ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTQuantum and statistical mechanical studies of liquids. 25. Solvation and conformation of methanol in waterWilliam L. Jorgensen and Jeffry D. MaduraCite this: J. Am. Chem. Soc. 1983, 105, 6, 1407–1413Publication Date (Print):March 1, 1983Publication History Published online1 May 2002Published inissue 1 March 1983https://pubs.acs.org/doi/10.1021/ja00344a001https://doi.org/10.1021/ja00344a001research-articleACS PublicationsRequest reuse permissionsArticle Views1036Altmetric-Citations358LEARN 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
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Application of combined quantum and molecular mechanical (QM/MM) methods focuses on predicting activation barriers and the structures of stationary points for organic and enzymatic reactions. Characterization of the factors that stabilize transition structures in solution and in enzyme active sites provides a basis for design and optimization of catalysts. Continued technological advances allowed for expansion from prototypical cases to mechanistic studies featuring detailed enzyme and condensed-phase environments with full integration of the QM calculations and configurational sampling. This required improved algorithms featuring fast QM methods, advances in computing changes in free energies including free-energy perturbation (FEP) calculations, and enhanced configurational sampling. In particular, the present Account highlights development of the PDDG/PM3 semi-empirical QM method, computation of multi-dimensional potentials of mean force (PMF), incorporation of on-the-fly QM in Monte Carlo (MC) simulations, and a polynomial quadrature method for efficient modeling of proton-transfer reactions. The utility of this QM/MM/MC/FEP methodology is illustrated for a variety of organic reactions including substitution, decarboxylation, elimination, and pericyclic reactions. A comparison to experimental kinetic results on medium effects has verified the accuracy of the QM/MM approach in the full range of solvents from hydrocarbons to water to ionic liquids. Corresponding results from ab initio and density functional theory (DFT) methods with continuum-based treatments of solvation reveal deficiencies, particularly for protic solvents. Also summarized in this Account are three specific QM/MM applications to biomolecular systems: (1) a recent study that clarified the mechanism for the reaction of 2-pyrone derivatives catalyzed by macrophomate synthase as a tandem Michael−aldol sequence rather than a Diels−Alder reaction, (2) elucidation of the mechanism of action of fatty acid amide hydrolase (FAAH), an unusual Ser-Ser-Lys proteolytic enzyme, and (3) the construction of enzymes for Kemp elimination of 5-nitrobenzisoxazole that highlights the utility of QM/MM in the design of artificial enzymes.
Molecular dynamics (MD) and free energy perturbation (FEP) methods are used to study the binding and mechanism of isomerization of a tetrapeptide (AcAAPFNMe) by FK506 binding protein (FKBP). Detailed structures are predicted for the complexes of FKBP with the peptide in both ground-state and transition-state forms. The results support a mechanism of catalysis by distortion, where a large number of nonbonded interactions act together to stabilize preferentially the twisted transition state. The two most important groups for the catalysis are suggested to be Trp59 and Asp37, but several other groups are identified as directly or indirectly involved in the binding and catalysis. However, the structural results do not support the notion that the keto oxygen of the immunosuppressive agents FK506 and rapamycin mimics the oxygen for the twisted peptide bond in the FKBP-transition-state complex.
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The prototypical SN2 reaction of chloride ion with methyl chloride has been reinvestigated in aqueous solution using QM/MM methodology featuring MO6-2X/6-31+G(d) calculations with the TIP4P water model, and partial charges were computed with the CM5 method. Though the DFT method yields excellent gas-phase energetics for the reaction, the QM/MM approach is found to yield overestimation of the activation barrier by ca. 12 kcal/mol. The discrepancy is traced to underestimate of the magnitude of the partial charges on the chlorine atoms in the transition structure. When CM1 or CM3 charges based on semiempirical wave functions are used instead, the agreement with experiment is much improved. The findings emphasize the sensitivity of the results of QM/MM calculations to the choice of QM method, the MM force field, and implementation of the QM/MM interface.
Monte Carlo statistical mechanics simulations have been carried out for 150 organic solutes in water. Physically significant descriptors such as the solvent-accessible surface area, numbers of hydrogen bonds, and indices for cohesive interactions in solids are correlated with pharmacologically important properties including octanol/water partition coefficient (log P) and aqueous solubility (log S). The regression equation for log S only requires five descriptors to provide a correlation coefficient, r 2, of 0.9 and rms error of 0.7 for the 150 solutes. The descriptors can form a basis for structural modifications to guide an analogue's properties into desired ranges.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTChemical consequences of orbital interactions in hydrocarbons containing unsaturativety bridged small ringsWilliam L. Jorgensen and Weston T. BordenCite this: J. Am. Chem. Soc. 1973, 95, 20, 6649–6654Publication Date (Print):October 1, 1973Publication History Published online1 May 2002Published inissue 1 October 1973https://pubs.acs.org/doi/10.1021/ja00801a021https://doi.org/10.1021/ja00801a021research-articleACS PublicationsRequest reuse permissionsArticle Views164Altmetric-Citations51LEARN 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 ISSUEPREVArticleNEXTQuantum and statistical mechanical studies of liquids. 11. Transferable intermolecular potential functions. Application to liquid methanol including internal rotationWilliam L. JorgensenCite this: J. Am. Chem. Soc. 1981, 103, 2, 341–345Publication Date (Print):January 1, 1981Publication History Published online1 May 2002Published inissue 1 January 1981https://pubs.acs.org/doi/10.1021/ja00392a017https://doi.org/10.1021/ja00392a017research-articleACS PublicationsRequest reuse permissionsArticle Views499Altmetric-Citations148LEARN 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
Thermochemical data have been obtained from G3B3 quantum mechanical calculations for 18 prototypical organic molecules, which exhibit E/Z conformational equilibria. The results are fundamentally important for molecular design including evaluation of structures from protein-ligand docking. For the 18 E/Z pairs, relative energies, enthalpies, free energies, and dipole moments are reported; the E - Z free-energy differences at 298 K range from +8.2 kcal/mol for 1,3-dimethyl carbamate to -6.4 kcal/mol for acetone oxime. A combination of steric and electronic effects can rationalize the variations. Free energies of hydration were also estimated using the GB/SA continuum solvent model. These results indicate that differential hydration is unlikely to qualitatively change the preferred direction of the E/Z equilibria, though further study with free-energy methods using explicit solvent is desirable.
