ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMonte Carlo simulations of the hydration of ammonium and carboxylate ionsWilliam L. Jorgensen and Jiali GaoCite this: J. Phys. Chem. 1986, 90, 10, 2174–2182Publication Date (Print):May 1, 1986Publication History Published online1 May 2002Published inissue 1 May 1986https://pubs.acs.org/doi/10.1021/j100401a037https://doi.org/10.1021/j100401a037research-articleACS PublicationsRequest reuse permissionsArticle Views1620Altmetric-Citations277LEARN 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
Solvent effects on the polar [2+2] cycloaddition of 1,1-dicyanoethylene (DCNE) and methyl vinyl ether (MVE) have been studied using ab initio self-consistent reaction field (SCRF) and Monte Carlo (MC) statistical mechanics calculations. Emphasis is placed on the dependence of transition-state structure and energetics on solvation and on the impact of using different charge sets and geometries from the SCRF calculations in the MC simulations. The ab initio calculations were performed with dielectric constants e of 1.0, 2.23 (CCl4), and 35.94 (CH3CN) with the 6-31G* basis set at the Hartree−Fock (HF) level and incorporating electron correlation through MP2 and Becke3LYP density functional methods. Computed dipole moments of 10−17 D for the transition structures overlap estimates based on the solvent effects observed by Steiner and Huisgen. However, the mechanistic picture that emerges is medium dependent. In the gas phase and nonpolar solvent, the results here indicate a concerted (single barrier) process w...
No abstract is provided for this article.
A summary of the development of Monte Carlo statistical mechanics simulations for the computation of free energies of hydration of organic molecules is followed by presentation of results with the latest version of the optimized potentials for liquid simulations–all atom force field and the TIP4P water model. Scaling of the Lennard-Jones interactions between water, oxygen, and carbon atoms by a factor of 1.25 is found to improve the accuracy of free energies of hydration for 50 prototypical organic molecules from a mean unsigned error of 1.0–1.2 to 0.4 kcal/mol.
Ab initio molecular orbital calculations are reported for complexes of hydroxide and methoxide anions with water and methanol. The basis set dependence of the results is carefully considered for HO − ⃛ H 2 O. 4‐31G and 6‐31G* calculations yield similar geometrical predictions; however, the 6‐31G* basis set is superior for computing dissociation energies. Further extension to the 6‐31G** level provides little change. The dissociation energies for the complexes range from 25 to 37 kcal/mole with hydroxide ion and methanol acting as the strongest base and acid. The difference in gas phase acidities of water and methanol is halved by the introduction of one solvent molecule.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTImportance of Polarization for Dipolar Solutes in Low-Dielectric Media: 1,2-Dichloroethane and Water in CyclohexaneWilliam L. Jorgensen, Nora A. McDonald, Massimo Selmi, and Paul R. RablenCite this: J. Am. Chem. Soc. 1995, 117, 47, 11809–11810Publication Date (Print):November 1, 1995Publication History Published online1 May 2002Published inissue 1 November 1995https://pubs.acs.org/doi/10.1021/ja00152a025https://doi.org/10.1021/ja00152a025research-articleACS PublicationsRequest reuse permissionsArticle Views385Altmetric-Citations69LEARN 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 (2)»Supporting Information Supporting Information Get e-Alerts
Classical force-field parameters have been developed for amines primarily by fitting to experimental data for pure liquids and to hydrogen-bond strengths from gas-phase ab initio calculations. The resultant parameters were used to calculate relative free energies of hydration for ammonia, methylamine, dimethylamine, and trimethylamine using free energy perturbation calculations in Monte Carlo simulations (MC/FEP). The results including the fact that the most favorable ΔGhyd occurs for methylamine are in excellent agreement with the experimental data, in contrast to numerous prior computational reports. The calculations reveal two opposing trends in water: increased contribution from hydrogen-bond acceptance and diminished contribution from hydrogen-bond donation with increasing methylation of the amines. The proper balance of hydrogen-bond strengths, which is achieved with the OPLS-AA force field, is essential for correct ordering of the free energies of hydration. MC simulations for the pure liquids of thirteen additional amines, not included in the original parametrization, then demonstrated the transferability of the force field. These simulations covered aliphatic as well as cyclic and aromatic amines. Furthermore, the appropriateness of the force field for less polar environments was confirmed through MC/FEP calculations of relative free energies of solvation and log P values in chloroform. It is apparent that the prior problems with classical force fields for amines were simply a result of nonoptimal parametrization rather than to a critical omission such as the lack of explicit polarization.
Perturbation theory has been applied to calculate the relative free energies of hydration of methanol and ethane in dilute soluton. It is demonstrated that only two or three Monte Carlo simulations using double-wide sampling are necessary to obtain results with high precision. The small statistical uncertainty in the computed change in free energy of hydration and the good accord with experimental thermodynamic data are most encouraging for application of the procedure to a wide range of problems. Structural effects accompanying the mutation of methanol to ethane in water are also discussed; hydrogen bonding to the solute is essentialy eliminated by only a 25% reduction in the atomic charges of methanol.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTRelative partition coefficients for organic solutes from fluid simulationsWilliam L. Jorgensen, James M. Briggs, and M. Leonor. ContrerasCite this: J. Phys. Chem. 1990, 94, 4, 1683–1686Publication Date (Print):February 1, 1990Publication History Published online1 May 2002Published inissue 1 February 1990https://pubs.acs.org/doi/10.1021/j100367a084https://doi.org/10.1021/j100367a084research-articleACS PublicationsRequest reuse permissionsArticle Views1798Altmetric-Citations473LEARN 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
The interactions and energetics associated with the binding of 20 HEPT and 20 nevirapine nonnucleoside inhibitors of HIV-1 reverse transcriptase (RT) have been explored in an effort to establish simulation protocols and methods that can be used in the development of more effective anti-HIV drugs. Using crystallographic structures as starting points, all 40 inhibitors were modeled in the bound and unbound states via Monte Carlo (MC) statistical mechanics methods. Potentially useful descriptors of binding affinity were configurationally averaged for each inhibitor during the MC simulations, and correlations were sought with reported experimental activities. A viable regression equation was obtained using only four descriptors to correlate the 40 experimental activities with an r2 of 0.75 and cross-validated q2 of 0.69. The computed activities show a rmsd of 0.94 kcal/mol in comparison with experiment and an average unsigned error of 0.69 kcal/mol. The MC results reveal three physically reasonable parameters that control the binding affinities: (1) loss of hydrogen bonds with the inhibitor is unfavorable, (2) burial of hydrophobic surface area is favorable, and (3) a good geometrical fit without steric clashes is needed for the protein−inhibitor complex. It is gratifying that the corresponding descriptors are statistically the most important quantities for determining the anti-HIVRT activity for the 40 compounds. Representative examples are also given in which structural and thermodynamic information from the MC simulations is used to help understand binding differences for related compounds. A key π-type hydrogen bond has been identified between secondary-amide nevirapine analogues and Tyr188A of HIVRT that explains their otherwise surprising activity and the ineffectiveness of nevirapine against the Y188C mutant.
An efficient and general strategy for the determination of all low‐energy minima of a molecule, viz., the stochastic conformational jump procedure, has been implemented in the BOSS package. In this method, a new structure is generated by random movement (“kick”) of individual atoms with a predefined maximum displacement, and the resultant geometry is optimized. Using the OPLS‐AA force field, two series of oligomers of β‐amino acids with methyl ester terminal groups have been chosen for detailed examination. Monomeric (S)‐3‐pyrrolidine‐3‐carboxylic acid (PCA) and (S)‐nipecotic acid (Nip) have 4 and 2 nearly equi‐energy conformers, respectively. The dimers and trimers have substantially larger number of low‐energy conformers within 1 kcal/mol of the global minimum. However, the low‐energy conformers of the tetramers can all be classified as belonging to a few distinct families, in terms of variations in total interatomic distances. Even in the absence of hydrogen bonding, the larger oligomers have two well‐defined conformers, a compact helical form, and an extended structure. The preferences for these forms are determined exclusively by intramolecular dipolar interactions and van der Waals' forces. These results are consistent with experimental CD spectral trends, which reveal sharp features only for the higher oligomers ( n >3). © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1646–1654, 2001
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTComputer-assisted synthetic analysis. Generation of synthetic sequences involving sequential functional group interchangesE. J. Corey and William L. JorgensenCite this: J. Am. Chem. Soc. 1976, 98, 1, 203–209Publication Date (Print):January 1, 1976Publication History Published online1 May 2002Published inissue 1 January 1976https://pubs.acs.org/doi/10.1021/ja00417a031https://doi.org/10.1021/ja00417a031research-articleACS PublicationsRequest reuse permissionsArticle Views214Altmetric-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
No abstract is provided for this article.
A QM/MM approach, where reactants are treated quantum mechanically in the presence of a large number of explicit solvent molecules modeled with molecular mechanics, is better suited to explore solute–solvent interactions. This chapter focuses on determining the origin of solvent effects for three different organic reactions: Menshutkin, nucleophilic aromatic substitution (SNAr), and Kemp decarboxylation. QM/MM/MC simulations have been applied to a series of organic reactions with good success in reproducing the observed substrate and solvent effects on the free energies of activation and reaction. The overall quantitative success supports the utility of the present QM/MM/MC approach using PDDG/PM3 as the QM method. The importance of variations in specific solute–solvent interactions along the reaction paths is evident in the ion pairing in chloroform for the Kemp decarboxylation, in the failure of DFT/PCM calculations to reproduce the rate retardation in the SNAr reaction, and in the rate enhancement computed for the Menshutkin reaction in water over dimethyl sulfoxide (DMSO).
The OPLS all-atom force field was updated and applied to modeling unsaturated hydrocarbons, alcohols, and ethers. Testing has included gas-phase conformational energetics, properties of pure liquids, and free energies of hydration. Monte Carlo statistical mechanics (MC) calculations were used to model 60 liquids. In addition, a robust, automated procedure was devised to compute the free energies of hydration with high precision via free-energy perturbation (FEP) calculations using double annihilation. Testing has included larger molecules than in the past, and parameters are reported for the first time for some less common groups including alkynes, allenes, dienes, and acetals. The average errors in comparison with experimental data for the computed properties of the pure liquids were improved with the modified force field (OPLS/2020). For liquid densities and heats of vaporization, the average unsigned errors are 0.01 g/cm3 and 0.2 kcal/mol. The average error and signed error for free energies of hydration are both 1.2 kcal/mol. As noted before, this reflects a systematic overestimate of the hydrophobicity of organic molecules when the parametrization is done to minimize the errors for properties of pure liquids. Implications for the modeling of biomolecular systems with standard force fields are considered.
