A variable dielectric model based on residue types for better description of protein–ligand electrostatics in MM-GBSA scoring is reported. The variable dielectric approach provides better correlation with binding data and reduces the score dynamic range, typically observed in the standard MM-GB/SA method. The latter supports the view that exaggerated enthalpic separation between weak and potent compounds due to the lack of shielding effects in the model is greatly responsible for the wide scoring spread.
A series of non-immunosuppressive inhibitors of FK506 binding protein (FKBP12) are investigated using Monte Carlo statistical mechanics simulations. These small molecules may serve as scaffolds for chemical inducers of protein dimerization, and have recently been found to have FKBP12-dependent neurotrophic activity. A linear response model was developed for estimation of absolute binding free energies based on changes in electrostatic and van der Waals energies and solvent-accessible surface areas, which are accumulated during simulations of bound and unbound ligands. With average errors of 0.5 kcal/mol, this method provides a relatively rapid way to screen the binding of ligands while retaining the structural information content of more rigorous free energy calculations.
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Hydrogen bonding between water and a series of small organic molecules was examined via electronic structure calculations. Several computational methods were examined, including both a hybrid density functional procedure (Becke3LYP) and second-order Møller−Plesset theory (MP2) coupled with a double-ζ basis set augmented by diffuse polarization functions on heteroatoms. The agreement between Becke3LYP and MP2 energies was generally good, as was the agreement with energies obtained using more sophisticated and costly methods. The energies and structures of 53 hydrogen-bonded complexes of water with various small organic molecules, including alcohols, thiols, ethers, thioethers, carboxylic acids, esters, amines, amides, nitriles, and nitro compounds, were then examined systematically using the Becke3LYP and MP2 procedures. The hydrogen bond geometries were generally linear, and acceptor sites corresponded closely to the positions of lone pairs as predicted by simple hybridization arguments. Structures with sulfur and chlorine atoms showed some deviation from these simple expectations and seemed to be largely determined by molecular dipole−dipole interactions. Categorization of the hydrogen bonds involved in the various complexes led to an ordering of hydrogen bond donor and acceptor abilities for some common functional groups. The strength of association was found to correlate moderately well with experimental gas-phase basicity in those cases where water acted unambiguously as the hydrogen bond donor at a single site. Interestingly, sulfur was found to be close to oxygen in hydrogen bond acceptor strength, and the surprisingly strong acceptor ability of sulfur could not be explained in terms of its enhanced polarizability relative to oxygen. Calculations were also carried out on the AT and GC base pairs and yielded results in very close agreement with the highest levels of calculation previously reported.
Free energies of solvation in water and liquid cyclohexane have been computed for 20 arenes ranging in size from cyclobutadiene to coronene. Monte Carlo statistical mechanics (MC) was used with free-energy perturbation theory (FEP) and the OPLS-AA force field. The computed results for free energies of hydration are in close agreement with experimental data giving an average error of 0.4 kcal/mol. Some discrepancies are found for larger arenes for which the experimental data have greater uncertainties owing to low solubility. The free energies of solvation and free energy of transfer from cyclohexane to water all display strong correlations with the solvent-accessible surface area (SASA) or volume of the arene. In contrast to the hydration of alkanes, the free energies of hydration of arenes become much more favorable with increasing size covering an 11 kcal/mol range. The free energies of solvation in cyclohexane are still more favorable, resulting in a 5 kcal/mol range for the resistance to transfer of arenes from cyclohexane to aqueous solution. Strong correlations are also found between the aqueous solubility of arenes and the free energies of solvation in cyclohexane and water. The reported results provide fundamental thermodynamic data for solution-phase properties of arenes, with relevance to materials and environmental science.
No abstract is provided for this article.
No abstract is provided for this article.
A series of Monte Carlo simulations has been carried out to characterize the temperature and size dependence of the results for liquid water using the TIP4P potential function. Five temperatures from -25 to 100°C and four system sizes from 64 to 512 molecules have been studied. Comparisons are made with experimental thermodynamic and structural data as well as results of prior simulations.
A simple, intermolecular potential function has been derived empirically to yield good thermodynamic and structural results for liquid hydrogen fluoride. The function was tested in Monte Carlo statistical mechanics simulations for the liquid at temperatures of 0°C and -70°C at 1 atm. The average errors in the computed densities and energies are 1 and 5 per cent, respectively. The temperature dependence of the structural results is also analysed by means of radial distribution functions and hydrogen bond distributions. As expected, hydrogen bonded chains dominate the liquid's structure. Enhanced structure and hydrogen bonding are evident as the temperature is lowered. In view of the simplicity of the potential function and the quality of the results, the potential is well suited for simulations of dilute solutions including studies of the solvation of carbonium ions in a model superacid solvent.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTOptimized intermolecular potential functions for liquid hydrocarbonsWilliam L. Jorgensen, Jeffry D. Madura, and Carol J. SwensonCite this: J. Am. Chem. Soc. 1984, 106, 22, 6638–6646Publication Date (Print):October 1, 1984Publication History Published online1 May 2002Published inissue 1 October 1984https://pubs.acs.org/doi/10.1021/ja00334a030https://doi.org/10.1021/ja00334a030research-articleACS PublicationsRequest reuse permissionsArticle Views7804Altmetric-Citations1972LEARN 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
