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Molecular dynamics (MD) and Monte Carlo (MC) simulations are being used to investigate protein denaturation. The calculations use the AMBER/OPLS force field with explicit representation of the solvent via the TIP3P and TIP4P models of water. The thermal denaturation of apomyoglobin has been followed in two 500 ps MD simulations at 85 °C. The resultant structures provide a detailed model of a molten globule, and close agreement is obtained with experimental data on the helical content of both native apomyoglobin and the low pH folding intermediate. The mechanism of protein denaturation by chaotropic agents is also being pursued. The possibility of direct contact between the chaotropes and aromatic sidechains is supported by MC computations of free energy profiles for the approach of urea and guanidinium ion to aromatic hydrocarbons in water.
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A quantum mechanical bespoke molecular mechanics force field is derived for the L99A mutant of T4 lysozyme and used to compute absolute binding free energies of six benzene analogs to the protein. Promising agreement between theory and experiment highlights the potential for future use of system-specific force fields in computer-aided drug design.
In enzymes, multiple structural effects cooperatively lead to the high catalytic activity, while individually these effects can be small. The design of artificial enzymes requires the understanding and ability to manipulate such subtle effects. The 34E4 catalytic antibody, catalyzing Kemp elimination of 5-nitrobenzisoxazole, and its Glu50Asp (E50D) variant are the subject of the present investigation. This removal of only a methylene group yields an approximately 30-fold reduction in the rate for the catalyzed Kemp elimination. Here, the aim is to understand this difference in the catalytic performance. The mechanism of Kemp elimination catalyzed by 34E4 and the E50D mutant is elucidated using QM/MM Monte Carlo simulations and free energy perturbation theory. In both proteins, the reaction is shown to follow a single-step, concerted mechanism. In the mutant, the activation barrier rises by 2.4 kcal/mol, which corresponds to a 62-fold rate deceleration, which is in good agreement with the experimental data. The positions and functionality of the residues in the active site are monitored throughout the reaction. It is concluded that the looser contact with the base, shorter base-Asn58 contact, less favorable pi-stacking with Trp91 in the transition state of the reaction, and different solvation pattern all contribute to the reduction of the reaction rate in the E50D variant of 34E4.
An intermolecular potential function for the methanol dimer has been derived from ab initio molecular orbital calculations with a minimal basis set (STO-3G). Dimerization energies for 270 orientations of the dimer chosen using the energy distributed random geometries method were fit to a 12-6-1 potential function. A five particle model was adopted for each monomer consisting of the oxygen atom with two pseudotone pairs, the hydroxyl hydrogen and the methyl group. The fit for bound geometries is excellent, while repulsive points are less well represented owing to the simple model for the methyl group. By analyzing accurate potential functions for the methane and water dimers, corrections for the methyl–methyl and oxygen–hydrogen dispersion interactions are estimated. The modified potential has proven successful in simulations of liquid methanol.
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The binding energies for cation−π complexation are underestimated by traditional fixed-charge force fields owing to their lack of explicit treatment of ion-induced dipole interactions. To address this deficiency, an explicit treatment of cation−π interactions has been introduced into the OPLS-AA force field. Following prior work with atomic cations, it is found that cation−π interactions can be handled efficiently by augmenting the usual 12–6 Lennard-Jones potentials with 1/r4 terms. Results are provided for prototypical complexes as well as protein–ligand systems of relevance for drug design. Alkali cation, ammonium, guanidinium, and tetramethylammonium were chosen for the representative cations, while benzene and six heteroaromatic molecules were used as the π systems. The required nonbonded parameters were fit to reproduce structure and interaction energies for gas-phase complexes from density functional theory (DFT) calculations at the ωB97X-D/6-311++G(d,p) level. The impact of the solvent was then examined by computing potentials of mean force (pmfs) in both aqueous and tetrahydrofuran (THF) solutions using the free-energy perturbation (FEP) theory. Further testing was carried out for two cases of strong and one case of weak cation−π interactions between druglike molecules and their protein hosts, namely, the JH2 domain of JAK2 kinase and macrophage migration inhibitory factor. FEP results reveal greater binding by 1.5–4.4 kcal/mol from the addition of the explicit cation−π contributions. Thus, in the absence of such treatment of cation−π interactions, errors for computed binding or inhibition constants of 101–103 are expected.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTChemical consequences of orbital interactions. 6. The similarity of solvent effects on carbocationsWilliam L. JorgensenCite this: J. Am. Chem. Soc. 1977, 99, 1, 280–283Publication Date (Print):January 1, 1977Publication History Published online1 May 2002Published inissue 1 January 1977https://pubs.acs.org/doi/10.1021/ja00443a067https://doi.org/10.1021/ja00443a067research-articleACS PublicationsRequest reuse permissionsArticle Views112Altmetric-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 InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
