With a view to improving the consistency of free energy perturbation calculations in Monte Carlo simulations of protein-ligand complexes, we have implemented the replica exchange with solute tempering (REST) method in the MCPRO software. By augmenting the standard REST approach with regular attempted jumps in selected dihedral angles, our combined method facilitates sampling of ligand binding modes that are separated by high free energy barriers and ensures that computed free energy changes are considerably less dependent on the starting conditions and the chosen mutation pathway than those calculated with standard Monte Carlo sampling. We have applied the enhanced sampling method to the calculation of the activities of seven non-nucleoside inhibitors of HIV-1 reverse transcriptase, and its Tyr181Cys variant, and have shown that a range of binding orientations is possible depending on the nature of the ligand and the presence of mutations at the binding site.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStructure and Binding for Complexes of Rebek's Acridine Diacid with Pyrazine, Quinoxaline, and Pyridine from Monte Carlo Simulations with an All-Atom Force FieldErin M. Duffy and William L. JorgensenCite this: J. Am. Chem. Soc. 1994, 116, 14, 6337–6343Publication Date (Print):July 1, 1994Publication History Published online1 May 2002Published inissue 1 July 1994https://pubs.acs.org/doi/10.1021/ja00093a038https://doi.org/10.1021/ja00093a038research-articleACS PublicationsRequest reuse permissionsArticle Views198Altmetric-Citations18LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (2)»Supporting Information Supporting Information Get e-Alerts
No abstract is provided for this article.
No abstract is provided for this article.
Monte Carlo statistical mechanics simulations have been carried out for liquid tetrahydrofuran (THF) with and without pseudorotation at 1 atm and 25 °C. The intermolecular potential functions consisted of Lennard-Jones and Coulomb terms in the TIPS format reported previously for ethers. Pseudorotation of the ring was described using the generalized coordinates defined by Cremer and Pople, viz., the puckering amplitude and the phase angle of the ring. The corresponding intramolecular potential function was derived from molecular mechanics (MM2) calculations. Compared to the gas phase, the rings tend to be more flat and the population of the C2 twist geometry is slightly higher in liquid THF. However, pseudorotation has negligible effect on the calculated intermolecular structure and thermodynamic properties. The computed density, heat of vaporization, and heat capacity are in good agreement with experiment. The results are also compared with those from previous simulations of acyclic ethers. The present study provides the foundation for investigations of the solvating ability of THF.
Monte Carlo simulations have been used to determine changes in free energies of solvation for the rearrangement of chorismate to prephenate in water and methanol. Structures and partial charges from the ab initio RHF/6-31G* calculations of Wiest and Houk were used for the pseudodiequatorial and pseudodiaxial conformers of chorismate and for the transition structure. Free energy perturbation calculations yielded the differences in free energies of solvation for the three structures. The calculations reproduce the observed 100-fold rate increase in water over methanol. The origin of the rate difference is traced solely to an enhanced population of the pseudodiaxial conformer in water, which arises largely from a unique water molecule acting as a double hydrogen bond donor to the C4 hydroxyl group and the side-chain carboxylate. A Monte Carlo simulation was also carried out for the transition structure bound to E. coli chorismate mutase in order to characterize the key interactions in the active site. Consistent with earlier computational results for the Claisen rearrangement of allyl vinyl ether and inferences from crystal structures, the Monte Carlo simulations reveal two hydrogen bonds to the enolic oxygen in the transition structure for both the uncatalyzed reaction in water and the enzyme-catalyzed rearrangement.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMonte Carlo Results for the Effect of Solvation on the Anomeric Equilibrium for 2-MethoxytetrahydropyranWilliam L. Jorgensen, Patricia I. Morales de Tirado, and Daniel L. SeveranceCite this: J. Am. Chem. Soc. 1994, 116, 5, 2199–2200Publication Date (Print):March 1, 1994Publication History Published online1 May 2002Published inissue 1 March 1994https://pubs.acs.org/doi/10.1021/ja00084a092https://doi.org/10.1021/ja00084a092research-articleACS PublicationsRequest reuse permissionsArticle Views120Altmetric-Citations47LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (2)»Supporting Information Supporting Information Get e-Alerts
Current "second-generation" force fields have been developed for use in Monte Carlo and molecular dynamics simulations for organic and biomolecular systems in solution. The performance of three such force fields, AMBER94, MMFF94, and OPLS-AA, is tested here through Monte Carlo (MC) statistical mechanics simulations for liquid butane, methanol, and N-methylacetamide (NMA). These liquids were chosen for their range of polarity and their representation of typical interactions found in proteins. From simulations at constant temperature and 1 atm pressure, the average errors in the computed densities and heats of vaporization are 3.8% and 5.1% with AMBER94 and 1.5% and 1.3% with OPLS-AA. With MMFF94, the computed densities and heats of vaporization for methanol and NMA are too low by 21−27%, while butane at −0.5 °C does not stop expanding during the simulation. A MC simulation using MMFF94 for butane with the density fixed at the experimental value yields a 32% error in the energy of vaporization. Analyses show that the optimal C−H and H−H nonbonded interactions with MMFF94 are too weak and occur at too large separations. Scaling of the MMFF94 parameter Ai, which is linearly related to the atomic radii, by 0.92 yields improved results for liquid butane.
No abstract is provided for this article.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTComputer-assisted mechanistic evaluation of organic reactions. 2. Perception of rings, aromaticity, and tautomersBarbara L. Roos-Kozel and William L. JorgensenCite this: J. Chem. Inf. Comput. Sci. 1981, 21, 2, 101–111Publication Date (Print):May 1, 1981Publication History Published online1 May 2002Published inissue 1 May 1981https://pubs.acs.org/doi/10.1021/ci00030a010https://doi.org/10.1021/ci00030a010research-articleACS PublicationsRequest reuse permissionsArticle Views179Altmetric-Citations20LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access options Get e-Alerts
Monte Carlo statistical mechanics simulations were used in combination with the extended linear response (ELR) approach to develop a model to predict the activities of kinase inhibitors. One hundred forty eight inhibitors of three protein kinases, cyclin-dependent kinase 2 (CDK2), lymphocyte-specific kinase (Lck), and p38 mitogen-activated protein kinase were considered. The inhibitor sets for the individual kinases were analyzed first, and ELR models using only three descriptors were obtained with correlation coefficients, r2, of 0.7−0.8. Models for each pair of kinases were then developed and used to predict the activities of the inhibitors for the remaining kinase with resultant q2 values of 0.71 (CDK2), 0.70 (Lck), and 0.54 (p38). Finally, the three datasets were combined to yield a general ELR model for kinase inhibition; with just three physically reasonable descriptors, EXX, ΔHBtotal, and ΔSASA, the r2 and leave-one-out q2 are 0.69 and 0.67. The optimization of the model was confirmed using a genetic algorithm. The descriptors reflect the structural requirements for strong inhibition: good steric and electrostatic complementarities between inhibitor and protein, limited loss of hydrogen bonds for the inhibitor upon binding, and increased burial of surface area of the inhibitor.
