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A valuable tool for the design of ligands for bioreceptors is provided by the presented combination of Monte Carlo simulations and free energy perturbation calculations. Application of this methodology to an orthogonal receptor–ligand pair based on cyclosporin A and human cyclophilin reproduced the experimentally observed differences in binding affinities and gave detailed insights into the origin of binding preferences with the thermodynamic cycles given on the right. L: reference ligand; P: original protein; bL: bumped ligand; hP: holed protein.
An intermolecular potential function for the hydrogen fluoride dimer has been obtained from ab initio molecular orbital calculations with a minimal basis set (STO-3G). Dimerization energies for 285 orientations of (HF)2 selected using the enery distributed random geometries method were fit to a 12–6–3–1 potential with standard deviations of ∼0.3 kcal/mol. The function was used in a Monte Carlo simulation of liquid hydrogen fluoride at 0 °C. Structural and thermodynamic results are compared with those based on an earlier potential derived from double zeta basis set (6-31G) calculations. The structural predictions are affected by the local density which is too high from the 6-31G potential. Significant improvement is obtained with the STO-3G function. A detailed analysis of the structure of liquid HF is presented including coordination number and energy distribution functions. Each HF monomer has an average of two hydrogen bonded neighbors with an additional five peripheral contacts within 3.6 Å. The hydrogen bonded monomers form winding chains with significantly bent hydrogens bonds in contrast to the linear hydrogen bonds found in the solid and in the gas phase dimer. As in the case for water, it is apparent that reasonable intermolecular potential functions for hydrogen bonded dimers can be obtained from minimal basis set calculations. In the absence of CI level calculations, this appears to be the method of choice.
Spontaneous decarboxylation of amino acids is among the slowest known reactions; it is much less facile than the cleavage of amide bonds in polypeptides. Establishment of the kinetics and mechanisms for this fundamental reaction is important for gauging the proficiency of enzymes. In the present study, multiple mechanisms for glycine decomposition in water are explored using QM/MM Monte Carlo simulations and free energy perturbation theory. Simple CO2 detachment emerges as the preferred pathway for decarboxylation; it is followed by water-assisted proton transfer to yield the products: CO2 and methylamine. The computed free energy of activation of 45 kcal/mol, and the resulting rate-constant of 1 × 10–21 s–1, can be compared with an extrapolated experimental rate constant of ∼2 × 10–17 s–1 at 25 °C. The half-life for the reaction is more than 1 billion years. Furthermore, examination of deamination finds simple NH3-detachment yielding α-lactone to be the favored route, though it is less facile than decarboxylation by 6 kcal/mol. Ab initio and DFT calculations with the CPCM hydration model were also carried out for the reactions; the computed free energies of activation for glycine decarboxylation agree with the QM/MM result, whereas deamination is predicted to be more favorable. QM/MM calculations were also performed for decarboxylation of alanine; the computed barrier is 2 kcal/mol higher than for glycine in qualitative accord with experiment.
Thymidylate synthase (TS), found in all organisms, is an essential enzyme responsible for the de novo synthesis of deoxythymidine monophosphate. The TS active sites of the protozoal parasite Cryptosporidium hominis and human are relatively conserved. Evaluation of antifolate compound 1 and its R-enantiomer 2 against both enzymes reveals divergent inhibitor selectivity and enzyme stereospecificity. To establish how C. hominis and human TS (ChTS and hTS) selectively discriminate 1 and 2, respectively, we determined crystal structures of ChTS complexed with 2 and hTS complexed with 1 or 2. Coupled with the previously determined structure of ChTS complexed with 1, we discuss a possible mechanism for enzyme stereospecificity and inhibitor selectivity.
Monte Carlo (MC) statistical mechanics simulations have been carried out for the homologous alkane series of n-butane through n-dodecane in the gas phase and for the pure liquids at 298 K and 1 atm using the OPLS-AA force field. The study addresses potential cumulative deviations of computed properties and potential conformational differences between the gas phase and pure liquids, for example, from self-solvation in the gas phase. The average errors in comparison with experimental data for the computed densities and heats of vaporization are modest at 0.7% and 6.9%, respectively. Also, the invariant gas and liquid-phase results for average end-to-end distances and percentages of trans conformations for each nonterminal C−C bond assert that the conformer populations are not altered upon transfer from the gas phase to the pure liquid for the n-alkanes in this size range. Average end-to-end distances were also computed from the results of conformational searches and corroborated the MC findings. Quantitatively, the OPLS-AA result for the trans population of the C3−C4 bond in n-undecane is in close agreement with the findings from 13C NMR experiments. Finally, previous work on determining the shortest n-alkane that does not have an all-trans global energy minimum has been extended. The smallest n-alkane with a hairpin geometry that is lower in energy than the all-trans conformer occurs for C22H46 with OPLS-AA, though with a correction for GG sequences, the true turning point is likely in the C16−C18 range.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTComputer-assisted mechanistic evaluation of organic reactions. 13. A general treatment of nucleophilic chemistryPascal Metivier, Alan J. Gushurst, and William L. JorgensenCite this: J. Org. Chem. 1987, 52, 17, 3724–3738Publication Date (Print):August 1, 1987Publication History Published online1 May 2002Published inissue 1 August 1987https://pubs.acs.org/doi/10.1021/jo00226a003https://doi.org/10.1021/jo00226a003research-articleACS PublicationsRequest reuse permissionsArticle Views155Altmetric-Citations11LEARN 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. 7. Structure and properties of liquid methanolWilliam L. JorgensenCite this: J. Am. Chem. Soc. 1980, 102, 2, 543–549Publication Date (Print):January 1, 1980Publication History Published online1 May 2002Published inissue 1 January 1980https://pubs.acs.org/doi/10.1021/ja00522a018https://doi.org/10.1021/ja00522a018research-articleACS PublicationsRequest reuse permissionsArticle Views579Altmetric-Citations138LEARN 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
This book addresses current topics in computerized simulation of chemical and biomolecular systems. Included are free energy simulations; molecular dynamics simulations; properties of crystal hydrates, such as proteins and nucleic acids; reactions of DNA; and biological micromolecules simulations.
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Monte Carlo statistical mechanics simulations have been carried out for a dilute solution of n-butane in water at 25 °C and 1 atm. The intermolecular interactions were described by Coulomb and Lennard-Jones terms in the TIPS format including the TIPS2 parameters for water. The internal rotation about the central CC bond in n-butane was included using a rotational potential based on molecular mechanics (MM2) calculations. The precision of the simulation results was enhanced by preferential sampling and by umbrella sampling for the internal rotation over chopped barriers. Conformational results are also reported from a long Monte Carlo run for pure liquid n-butane using umbrella sampling. Although no condensed phase effect is found on the conformational equilibrium in pure liquid n-butane, there is a pronounced increase in the gauche population of n-butane upon transfer from the gas phase to aqueous solution. The latter finding is in near quantitative accord with the shift predicted by Pratt and Chandler from their theoretical model. It is also consistent with the basic tenet of the hydrophobic effect regarding the folding of natural and synthetic polymers in water. In addition, detailed structural results for the system are reported. Notably, the water molecules in the first shell around n-butane have normal bonding energies and hydrogen bonding profiles for bulk water. However, since their coordination numbers are low, this situation can only be achieved by greater ordering which is entropically costly. The validity of the observations is supported by the computed heat and volume of solution which are in accord with experimental data.
Design principles are delineated for non-nucleoside inhibitors for HIV-1 reverse transcriptase (NNRTIs). Simultaneous optimization of binding affinity for wild-type RT, tolerance for viral mutations, and physical properties is pursued. Automated lead generation with the growing program BOMB, Monte Carlo simulations with free-energy perturbation theory for lead optimization, and property analysis with QikProp are featured. An initial 30μM lead has been optimized rapidly to the 10nM level.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTQuantum and statistical mechanical studies of liquids. Part 22. Pressure dependence of mixing enantiomeric liquids: 1,2-dichloropropaneWilliam L. Jorgensen and Bernard BigotCite this: J. Phys. Chem. 1982, 86, 15, 2867–2873Publication Date (Print):July 1, 1982Publication History Published online1 May 2002Published inissue 1 July 1982https://pubs.acs.org/doi/10.1021/j100212a013https://doi.org/10.1021/j100212a013research-articleACS PublicationsRequest reuse permissionsArticle Views64Altmetric-Citations14LEARN 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
Monte Carlo simulations have been used to determine the ΔΔGb for steroid-cyclophane complexes in four different conformations. Statistical perturbation theory provided changes of free energy in good agreement with experimental data. Hydrogen bonding and energy component analyses yielded insights into the interaction of the steroid with the cyclophane and with the mixed water/methanol solvent; this information should prove useful to steroid host design.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTComputer-assisted mechanistic evaluation of organic reactions. 18. Reductions with hydridesGenevieve D. Paderes, Pascal Metivier, and William L. JorgensenCite this: J. Org. Chem. 1991, 56, 15, 4718–4733Publication Date (Print):July 1, 1991Publication History Published online1 May 2002Published inissue 1 July 1991https://pubs.acs.org/doi/10.1021/jo00015a028https://doi.org/10.1021/jo00015a028research-articleACS PublicationsRequest reuse permissionsArticle Views200Altmetric-Citations17LEARN 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
