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To seek vancomycin analogs with broader antibacterial activity, effects of backbone modifications for the agylcon 2 on binding with d-Ala-d-Ala- and d-Ala-d-Lac-containing peptides were investigated by Monte Carlo/free energy perturbation (MC/FEP) calculations. The experimental trend in binding affinities for 2 with three tripeptides was well reproduced. Possible modifications of the peptide bond between residues 4 and 5 were then considered, specifically for conversion of the OCNH linkage to CH2NH2 + (6), FCCH (7), HCCH (8), and HNCO (9). The MC/FEP results did not yield binding improvements for 7, 8, and 9, though the fluorovinyl replacement is relatively benign. The previously reported analog 6 remains as the only variant that exhibits improved affinity for the d-Ala-d-Lac sequence and acceptable affinity for the d-Ala-d-Ala sequence.
No abstract is provided for this article.
Due to the importance of water in chemical and biological systems, a coarse-grained representation of the solvent can greatly simplify the description of the system while retaining key thermodynamic properties of the medium. A multiscale solvation model that couples all-atom solutes and polarizable Martini coarse-grained water (AAX/CGS) is developed to reproduce free energies of hydration of organic solutes. Using Monte Carlo/free energy perturbation (MC/FEP) calculations, results from multiscale and all-atom simulations are compared. Improved accuracy is obtained with the AAX/CGS approach for hydrophobic and sulfur- or halogen-containing solutes, but larger deviations are found for polar solute molecules where hydrogen bonding is featured. Furthermore, solvent effects on conformational and tautomeric equilibria of AA solutes were investigated using AA, CG, and GB/SA solvent models. It is found that the CG solvent model can reproduce well the medium effects from experiment and AA simulations; however, the GB/SA solvent model fails in some cases. A 7–30-fold reduction in computational cost is found for the present AAX/CGS multiscale simulations compared to the AA alternative.
Two new semiempirical methods employing a Pairwise Distance Directed Gaussian modification have been developed: PDDG/PM3 and PDDG/MNDO; they are easily implemented in existing software, and yield heats of formation for compounds containing C, H, N, and O atoms with significantly improved accuracy over the standard NDDO schemes, PM5, PM3, AM1, and MNDO. The PDDG/PM3 results for heats of formation also show substantial improvement over density functional theory with large basis sets. The PDDG modifications consist of a single function, which is added to the existing pairwise core repulsion functions within PM3 and MNDO, a reparameterized semiempirical parameter set, and modified computation of the energy of formation of a gaseous atom. The PDDG addition introduces functional group information via pairwise atomic interactions using only atom‐based parameters. For 622 diverse molecules containing C, H, N, and O atoms, mean absolute errors in calculated heats of formation are reduced from 4.4 to 3.2 kcal/mol and from 8.4 to 5.2 kcal/mol using the PDDG modified versions of PM3 and MNDO over the standard versions, respectively. Several specific problems are overcome, including the relative stability of hydrocarbon isomers, and energetics of small rings and molecules containing multiple heteroatoms. The internal consistency of PDDG energies is also significantly improved, enabling more reliable analysis of isomerization energies and trends across series of molecules; PDDG isomerization energies show significant improvement over B3LYP/6‐31G* results. Comparison of heats of formation, ionization potentials, dipole moments, isomer, and conformer energetics, intermolecular interaction energies, activation energies, and molecular geometries from the PDDG techniques is made to experimental data and values from other semiempirical and ab initio methods. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 1601–1622, 2002
No abstract is provided for this article.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTComputational studies on FK506: conformational search and molecular dynamics simulation in waterJulianto Pranata and William L. JorgensenCite this: J. Am. Chem. Soc. 1991, 113, 25, 9483–9493Publication Date (Print):December 1, 1991Publication History Published online1 May 2002Published inissue 1 December 1991https://pubs.acs.org/doi/10.1021/ja00025a010https://doi.org/10.1021/ja00025a010research-articleACS PublicationsRequest reuse permissionsArticle Views240Altmetric-Citations16LEARN 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
Classical OPLS-AA force-field parameters are developed for perfluoroalkanes primarily by fitting to conformational profiles from gas-phase ab initio calculations (LMP2/cc-pVTZ(-f)//HF/6-31G*) and to experimental data for pure liquids. The ab initio C−C−C−C profile of n-C4F10 (perfluorobutane) is similar to those from prior high-level calculations and indicates the presence of gauche (g) and ortho (o) minima and of anti (a) minima slightly offset from 180°. Ab initio torsional profiles for n-C5F12 (perfluoropentane) and (CF3)2CFCF2CF3 (perfluoro-2-methylbutane) also show three sets of energy minima. Special OPLS-AA torsional parameters for these three molecules closely match ab initio and experimental geometries, conformational energies (ΔEmin), and conformational energy barriers. These specialized force fields were merged to provide a generalized force field for linear, branched, and cyclic perfluoroalkanes. The resultant parameters yield key ΔEmin values within 0.6 kcal/mol of the ab initio results for the three test compounds but more poorly represent the energy barriers. The parametrization also included reproduction of experimental liquid properties of these compounds, CF4 (perfluoromethane) and c-C5F10 (perfluorocyclopentane) via Monte Carlo (MC) simulations. MC simulations of six additional molecules were also performed in order to test the transferability of the force field.
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Intermolecular potential functions have been developed for use in computer simulations of substituted benzenes. Previously reported optimized potentials for liquid simulations (OPLS) for benzene and organic functional groups were merged and tested by computing free energies of hydration for toluene, p ‐xylene, phenol, anisole, benzonitrile, p ‐cresol, hydroquinone, and p ‐dicyanobenzene. The calculations featured Monte Carlo simulations at 25°C and 1 atm with statistical perturbation theory. The average difference between the computed results and experimental data for the absolute free energies of hydration is 0.5 kcal/mol. The AM1‐SM2 method is also found to perform well in predicting the free energies of hydration for the substituted benzenes. In addition, the Monte Carlo simulations provided details on the hydration of the substituted benzenes, in particular for the solute–water hydrogen bonding. © 1993 John Wiley & Sons, Inc.
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ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAromatic-aromatic interactions: free energy profiles for the benzene dimer in water, chloroform, and liquid benzeneWilliam L. Jorgensen and Daniel L. SeveranceCite this: J. Am. Chem. Soc. 1990, 112, 12, 4768–4774Publication Date (Print):June 1, 1990Publication History Published online1 May 2002Published inissue 1 June 1990https://pubs.acs.org/doi/10.1021/ja00168a022https://doi.org/10.1021/ja00168a022research-articleACS PublicationsRequest reuse permissionsArticle Views4889Altmetric-Citations941LEARN 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
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTheoretical examination of hexanol-water interfacesJiali Gao and William L. JorgensenCite this: J. Phys. Chem. 1988, 92, 20, 5813–5822Publication Date (Print):October 1, 1988Publication History Published online1 May 2002Published inissue 1 October 1988https://pubs.acs.org/doi/10.1021/j100331a053https://doi.org/10.1021/j100331a053research-articleACS PublicationsRequest reuse permissionsArticle Views394Altmetric-Citations64LEARN 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
Computational studies have yielded an analysis of the contributions to the free energy difference between the binding of celecoxib to COX-1 and to COX-2. The energetic and structural results point to the Ile to Val mutation at residue 523 as the key contributor to COX-2 selectivity; unfavorable steric contact between a sulfonamide oxygen and the δ methyl group of Ile523 destabilizes the complex with COX-1. The His to Arg change at residue 513 is less significant.
Monte Carlo simulations with statistical perturbation theory and the OPLS potential functions were employed to calculate the absolute free energies of binding between 9-methyladenine (A) and 1-methyluracil (U) and between 9-methylguanine (G) and 1-methylcytosine (C). The results for both AU (ca. −3.6 kcal/mol) and GC (ca. −7.9 kcal/mol) compare well with the values from experimentally determined association constants for these systems. Several thermodynamic cycles were also considered that demonstrated the high precision of the methodology. Monte Carlo simulations with statistical perturbation theory and the OPLS potential functions were employed to calculate the absolute free energies of binding between 9-methyladenine (A) and 1-methyluracil (U) and between 9-methylguanine (G) and 1-methylcytosine (C) in chloroform at 25 °C. A + U → A−U ΔG= −3.6 kcal/mol G + C → G−C ΔG= −7.9 kcal/mol
