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The binding of sulfonamide inhibitors to human thrombin is examined to evaluate the viability of calculating free energies of binding, deltaGb, utilizing Monte Carlo (MC) statistical mechanics with a linear response approach. Coulombic and van der Waals energy components determined from MC simulations of the bound and unbound inhibitors solvated in water plus a solvent-accessible surface area term, as an index for cavity formation, were correlated with the free energies of binding for the inhibitor MD-805 and six derivatives. The best correlations yield an average error of 0.8 kcal/mol for the seven binding affinities, which cover an observed range of 6.0 kcal/mol. The MC simulations also provided insights into the interactions occurring in the active site and the origins of variations in deltaGb. Equatorial placement of the carboxylate group at C2 in the piperidine ring of the inhibitors causes electrostatic destabilization with the side chain of Glu-H192, while axial disposition of the C4-methyl group reduces favorable hydrophobic interactions in the P-pocket of the enzyme.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTHomoaromaticity and bicycloaromaticity in carbanionsJohn B. Grutzner and William L. JorgensenCite this: J. Am. Chem. Soc. 1981, 103, 6, 1372–1375Publication Date (Print):March 1, 1981Publication History Published online1 May 2002Published inissue 1 March 1981https://pubs.acs.org/doi/10.1021/ja00396a013https://doi.org/10.1021/ja00396a013research-articleACS PublicationsRequest reuse permissionsArticle Views207Altmetric-Citations39LEARN 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
Monte Carlo statistical mechanics simulations have been employed to elucidate the complexation of halide ions in chloroform by the bis(phenylurea) p-tert-butylcalix[4]arene of Scheerder et al. The calculations employed OPLS potential functions including new parameters for iodide ion. Gas-phase optimizations for the host−guest systems, as well as for halide−water and halide−urea complexes, were performed to characterize the structures of the complexes and to quantify the intrinsic binding affinities. The computations reveal that the gas-phase optimized structures of the complexes are largely maintained in chloroform solution, though there is a ca. 20 kcal/mol reorganization penalty for the host to achieve the binding geometry. Statistical perturbation theory was used to compute the relative free energies of binding for the halide ions with the calixarene in chloroform. The observed affinity order, Cl- > Br- > I-, was quantitatively well reproduced; however, in contrast to the experimental report of no complexation for F-, the simulations find that F- should bind with by far the greatest affinity among the halides. The possibility that interference by water in the experiments led to the observed lack of fluoride binding was explored through simulations of the halides with water molecules in chloroform. The results indicate that complexation of F- by two water molecules would be sufficient to overcome complexation by the bis-urea host.
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Intermolecular potential functions have been developed for use in computer simulations of alkyl ethers. The simple OPLS model was adopted and parameterized to yield good descriptions of bimolecular and ion‐molecule complexes as well as to reproduce experimental thermodynamic properties of liquid ethers. The principal testing featured Monte Carlo statistical mechanics simulations for liquid dimethyl ether (DME), ethyl methyl ether (EME), diethyl ether (DEE), and tetrahydrofuran (THF). Average errors of 1–3% are obtained for the computed densities and heats of vaporization including results for THF at pressures up to 5000 atm. The torsional motion about the central CO bonds in EME and DEE was included in the simulations using rotational potential functions fit to results of molecular mechanics (MM2) calculations. The liquid‐state environment is found to have negligible effect on the conformational equilibria.
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ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEnhanced view of structure and binding for cyclophane-arene complexes through joint theoretical and experimental studyWilliam L. Jorgensen, Toan B. Nguyen, Elizabeth M. Sanford, Ito Chao, K. N. Houk, and Francois DiederichCite this: J. Am. Chem. Soc. 1992, 114, 10, 4003–4004Publication Date (Print):May 1, 1992Publication History Published online1 May 2002Published inissue 1 May 1992https://pubs.acs.org/doi/10.1021/ja00036a074https://doi.org/10.1021/ja00036a074research-articleACS PublicationsRequest reuse permissionsArticle Views155Altmetric-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
Quantum and molecular mechanics calculations for the Diels−Alder reactions of cyclopentadiene with 1,4-naphthoquinone, methyl vinyl ketone, and acrylonitrile have been carried out at the vacuum−water interface and in the gas phase. In conjunction with previous studies of these cycloadditions in dilute solution, a more complete picture of aqueous environmental effects emerges with implications for the origin of observed rate accelerations using heterogeneous aqueous suspensions, "on water" conditions. The pure TIP4P water slab maintains the bulk density and hydrogen-bonding properties in central water layers. The bulk region merges to vacuum over a ca. 5 Å band with progressive diminution of the density and hydrogen bonding. The relative free energies of activation and transition structures for the reactions at the interface are found to be intermediate between those calculated in the gas phase and in bulk water; i.e., for the reaction with 1,4-naphthoquinone, the ΔΔG⧧ values relative to the gas phase are −3.6 and −7.3 kcal/mol at the interface and in bulk water, respectively. Thus, the results do not support the notion that a water surface is more effective than bulk water for catalysis of such pericyclic reactions. The trend is in qualitative agreement with expectations based on density considerations and estimates of experimental rate constants for the gas phase, a heterogeneous aqueous suspension, and a dilute aqueous solution for the reaction of cyclopentadiene with methyl vinyl ketone. Computed energy pair distributions reveal a uniform loss of 0.5−1.0 hydrogen bond for the reactants and transition states in progressing from bulk water to the vacuum−water interface. Orientational effects are apparent at the surface; e.g., the carbonyl group in the methyl vinyl ketone transition structure is preferentially oriented into the surface. Also, the transition structure for the 1,4-naphthoquinone case is buried more in the surface, and the free energy of activation for this reaction is most similar to the result in bulk water.
The ability to accurately perform molecular dynamics and free energy perturbation calculations for protein–ligand systems is of broad interest to the biophysical and pharmaceutical sciences. In this work, several popular force fields are evaluated for reproducing experimental properties of the flavodoxin/flavin mononucleotide system. Calculated 3J couplings from molecular dynamics simulations probing φ and χ1 dihedral angles are compared to over 1000 experimental measurements. Free energy perturbation calculations were also executed between different protein mutants for comparison with experimental data for relative free energies of binding. Newer versions of popular protein force fields reproduced 3J backbone and side chain couplings with good accuracy, with RMSD values near or below one hertz in most cases. OPLS-AA/M paired with CM5 charges for the ligand performed particularly well, both for the 3J couplings and FEP results, with a mean unsigned error for relative free energies of binding of 0.36 kcal/mol.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTComputer-assisted mechanistic evaluation of organic reactions. 10. StereochemistryCatherine E. Peishoff and William L. JorgensenCite this: J. Org. Chem. 1985, 50, 17, 3174–3184Publication Date (Print):August 1, 1985Publication History Published online1 May 2002Published inissue 1 August 1985https://pubs.acs.org/doi/10.1021/jo00217a032https://doi.org/10.1021/jo00217a032research-articleACS PublicationsRequest reuse permissionsArticle Views72Altmetric-Citations9LEARN 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
