, Yuqing; Kim, Byungchan; Pierce, Levi; Krilov, Goran; Lupyan, Dmitry; Robinson, Shaughnessy; Dahlgren, Markus K; Greenwood, Jeremy; Romero, Donna L; Masse, Craig; Knight, Jennifer L; Steinbrecher, Thomas; Beuming, Thijs; Damm, Wolfgang; Harder, Ed; Sherman, Woody; Brewer, Mark; Wester, Ron; Murcko, Mark; Frye, Leah; Farid, Ramy; Lin, Teng; Mobley, David L; Jorgensen, William L; Berne, Bruce J; Friesner, Richard A; Abel, Robert

2015-02-25

Designing tight-binding ligands is a primary objective of small-molecule drug discovery. Over the past few decades, free-energy calculations have benefited from improved force fields and sampling algorithms, as well as the advent of low-cost parallel computing. However, it has proven to be challenging to reliably achieve the level of accuracy that would be needed to guide lead optimization (∼5× in binding affinity) for a wide range of ligands and protein targets. Not surprisingly, widespread commercial application of free-energy simulations has been limited due to the lack of large-scale validation coupled with the technical challenges traditionally associated with running these types of calculations. Here, we report an approach that achieves an unprecedented level of accuracy across a broad range of target classes and ligands, with retrospective results encompassing 200 ligands and a wide variety of chemical perturbations, many of which involve significant changes in ligand chemical structures. In addition, we have applied the method in prospective drug discovery projects and found a significant improvement in the quality of the compounds synthesized that have been predicted to be potent. Compounds predicted to be potent by this approach have a substantial reduction in false positives relative to compounds synthesized on the basis of other computational or medicinal chemistry approaches. Furthermore, the results are consistent with those obtained from our retrospective studies, demonstrating the robustness and broad range of applicability of this approach, which can be used to drive decisions in lead optimization.

Endohedral metallofullerene Sc3NC@C84: a theoretical prediction.

PubMed

Wang, Dong-Lai; Xu, Hong-Liang; Su, Zhong-Min; Xin, Guang

2012-11-21

Very recently, two novel Sc(3)NC-based cluster fullerenes Sc(3)NC@C(80) (Wang et. al. J. Am. Chem. Soc. 2010, 132, 16362) and Sc(3)NC@C(78) (Wu et. al. J. Phys. Chem. C 2011, 115, 23755) were prepared and characterized, respectively. Inspired by these findings, the possibility of encapsulating Sc(3)NC cluster in the C(84) fullerene is performed using density functional theory (DFT). Firstly, the isolated pentagon rule (IPR) D(2d) (23) C(84) fullerene is employed to encase the Sc(3)NC cluster: four possible endohedral metallofullerene isomers a-d are designed. The large binding energies (ranging from 163.7 to 210.0 kcal mol(-1)) indicate that the planar quinary cluster Sc(3)NC can be stably encapsulated in the C(84) (isomer 23) cage. Further, we consider the incorporation of Sc(3)NC into the non-IPR C(s) (51365) C(84) cage leading to isomer e and show the high stability of isomer e, which has a larger binding energy, larger HOMO-LUMO gap, higher adiabatic (vertical) ionization potential, and lower adiabatic (vertical) electron affinity than the former four Sc(3)NC@C(84) (isomer 23). Significantly, the predicted binding energy (294.2 kcal mol(-1)) of isomer e is even larger than that (289.2 and 277.7 kcal mol(-1), respectively) of the synthesized Sc(3)NC@C(80) and Sc(3)NC@C(78,) suggesting a considerable possibility for experimental realization. The (13)C NMR chemical shifts and Raman spectra of this a new endofullerene have been explored to assist future experimental characterization.

Are Anion/π Interactions Actually a Case of Simple Charge–Dipole Interactions?†

PubMed Central

Wheeler, Steven E.; Houk, K. N.

2011-01-01

Substituent effects in Cl− ••• C6H6−nXn complexes, models for anion/π interactions, have been examined using density functional theory and robust ab initio methods paired with large basis sets. Predicted interaction energies for 83 model Cl− ••• C6H6−nXn complexes span almost 40 kcal mol−1 and show an excellent correlation (r = 0.99) with computed electrostatic potentials. In contrast to prevailing models of anion/π interactions, which rely on substituent-induced changes in the aryl π-system, it is shown that substituent effects in these systems are due mostly to direct interactions between the anion and the substituents. Specifically, interaction energies for Cl− ••• C6H6−nXn complexes are recovered using a model system in which the substituents are isolated from the aromatic ring and π-resonance effects are impossible. Additionally, accurate potential energy curves for Cl− interacting with prototypical anion-binding arenes can be qualitatively reproduced by adding a classical charge–dipole interaction to the Cl− ••• C6H6 interaction potential. In substituted benzenes, binding of anions arises primarily from interactions of the anion with the local dipoles induced by the substituents, not changes in the interaction with the aromatic ring itself. When designing anion-binding motifs, phenyl rings should be viewed as a scaffold upon which appropriate substituents can be placed, because there are no attractive interactions between anions and the aryl π-system of substituted benzenes. PMID:20433187

Multiexcitation Fluorogenic Labeling of Surface, Intracellular, and Total Protein Pools in Living Cells

PubMed Central

2016-01-01

Malachite green (MG) is a fluorogenic dye that shows fluorescence enhancement upon binding to its engineered cognate protein, a fluorogen activating protein (FAP). Energy transfer donors such as cyanine and rhodamine dyes have been conjugated with MG to modify the spectral properties of the fluorescent complexes, where the donor dyes transfer energy through Förster resonance energy transfer to the MG complex resulting in binding-conditional fluorescence emission in the far-red region. In this article, we use a violet-excitable dye as a donor to sensitize the far-red emission of the MG-FAP complex. Two blue emitting fluorescent coumarin dyes were coupled to MG and evaluated for energy transfer to the MG-FAP complex via its secondary excitation band. 6,8-Difluoro-7-hydroxycoumarin-3-carboxylic acid (Pacific blue, PB) showed the most efficient energy transfer and maximum brightness in the far-red region upon violet (405 nm) excitation. These blue-red (BluR) tandem dyes are spectrally varied from other tandem dyes and are able to produce fluorescence images of the MG-FAP complex with a large Stokes shift (>250 nm). These dyes are cell-permeable and are used to label intracellular proteins. Used together with a cell-impermeable hexa-Cy3-MG (HCM) dye that labels extracellular proteins, we are able to visualize extracellular, intracellular, and total pools of cellular protein using one fluorogenic tag that combines with distinct dyes to effect different spectral characteristics. PMID:27159569

Simulations of flow induced structural transition of the β-switch region of glycoprotein Ibα.

PubMed

Han, Mengzhi; Xu, Ji; Ren, Ying; Li, Jinghai

2016-02-01

Binding of glycoprotein Ibα to von Willebrand factor induces platelet adhesion to injured vessel walls and initiates a multistep hemostatic process. It has been hypothesized that the flow condition could induce a loop to β-sheet conformational change in the β-switch region of glycoprotein Ibα, which regulates it binding to the von Willebrand factor and facilitates the blood clot formation and wound healing. In this work, direct molecular dynamics (MD), flow MD and metadynamics, were employed to investigate the mechanisms of this flow induced conformational transition process. Specifically, the free energy landscape of the whole transition process was drawn by metadynamics with the path collective variable approach. The results reveal that without flow, the free energy landscape has two main basins, including a random loop basin stabilized by large conformational entropy and a partially folded β-sheet basin. The free energy barrier separating these two basins is relatively high and the β-switch could not fold from loop to β-sheet state spontaneously. The fully β-sheet conformations located in high free energy regions, which are also unstable and gradually unfold into partially folded β-sheet state with flow. Relatively weak flow could trigger some folding of the β-switch but could not fold it into fully β-sheet state. Under strong flow conditions, the β-switch could readily overcome the high free energy barrier and fold into fully β-sheet state. Copyright © 2015 Elsevier B.V. All rights reserved.

Calculation of absolute protein-ligand binding free energy using distributed replica sampling.

PubMed

Rodinger, Tomas; Howell, P Lynne; Pomès, Régis

2008-10-21

Distributed replica sampling [T. Rodinger et al., J. Chem. Theory Comput. 2, 725 (2006)] is a simple and general scheme for Boltzmann sampling of conformational space by computer simulation in which multiple replicas of the system undergo a random walk in reaction coordinate or temperature space. Individual replicas are linked through a generalized Hamiltonian containing an extra potential energy term or bias which depends on the distribution of all replicas, thus enforcing the desired sampling distribution along the coordinate or parameter of interest regardless of free energy barriers. In contrast to replica exchange methods, efficient implementation of the algorithm does not require synchronicity of the individual simulations. The algorithm is inherently suited for large-scale simulations using shared or heterogeneous computing platforms such as a distributed network. In this work, we build on our original algorithm by introducing Boltzmann-weighted jumping, which allows moves of a larger magnitude and thus enhances sampling efficiency along the reaction coordinate. The approach is demonstrated using a realistic and biologically relevant application; we calculate the standard binding free energy of benzene to the L99A mutant of T4 lysozyme. Distributed replica sampling is used in conjunction with thermodynamic integration to compute the potential of mean force for extracting the ligand from protein and solvent along a nonphysical spatial coordinate. Dynamic treatment of the reaction coordinate leads to faster statistical convergence of the potential of mean force than a conventional static coordinate, which suffers from slow transitions on a rugged potential energy surface.

Fermi-edge exciton-polaritons in doped semiconductor microcavities with finite hole mass

NASA Astrophysics Data System (ADS)

Pimenov, Dimitri; von Delft, Jan; Glazman, Leonid; Goldstein, Moshe

2017-10-01

The coupling between a 2D semiconductor quantum well and an optical cavity gives rise to combined light-matter excitations, the exciton-polaritons. These were usually measured when the conduction band is empty, making the single polariton physics a simple single-body problem. The situation is dramatically different in the presence of a finite conduction-band population, where the creation or annihilation of a single exciton involves a many-body shakeup of the Fermi sea. Recent experiments in this regime revealed a strong modification of the exciton-polariton spectrum. Previous theoretical studies concerned with nonzero Fermi energy mostly relied on the approximation of an immobile valence-band hole with infinite mass, which is appropriate for low-mobility samples only; for high-mobility samples, one needs to consider a mobile hole with large but finite mass. To bridge this gap, we present an analytical diagrammatic approach and tackle a model with short-ranged (screened) electron-hole interaction, studying it in two complementary regimes. We find that the finite hole mass has opposite effects on the exciton-polariton spectra in the two regimes: in the first, where the Fermi energy is much smaller than the exciton binding energy, excitonic features are enhanced by the finite mass. In the second regime, where the Fermi energy is much larger than the exciton binding energy, finite mass effects cut off the excitonic features in the polariton spectra, in qualitative agreement with recent experiments.

Calculation of absolute protein-ligand binding free energy using distributed replica sampling

NASA Astrophysics Data System (ADS)

Rodinger, Tomas; Howell, P. Lynne; Pomès, Régis

2008-10-01

Distributed replica sampling [T. Rodinger et al., J. Chem. Theory Comput. 2, 725 (2006)] is a simple and general scheme for Boltzmann sampling of conformational space by computer simulation in which multiple replicas of the system undergo a random walk in reaction coordinate or temperature space. Individual replicas are linked through a generalized Hamiltonian containing an extra potential energy term or bias which depends on the distribution of all replicas, thus enforcing the desired sampling distribution along the coordinate or parameter of interest regardless of free energy barriers. In contrast to replica exchange methods, efficient implementation of the algorithm does not require synchronicity of the individual simulations. The algorithm is inherently suited for large-scale simulations using shared or heterogeneous computing platforms such as a distributed network. In this work, we build on our original algorithm by introducing Boltzmann-weighted jumping, which allows moves of a larger magnitude and thus enhances sampling efficiency along the reaction coordinate. The approach is demonstrated using a realistic and biologically relevant application; we calculate the standard binding free energy of benzene to the L99A mutant of T4 lysozyme. Distributed replica sampling is used in conjunction with thermodynamic integration to compute the potential of mean force for extracting the ligand from protein and solvent along a nonphysical spatial coordinate. Dynamic treatment of the reaction coordinate leads to faster statistical convergence of the potential of mean force than a conventional static coordinate, which suffers from slow transitions on a rugged potential energy surface.

AMMOS2: a web server for protein-ligand-water complexes refinement via molecular mechanics.

PubMed

Labbé, Céline M; Pencheva, Tania; Jereva, Dessislava; Desvillechabrol, Dimitri; Becot, Jérôme; Villoutreix, Bruno O; Pajeva, Ilza; Miteva, Maria A

2017-07-03

AMMOS2 is an interactive web server for efficient computational refinement of protein-small organic molecule complexes. The AMMOS2 protocol employs atomic-level energy minimization of a large number of experimental or modeled protein-ligand complexes. The web server is based on the previously developed standalone software AMMOS (Automatic Molecular Mechanics Optimization for in silico Screening). AMMOS utilizes the physics-based force field AMMP sp4 and performs optimization of protein-ligand interactions at five levels of flexibility of the protein receptor. The new version 2 of AMMOS implemented in the AMMOS2 web server allows the users to include explicit water molecules and individual metal ions in the protein-ligand complexes during minimization. The web server provides comprehensive analysis of computed energies and interactive visualization of refined protein-ligand complexes. The ligands are ranked by the minimized binding energies allowing the users to perform additional analysis for drug discovery or chemical biology projects. The web server has been extensively tested on 21 diverse protein-ligand complexes. AMMOS2 minimization shows consistent improvement over the initial complex structures in terms of minimized protein-ligand binding energies and water positions optimization. The AMMOS2 web server is freely available without any registration requirement at the URL: http://drugmod.rpbs.univ-paris-diderot.fr/ammosHome.php. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

AMMOS2: a web server for protein–ligand–water complexes refinement via molecular mechanics

PubMed Central

Labbé, Céline M.; Pencheva, Tania; Jereva, Dessislava; Desvillechabrol, Dimitri; Becot, Jérôme; Villoutreix, Bruno O.; Pajeva, Ilza

2017-01-01

Abstract AMMOS2 is an interactive web server for efficient computational refinement of protein–small organic molecule complexes. The AMMOS2 protocol employs atomic-level energy minimization of a large number of experimental or modeled protein–ligand complexes. The web server is based on the previously developed standalone software AMMOS (Automatic Molecular Mechanics Optimization for in silico Screening). AMMOS utilizes the physics-based force field AMMP sp4 and performs optimization of protein–ligand interactions at five levels of flexibility of the protein receptor. The new version 2 of AMMOS implemented in the AMMOS2 web server allows the users to include explicit water molecules and individual metal ions in the protein–ligand complexes during minimization. The web server provides comprehensive analysis of computed energies and interactive visualization of refined protein–ligand complexes. The ligands are ranked by the minimized binding energies allowing the users to perform additional analysis for drug discovery or chemical biology projects. The web server has been extensively tested on 21 diverse protein–ligand complexes. AMMOS2 minimization shows consistent improvement over the initial complex structures in terms of minimized protein–ligand binding energies and water positions optimization. The AMMOS2 web server is freely available without any registration requirement at the URL: http://drugmod.rpbs.univ-paris-diderot.fr/ammosHome.php. PMID:28486703

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.

Thermodynamics for the interaction of epsilon-dinitrophenyl-L-lysine and bovine colostral anti-dinitrophenyl immunoglobulin G2.

PubMed Central

Mukkur, T K

1978-01-01

The effect of varying the temperature over a wide range (4--60 degrees C) on the binding of epsilon-dinitrophenyl-L-lysine to bovine colostral anti-dinitrophenyl immunoglobulin G2 yielded a non-linear van't Hoff plot. The extent of curvature was indicative of a large positive heat-capacity change, and the thermodynamic parameters, calculated by using a non-linear least squares computer procedure, revealed an enthalpy--entropy-compensation mechanism for hapten-antibody binding. The enthalpy factor was found to be the primary contributor for the complex-formation at low temperatures, but at increasing temperatures the entropy factor assumed greater importance. At physiological temperature (39 degrees C), the entropy factor was the major contributor to the free energy of reaction. PMID:687378

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).

Computational investigation of the HIV-1 Rev multimerization using molecular dynamics simulations and binding free energy calculations.

PubMed

Venken, Tom; Daelemans, Dirk; De Maeyer, Marc; Voet, Arnout

2012-06-01

The HIV Rev protein mediates the nuclear export of viral mRNA, and is thereby essential for the production of late viral proteins in the replication cycle. Rev forms a large organized multimeric protein-protein complex for proper functioning. Recently, the three-dimensional structures of a Rev dimer and tetramer have been resolved and provide the basis for a thorough structural analysis of the binding interaction. Here, molecular dynamics (MD) and binding free energy calculations were performed to elucidate the forces thriving dimerization and higher order multimerization of the Rev protein. It is found that despite the structural differences between each crystal structure, both display a similar behavior according to our calculations. Our analysis based on a molecular mechanics-generalized Born surface area (MM/GBSA) and a configurational entropy approach demonstrates that the higher order multimerization site is much weaker than the dimerization site. In addition, a quantitative hot spot analysis combined with a mutational analysis reveals the most contributing amino acid residues for protein interactions in agreement with experimental results. Additional residues were found in each interface, which are important for the protein interaction. The investigation of the thermodynamics of the Rev multimerization interactions performed here could be a further step in the development of novel antiretrovirals using structure based drug design. Moreover, the variability of the angle between each Rev monomer as measured during the MD simulations suggests a role of the Rev protein in allowing flexibility of the arginine rich domain (ARM) to accommodate RNA binding. Copyright © 2012 Wiley Periodicals, Inc.

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

NASA Astrophysics Data System (ADS)

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

2016-09-01

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

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

PubMed

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

2016-09-01

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

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

Crowding-Induced Mixing Behavior of Lipid Bilayers: Examination of Mixing Energy, Phase, Packing Geometry, and Reversibility.

PubMed

Zeno, Wade F; Rystov, Alice; Sasaki, Darryl Y; Risbud, Subhash H; Longo, Marjorie L

2016-05-10

In an effort to develop a general thermodynamic model from first-principles to describe the mixing behavior of lipid membranes, we examined lipid mixing induced by targeted binding of small (Green Fluorescent Protein (GFP)) and large (nanolipoprotein particles (NLPs)) structures to specific phases of phase-separated lipid bilayers. Phases were targeted by incorporation of phase-partitioning iminodiacetic acid (IDA)-functionalized lipids into ternary lipid mixtures consisting of DPPC, DOPC, and cholesterol. GFP and NLPs, containing histidine tags, bound the IDA portion of these lipids via a metal, Cu(2+), chelating mechanism. In giant unilamellar vesicles (GUVs), GFP and NLPs bound to the Lo domains of bilayers containing DPIDA, and bound to the Ld region of bilayers containing DOIDA. At sufficiently large concentrations of DPIDA or DOIDA, lipid mixing was induced by bound GFP and NLPs. The validity of the thermodynamic model was confirmed when it was found that the statistical mixing distribution as a function of crowding energy for smaller GFP and larger NLPs collapsed to the same trend line for each GUV composition. Moreover, results of this analysis show that the free energy of mixing for a ternary lipid bilayer consisting of DOPC, DPPC, and cholesterol varied from 7.9 × 10(-22) to 1.5 × 10(-20) J/lipid at the compositions observed, decreasing as the relative cholesterol concentration was increased. It was discovered that there appears to be a maximum packing density, and associated maximum crowding pressure, of the NLPs, suggestive of circular packing. A similarity in mixing induced by NLP1 and NLP3 despite large difference in projected areas was analytically consistent with monovalent (one histidine tag) versus divalent (two histidine tags) surface interactions, respectively. In addition to GUVs, binding and induced mixing behavior of NLPs was also observed on planar, supported lipid multibilayers. The mixing process was reversible, with Lo domains reappearing after addition of EDTA for NLP removal.

Crowding-induced mixing behavior of lipid bilayers: Examination of mixing energy, phase, packing geometry, and reversibility

DOE PAGES

Zeno, Wade F.; Rystov, Alice; Sasaki, Darryl Y.; ...

2016-04-20

In an effort to develop a general thermodynamic model from first-principles to describe the mixing behavior of lipid membranes, we examined lipid mixing induced by targeted binding of small (Green Fluorescent Protein (GFP)) and large (nanolipoprotein particles (NLPs)) structures to specific phases of phase-separated lipid bilayers. Phases were targeted by incorporation of phase-partitioning iminodiacetic acid (IDA)-functionalized lipids into ternary lipid mixtures consisting of DPPC, DOPC, and cholesterol. GFP and NLPs, containing histidine tags, bound the IDA portion of these lipids via a metal, Cu 2+, chelating mechanism. In giant unilamellar vesicles (GUVs), GFP and NLPs bound to the Lo domainsmore » of bilayers containing DPIDA, and bound to the Ld region of bilayers containing DOIDA. At sufficiently large concentrations of DPIDA or DOIDA, lipid mixing was induced by bound GFP and NLPs. The validity of the thermodynamic model was confirmed when it was found that the statistical mixing distribution as a function of crowding energy for smaller GFP and larger NLPs collapsed to the same trend line for each GUV composition. Moreover, results of this analysis show that the free energy of mixing for a ternary lipid bilayer consisting of DOPC, DPPC, and cholesterol varied from 7.9 × 10 –22 to 1.5 × 10 –20 J/lipid at the compositions observed, decreasing as the relative cholesterol concentration was increased. It was discovered that there appears to be a maximum packing density, and associated maximum crowding pressure, of the NLPs, suggestive of circular packing. A similarity in mixing induced by NLP1 and NLP3 despite large difference in projected areas was analytically consistent with monovalent (one histidine tag) versus divalent (two histidine tags) surface interactions, respectively. In addition to GUVs, binding and induced mixing behavior of NLPs was also observed on planar, supported lipid multibilayers. Furthermore, the mixing process was reversible, with Lo domains reappearing after addition of EDTA for NLP removal.« less

Crowding-induced mixing behavior of lipid bilayers: Examination of mixing energy, phase, packing geometry, and reversibility

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

Zeno, Wade F.; Rystov, Alice; Sasaki, Darryl Y.

In an effort to develop a general thermodynamic model from first-principles to describe the mixing behavior of lipid membranes, we examined lipid mixing induced by targeted binding of small (Green Fluorescent Protein (GFP)) and large (nanolipoprotein particles (NLPs)) structures to specific phases of phase-separated lipid bilayers. Phases were targeted by incorporation of phase-partitioning iminodiacetic acid (IDA)-functionalized lipids into ternary lipid mixtures consisting of DPPC, DOPC, and cholesterol. GFP and NLPs, containing histidine tags, bound the IDA portion of these lipids via a metal, Cu 2+, chelating mechanism. In giant unilamellar vesicles (GUVs), GFP and NLPs bound to the Lo domainsmore » of bilayers containing DPIDA, and bound to the Ld region of bilayers containing DOIDA. At sufficiently large concentrations of DPIDA or DOIDA, lipid mixing was induced by bound GFP and NLPs. The validity of the thermodynamic model was confirmed when it was found that the statistical mixing distribution as a function of crowding energy for smaller GFP and larger NLPs collapsed to the same trend line for each GUV composition. Moreover, results of this analysis show that the free energy of mixing for a ternary lipid bilayer consisting of DOPC, DPPC, and cholesterol varied from 7.9 × 10 –22 to 1.5 × 10 –20 J/lipid at the compositions observed, decreasing as the relative cholesterol concentration was increased. It was discovered that there appears to be a maximum packing density, and associated maximum crowding pressure, of the NLPs, suggestive of circular packing. A similarity in mixing induced by NLP1 and NLP3 despite large difference in projected areas was analytically consistent with monovalent (one histidine tag) versus divalent (two histidine tags) surface interactions, respectively. In addition to GUVs, binding and induced mixing behavior of NLPs was also observed on planar, supported lipid multibilayers. Furthermore, the mixing process was reversible, with Lo domains reappearing after addition of EDTA for NLP removal.« less

Energy and structure of bonds in the interaction of organic anions with layered double hydroxide nanosheets: A molecular dynamics study

NASA Astrophysics Data System (ADS)

Tsukanov, A. A.; Psakhie, S. G.

2016-01-01

The application of hybrid and hierarchical nanomaterials based on layered hydroxides and oxyhydroxides of metals is a swiftly progressing field in biomedicine. Layered double hydroxides (LDH) possess a large specific surface area, significant surface electric charge and biocompatibility. Their physical and structural properties enable them to adsorb various kinds of anionic species and to transport them into cells. However, possible side effects resulting from the interaction of LDH with anions of the intercellular and intracellular medium need to be considered, since such interaction can potentially disrupt ion transport, signaling processes, apoptosis, nutrition and proliferation of living cells. In the present paper molecular dynamics is used to determine the energies of interaction of organic anions (aspartic acid, glutamic acid and bicarbonate) with a fragment of layered double hydroxide Mg/Al-LDH. The average number of hydrogen bonds between the anions and the hydroxide surface and characteristic binding configurations are determined. Possible effects of LDH on the cell resulting from binding of protein fragments and replacement of native intracellular anions with delivered anions are considered.

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

Stier, Andreas V.; McCreary, Kathleen M.; Jonker, Berend T.

In bulk and quantum-confined semiconductors, magneto-optical studies have historically played an essential role in determining the fundamental parameters of excitons (size, binding energy, spin, dimensionality and so on). Here we report low-temperature polarized reflection spectroscopy of atomically thin WS 2 and MoS 2 in high magnetic fields to 65 T. Both the A and B excitons exhibit similar Zeeman splittings of approximately –230 μeV T–1 (g-factor ≃–4), thereby quantifying the valley Zeeman effect in monolayer transition-metal disulphides. Crucially, these large fields also allow observation of the small quadratic diamagnetic shifts of both A and B excitons in monolayer WS 2,more » from which radii of ~1.53 and ~1.16 nm are calculated. Further, when analysed within a model of non-local dielectric screening, these diamagnetic shifts also constrain estimates of the A and B exciton binding energies (410 and 470 meV, respectively, using a reduced A exciton mass of 0.16 times the free electron mass). Lastly, these results highlight the utility of high magnetic fields for understanding new two-dimensional materials.« less

Exciton diamagnetic shifts and valley Zeeman effects in monolayer WS2 and MoS2 to 65 Tesla

NASA Astrophysics Data System (ADS)

Stier, Andreas V.; McCreary, Kathleen M.; Jonker, Berend T.; Kono, Junichiro; Crooker, Scott A.

2016-02-01

In bulk and quantum-confined semiconductors, magneto-optical studies have historically played an essential role in determining the fundamental parameters of excitons (size, binding energy, spin, dimensionality and so on). Here we report low-temperature polarized reflection spectroscopy of atomically thin WS2 and MoS2 in high magnetic fields to 65 T. Both the A and B excitons exhibit similar Zeeman splittings of approximately -230 μeV T-1 (g-factor ~=-4), thereby quantifying the valley Zeeman effect in monolayer transition-metal disulphides. Crucially, these large fields also allow observation of the small quadratic diamagnetic shifts of both A and B excitons in monolayer WS2, from which radii of ~1.53 and ~1.16 nm are calculated. Further, when analysed within a model of non-local dielectric screening, these diamagnetic shifts also constrain estimates of the A and B exciton binding energies (410 and 470 meV, respectively, using a reduced A exciton mass of 0.16 times the free electron mass). These results highlight the utility of high magnetic fields for understanding new two-dimensional materials.

Direct Observation of Electron-Phonon Coupling and Slow Vibrational Relaxation in Organic-Inorganic Hybrid Perovskites.

PubMed

Straus, Daniel B; Hurtado Parra, Sebastian; Iotov, Natasha; Gebhardt, Julian; Rappe, Andrew M; Subotnik, Joseph E; Kikkawa, James M; Kagan, Cherie R

2016-10-05

Quantum and dielectric confinement effects in 2D hybrid perovskites create excitons with a binding energy exceeding 150 meV. We exploit the large exciton binding energy to study exciton and carrier dynamics as well as electron-phonon coupling in hybrid perovskites using absorption and photoluminescence (PL) spectroscopies. At temperatures below 75 K, we resolve splitting of the excitonic absorption and PL into multiple regularly-spaced resonances every 40-46 meV, consistent with electron-phonon coupling to phonons located on the organic cation. We also resolve resonances with a 14 meV spacing, in accord with coupling to phonons with mixed organic and inorganic character, and these assignments are supported by density-functional theory calculations. Hot exciton PL and time-resolved PL measurements show that vibrational relaxation occurs on a picosecond timescale competitive with that for PL. At temperatures above 75 K, excitonic absorption and PL exhibit homogeneous broadening. While absorption remains homogeneous, PL becomes inhomogeneous below 75K, which we speculate is caused by the formation and subsequent dynamics of a polaronic exciton.

First-Principles Study of Electronic Structure and Hydrogen Adsorption of 3d Transition Metal Exposed Paddle Wheel Frameworks

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

Bak, J. H.; Le, V. D.; Kang, J.

2012-04-05

Open-site paddle wheels, comprised of two transition metals bridged with four carboxylate ions, have been widely used for constructing metal-organic frameworks with large surface area and high binding energy sites. Using first-principles density functional theory calculations, we have investigated atomic and electronic structures of various 3d transition metal paddle wheels before and after metal exposure and their hydrogen adsorption properties at open metal sites. Notably, the hydrogen adsorption is impeded by covalent metal-metal bonds in early transition metal paddle wheels from Sc to Cr and by the strong ferromagnetic coupling of diatomic Mn and Fe in the paddle wheel configurations.more » A significantly enhanced H{sub 2} adsorption is predicted in the nonmagnetic Co{sub 2} and Zn{sub 2} paddle wheel with the binding energy of {approx}0.2 eV per H{sub 2}. We also propose the use of two-dimensional Co{sub 2} and Zn{sub 2} paddle wheel frameworks that could have strongly adsorbed dihydrogen up to 1.35 wt % for noncryogenic hydrogen storage applications.« less

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.

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.