Molecular modelling prediction of ligand binding site flexibility
| Autor: | Ricardo L. Mancera, Ami Yi-Ching Yang, Per Källblad |
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| Rok vydání: | 2004 |
| Předmět: |
Models
Molecular Binding Sites Magnetic Resonance Spectroscopy Chemistry Stereochemistry A protein Proteins Plasma protein binding Ligand (biochemistry) Crystallography X-Ray Ligands Computer Science Applications Low energy Searching the conformational space for docking Docking (molecular) Drug Discovery Physical and Theoretical Chemistry Binding site Conformational isomerism Algorithms Protein Binding |
| Zdroj: | Scopus-Elsevier |
| ISSN: | 0920-654X |
| Popis: | We have investigated the efficacy of generating multiple sidechain conformations using a rotamer library in order to find the experimentally observed ligand binding site conformation of a protein in the presence of a bound ligand. We made use of a recently published algorithm that performs an exhaustive conformational search using a rotamer library to enumerate all possible sidechain conformations in a binding site. This approach was applied to a dataset of proteins whose structures were determined by X-ray and NMR methods. All chosen proteins had two or more structures, generally involving different bound ligands. By taking one of these structures as a reference, we were able in most cases to successfully reproduce the experimentally determined conformations of the other structures, as well as to suggest alternative low-energy conformations of the binding site. In those few cases where this procedure failed, we observed that the bound ligand had induced a high-energy conformation of the binding site. These results suggest that for most proteins that exhibit limited backbone motion, ligands tend to bind to low energy conformations of their binding sites. Our results also reveal that it is possible in most cases to use a rotamer search-based approach to predict alternative low-energy protein binding site conformations that can be used by different ligands. This opens the possibility of incorporating alternative binding site conformations to improve the efficacy of docking and structure-based drug design algorithms. |
| Databáze: | OpenAIRE |
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