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Monte Carlo statistical mechanics simulations have been carried out with the TIP3P, SPC, and TIP4P models for liquid water at 13 temperatures from −50°C to 100°C at 1 atm. Long runs with 512 water molecules provided definitive results for densities. Although the TIP4P model yields a flat region in the density profile and a temperature of maximum density near −15°C, the SPC and TIP3P models show monotonically increasing density with decreasing temperature. Results for heats of vaporization, isothermal compressibilities, and coefficients of thermal expansion and their convergence characteristics are also reported. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1179–1186, 1998
The effect of the K103N mutation of HIV-1 reverse transcriptase (RT) on the activity of efavirenz analogues was studied via Monte Carlo/free energy perturbation calculations. The relative fold resistance energies indicate that efavirenz binds to K103N RT in a manner similar to the wild-type enzyme. The improved performance of the quinazolinones against the mutant enzyme is attributed to formation of a more optimal hydrogen-bonding network with bridging water molecules between the ligands and Glu138.
A modified derivation of the free energy perturbation (FEP) equation leads to a more general interpretation of the procedures for generating the geometry of a perturbed molecule from the reference one in FEP simulations of flexible systems. Using this form of the equation, it is possible to implement a wide variety of procedures which heretofore would have been considered impossible. A new method, generalized alteration of structure and parameters (GASP), has been implemented in the BOSS program and has been found to be more efficient for perturbations of harmonic degrees of freedom than the commonly adopted procedure. Additionally, an extreme example for which the new procedure proves less satisfactory is presented, and a more efficient method which is also derived from the new form of the FEP equation is devised and tested. It is concluded that the key to a convergent FEP method is efficient sampling of low‐energy configurations of the perturbed state; the new form of the equation suggests ways of generating such configurations. © 1995 by John Wiley & Sons, Inc.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA priori pKa calculations and the hydration of organic anionsWilliam L. Jorgensen and James M. BriggsCite this: J. Am. Chem. Soc. 1989, 111, 12, 4190–4197Publication Date (Print):June 1, 1989Publication History Published online1 May 2002Published inissue 1 June 1989https://pubs.acs.org/doi/10.1021/ja00194a007https://doi.org/10.1021/ja00194a007research-articleACS PublicationsRequest reuse permissionsArticle Views971Altmetric-Citations123LEARN 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 (1)»Supporting Information Supporting Information 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.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTFree energy calculations: a breakthrough for modeling organic chemistry in solutionWilliam L. JorgensenCite this: Acc. Chem. Res. 1989, 22, 5, 184–189Publication Date (Print):May 1, 1989Publication History Published online1 May 2002Published inissue 1 May 1989https://pubs.acs.org/doi/10.1021/ar00161a004https://doi.org/10.1021/ar00161a004research-articleACS PublicationsRequest reuse permissionsArticle Views2493Altmetric-Citations558LEARN 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-Alertsclose Get e-Alerts
Substituted N-phenylbenzisothiazolones have been investigated as inhibitors of the tautomerase activity of the proinflammatory cytokine MIF (macrophage migration inhibitory factor). Numerous compounds were found to possess antagonist activity in the low micromolar range with the most potent being the 6-hydroxy analog 1w. Compound 1w and the p-cyano analog 1c were also shown to exhibit significant inhibition of the binding of MIF to its transmembrane receptor CD74. Consistently, both compounds were also found to retard the MIF-dependent phosphorylation of ERK1/2 in human synovial fibroblasts.
