New parameterization approaches of the LIE method to improve free energy calculations of PlmII-Inhibitors complexes
2010 Wiley Periodicals, Inc.
| Publié dans: | Journal of computational chemistry. - 1984. - 31(2010), 15 vom: 30. Nov., Seite 2723-34 |
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| Auteur principal: | |
| Autres auteurs: | , , , , |
| Format: | Article en ligne |
| Langue: | English |
| Publié: |
2010
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| Accès à la collection: | Journal of computational chemistry |
| Sujets: | Journal Article Research Support, Non-U.S. Gov't Antimalarials Enzyme Inhibitors Ligands Protozoan Proteins Aspartic Acid Proteases EC 3.4.- Aspartic Acid Endopeptidases EC 3.4.23.- plus... |
| Résumé: | 2010 Wiley Periodicals, Inc. The standard parameterization of the Linear Interaction Energy (LIE) method has been applied with quite good results to reproduce the experimental absolute binding free energies for several protein-ligand systems. However, we found that this parameterization failed to reproduce the experimental binding free energy of Plasmepsin II (PlmII) in complexes with inhibitors belonging to four dissimilar scaffolds. To overcome this fact, we developed three approaches of LIE, which combine systematic approaches to predict the inhibitor-specific values of α, β, and γ parameters, to gauge their ability to calculate the absolute binding free energies for these PlmII-Inhibitor complexes. Specifically: (i) we modified the linear relationship between the weighted nonpolar desolvation ratio (WNDR) and the α parameter, by introducing two models of the β parameter determined by the free energy perturbation (FEP) method in the absence of the constant term γ, and (ii) we developed a new parameterization model to investigate the linear correlation between WNDR and the correction term γ. Using these parameterizations, we were able to reproduce the experimental binding free energy from these systems with mean absolute errors lower than 1.5 kcal/mol |
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| Description: | Date Completed 21.12.2010 Date Revised 14.09.2010 published: Print Citation Status MEDLINE |
| ISSN: | 1096-987X |
| DOI: | 10.1002/jcc.21566 |