Identification of Protein–Ligand Binding Sites by the Level-Set Variational Implicit-Solvent Approach
| Autor: | Zuojun Guo, J. Andrew McCammon, Li-Tien Cheng, Jianwei Che, Bo Li, Shenggao Zhou |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Surface Properties Stereochemistry Drug design Crystallography X-Ray Ligands Article Small Molecule Libraries Computer Software Molecular level Models Theoretical and Computational Chemistry Computational chemistry Physical and Theoretical Chemistry Binding site Level set (data structures) Crystallography Binding Sites Chemical Physics Chemistry Proteins Molecular Computer Science Applications Solvent Solvents X-Ray Biochemistry and Cell Biology Protein ligand |
| Zdroj: | Journal of chemical theory and computation, vol 11, iss 2 Guo, Z; Li, B; Cheng, LT; Zhou, S; McCammon, JA; & Che, J. (2015). Identification of protein-ligand binding sites by the level-set variational implicit-solvent approach. Journal of Chemical Theory and Computation, 11(2), 753-765. doi: 10.1021/ct500867u. UC San Diego: Retrieved from: http://www.escholarship.org/uc/item/6z55f5w3 Journal of Chemical Theory and Computation |
| ISSN: | 1549-9626 1549-9618 |
| DOI: | 10.1021/ct500867u |
| Popis: | © 2015 American Chemical Society. Protein-ligand binding is a key biological process at the molecular level. The identification and characterization of small-molecule binding sites on therapeutically relevant proteins have tremendous implications for target evaluation and rational drug design. In this work, we used the recently developed level-set variational implicit-solvent model (VISM) with the Coulomb field approximation (CFA) to locate and characterize potential protein-small-molecule binding sites. We applied our method to a data set of 515 protein-ligand complexes and found that 96.9% of the cocrystallized ligands bind to the VISM-CFA-identified pockets and that 71.8% of the identified pockets are occupied by cocrystallized ligands. For 228 tight-binding protein-ligand complexes (i.e, complexes with experimental pKdvalues larger than 6), 99.1% of the cocrystallized ligands are in the VISM-CFA-identified pockets. In addition, it was found that the ligand binding orientations are consistent with the hydrophilic and hydrophobic descriptions provided by VISM. Quantitative characterization of binding pockets with topological and physicochemical parameters was used to assess the "ligandability" of the pockets. The results illustrate the key interactions between ligands and receptors and can be very informative for rational drug design. |
| Databáze: | OpenAIRE |
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