A comparison between Miertus–Scrocco–Tomasi (MST) SCRF and free energy perturbation (FEP) estimates of the free energy of hydration of eight small neutral molecules is presented. In both cases, the 6‐31G* molecular electrostatic potential is used to describe the electrostatic properties of the molecules. The results demonstrate the ability of both methodologies to provide useful theoretical estimates of the total free energy of hydration; the average errors are only 1.5 kcal/mol (FEP) and 0.8 kcal/mol (MST/SCRF). The largest errors in the FEP and MST/SCRF results are less than 1.5 kcal/mol for all molecules except acetic acid, where the FEP method overestimates the free energy of hydration by 3.3 kcal/mol. © John Wiley & Sons, Inc.
The origins of binding affinity and COX-2/COX-1 selectivity for analogues of celecoxib have been explored using an approach that combines docking with Monte Carlo (MC) simulations. These inhibitors are COX-2-selective nonsteroidal antiinflammatory drugs (NSAIDs) that are of current interest because the gastrointestinal irritation they cause is reduced compared to that caused by traditional NSAIDs. We report a novel docking method, based on a combined Tabu and Monte Carlo protocol, that determines starting conformations for MC simulations. Using the docking-predicted starting conformations, relative changes in binding free energies were computed for methyl, ethyl, hydroxymethyl, hydroxyl, thiomethyl, methoxy, trifluoromethyl, chloro, fluoro, and unsubstituted derivatives with the MC free energy perturbation (FEP) method. The computed free energies are in good accord with IC50 values, and the structural information from the simulations can be used to explain the experimentally observed binding trends. In addition, the docking and FEP results have provided clarification of the binding conformation of the phenylsulfonamide moiety and the origin of COX-2/COX-1 selectivity. Namely, the COX-2 Val → COX-1 Ile subtitution is accompanied by an unfavorable conformational shift of the phenylsulfonamide ring.
The cation-olefin addition of 2-methyl-2-propyl cation and 2-methylpropene has been investigated in the gas phase and in solution with ab initio calculations and Monte Carlo statistical mechanics simulations. The reaction is exothermic by ca. 20 kcal/mol and proceeds without activation energy in the gas phase. However, solvation introduces a 3-4 kcal/mol barrier at a C-C separation near 5 Å in methylene chloride, THF, and methanol. An intermediate in a shallow energy well is found near 3-Å separation. Implications for sterol biosynthesis are discussed.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) that interfere with the replication of human immunodeficiency virus (HIV) are being pursued with guidance from molecular modeling including free-energy perturbation (FEP) calculations for protein-inhibitor binding affinities. The previously reported pyrimidinylphenylamine 1 and its chloro analogue 2 are potent anti-HIV agents; they inhibit replication of wild-type HIV-1 in infected human T-cells with EC(50) values of 2 and 10 nM, respectively. However, they show no activity against viral strains containing the Tyr181Cys (Y181C) mutation in HIV-RT. Modeling indicates that the problem is likely associated with extensive interaction between the dimethylallyloxy substituent and Tyr181. As an alternative, a phenoxy group is computed to be oriented in a manner diminishing the contact with Tyr181. However, this replacement leads to a roughly 1000-fold loss of activity for 3 (2.5 μM). The present report details the efficient, computationally driven evolution of 3 to novel NNRTIs with sub-10 nM potency toward both wild-type HIV-1 and Y181C-containing variants. The critical contributors were FEP substituent scans for the phenoxy and pyrimidine rings and recognition of potential benefits of addition of a cyanovinyl group to the phenoxy ring.
The recently developed Charge Model 5 (CM5) is tested for its utility in condensed-phase simulations. The CM5 approach, which derives partial atomic charges from Hirshfeld population analyses, provides excellent results for gas-phase dipole moments and is applicable to all elements of the periodic table. Herein, the adequacy of scaled CM5 charges for use in modeling aqueous solutions has been evaluated by computing free energies of hydration (Δ
No abstract is provided for this article.
Ab initio molecular orbital calculations have been carried out on over 50 model organic molecules and ions to provide the data necessary in the determination of torsional parameters for a force field involving polypeptides. The rotational energy profiles were obtained at the HF/6‐31G*//HF/6‐31G* level. The results were supported, in many cases, by full geometry optimizations and with consideration of correlation corrections at the MP2 level. With the exception of the dihedral angle being studied, all of the molecules were fully optimized with C 1 symmetry. © 1995 by John Wiley & Sons, Inc.
Es werden die π‐Orbital‐Wechselwirkungen zwischen den kleinen Ringen und den Äthylen‐ bzw. Butadienbrücken z.B. für Dewarbenzol und Benzvalen bzw. für 2,3‐Dimethylen‐bicyclo[2.
No abstract is provided for this article.
No abstract is provided for this article.
An efficient molecular simulation methodology has been developed to determine the positioning of water molecules in the binding site of a protein or protein−ligand complex. Occupancies and absolute binding free energies of water molecules are computed using a statistical thermodynamics approach. The methodology, referred to as Just Add Water Molecules (JAWS), features "θ-water" molecules that can appear and disappear on a binding-site grid. Key approximations render the technique far more efficient than conventional free energy simulations. Testing of JAWS on five diverse examples (neuraminidase, scytalone dehydratase, major urinary protein 1, β-lactoglobulin, and COX-2) demonstrates its accuracy in locating hydration sites in comparison to results from high-resolution crystal structures. Possible applications include aid in refinement of protein crystal structures, drug lead optimization, setup of docking calculations, and simulations of protein−ligand complexes.
ADVERTISEMENT RETURN TO ISSUEEditorialNEXTA Reflection on Paul von Ragué SchleyerWilliam L. Jorgensen*View Author Information Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States*E-mail: [email protected]Cite this: J. Chem. Theory Comput. 2015, 11, 1, 1Publication Date (Web):December 8, 2014Publication History Published online11 December 2014Published inissue 13 January 2015https://pubs.acs.org/doi/10.1021/ct501095whttps://doi.org/10.1021/ct501095weditorialACS PublicationsCopyright © 2014 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views890Altmetric-Citations1LEARN 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 PDF (112 KB) Get e-AlertscloseSUBJECTS:Aromatic compounds,Cations,Computational chemistry,Hydrocarbons,Rearrangement Get e-Alerts
Detailed analysXXXs of the hydrogen bonding in water have been made from a Monte Carlo simulation of the liquid at 25°C. Distributions for hydrogen bond numbers and angles are reported. Most monomers are in three or four hydrogen bonds and the average hydrogen bond is bent ca. 20°.
