Abstract
Here, we describe a family of methods based on residue-residue connectivity for characterizing binding sites and apply variants of the method to various types of protein-ligand complexes including proteases, allosteric-binding sites, correctly and incorrectly docked poses, and inhibitors of protein-protein interactions. Residues within ligand-binding sites have about 25% more contact neighbors than surface residues in general; high-connectivity residues are found in contact with the ligand in 84% of all complexes studied. In addition, a k-means algorithm was developed that may be useful for identifying potential binding sites with no obvious geometric or connectivity features. The analysis was primarily carried out on 61 protein-ligand structures from the MEROPS protease database, 250 protein-ligand structures from the PDBSelect (25%), and 30 protein-protein complexes. Analysis of four proteases with crystal structures for multiple bound ligands has shown that residues with high connectivity tend to have less variable side-chain conformation. The relevance to drug design is discussed in terms of identifying allosteric-binding sites, distinguishing between alternative docked poses and designing protein interface inhibitors. Taken together, this data indicate that residue-residue connectivity is highly relevant to medicinal chemistry.
Original language | English |
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Pages (from-to) | 2677-2688 |
Number of pages | 12 |
Journal | Journal of Computational Chemistry |
Volume | 31 |
Issue number | 15 |
Early online date | 8 Sep 2010 |
DOIs | |
Publication status | Published - 30 Nov 2010 |
Externally published | Yes |
Keywords
- allosteric-binding sites
- connectivity
- docking
- k-means
- ligand-binding sites
- local connectivity
- molecular chaperones
- protein-protein interface inhibitors
ASJC Scopus subject areas
- Chemistry(all)
- Computational Mathematics