No abstract is provided for this article.
The Diels-Alder reactions of cyclopentadiene with 1,4-naphthoquinone, methyl vinyl ketone, and acrylonitrile have been investigated using QM/MM calculations in water, methanol, acetonitrile, and hexane. This extends an earlier AM1-based QM/MM study (J. Phys. Chem. B 2002, 106, 8078) that only investigated the reactions in water and utilized gas-phase optimized structures as starting points for computations of one-dimensional potentials of mean force (PMFs). Presently, the stationary points were located automatically in multiple solvents by computing two-dimensional PMFs, and the QM method is now PDDG/PM3. The resultant geometries are improved, and relative free energies of activation are well reproduced, e.g., ΔG(‡) for the reaction with naphthoquinone is computed to increase upon transfer from water to methanol, acetonitrile, and hexane by 3.2, 4.1, and 5.1 kcal/mol, while the experimental values are 3.4, 4.0, and 5.0 kcal/mol. Ab initio MP2/6-311+G(2d,p) calculations using the CPCM continuum solvent model on gas-phase CBS-QB3 geometries were also found to yield accurate ΔG(‡) values in water. However, only the QM/MM methodology reproduced the large rate increases in proceeding from aprotic solvents to water. The dominant factors for the rate variations are enhanced hydrogen bonding for the polarized transition states and reduction in hydrophobic surface area.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMinimal basis set description of the structure and properties of liquid waterWilliam L. JorgensenCite this: J. Am. Chem. Soc. 1979, 101, 8, 2016–2021Publication Date (Print):April 1, 1979Publication History Published online1 May 2002Published inissue 1 April 1979https://doi.org/10.1021/ja00502a015RIGHTS & PERMISSIONSArticle Views174Altmetric-Citations25LEARN 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 InReddit PDF (778 KB) Get e-Alerts Get e-Alerts
A strategy in drug design is to consider enhancing the affinity of lead molecules with structural modifications that displace water molecules from a protein binding site. Because success of the approach is uncertain, clarification of the associated energetics was sought in cases where similar structural modifications yield qualitatively different outcomes. Specifically, free-energy perturbation calculations were carried out in the context of Monte Carlo statistical mechanics simulations to investigate ligand series that feature displacement of ordered water molecules in the binding sites of scytalone dehydratase, p38-alphaMAP kinase, and EGFR kinase. The change in affinity for a ligand modification is found to correlate with the ease of displacement of the ordered water molecule. However, as in the EGFR example, the binding affinity may diminish if the free-energy increase due to the removal of the bound water molecule is not more than compensated by the additional interactions of the water-displacing moiety. For accurate computation of the effects of ligand modifications, a complete thermodynamic analysis is shown to be needed. It requires identification of the location of water molecules in the protein-ligand interface and evaluation of the free-energy changes associated with their removal and with the introduction of the ligand modification. Direct modification of the ligand in free-energy calculations is likely to trap the ordered molecule and provide misleading guidance for lead optimization.
No abstract is provided for this article.
An overview is given on the diverse uses of computational chemistry in drug discovery. Particular emphasis is placed on virtual screening, de novo design, evaluation of drug-likeness, and advanced methods for determining protein-ligand binding.
Three new metallohosts (2−4) were synthesized by the uranyl-templated macrocyclization of the appropriate dialdehydes 13a−c and 1,2-phenylenediamine in methanol. Cyclization of the dialdehyde 13b led to two isomers (3a, major, and 3b, minor), which only differed in the orientation of the isopropyl substituents on the outer phenolic rings of the terphenyl moiety. The binding constants in CDCl3 of ammonia and benzylamine were determined by 1H NMR spectroscopy. The binding of ammonia by these hosts follows 1 ≈ 2 ≈ 4 < 3b < 3a. The binding of benzylamine follows 1 ≈ 2 ≈ 4 ≈ 3b ≪ 3a. Monte Carlo free-energy perturbation calculations reproduced the binding of ammonia and n-propylamine quite well. The much larger binding of benzylamine by host 3a was rationalized by a much deeper positioning of the guest in the cavity of the host compared to 3b.
No abstract is provided for this article.
An efficient concerted rotation algorithm for use in Monte Carlo statistical mechanics simulations of polypeptides is reported that includes flexible bond and dihedral angles. A Gaussian bias is applied with driver bond and dihedral angles to optimize the sampling efficiency. Jacobian weighting is required in the Metropolis test to correct for imbalances in resultant transition probabilities. Testing of the methodology includes Monte Carlo simulations for polyalanines with 8–14 residues and a 36-residue protein as well as a search to find the lowest-energy conformer of the pentapeptide Met-enkephalin. The results demonstrate the formal correctness and efficiency of the method.
