Protein-protein complexes play an important role in the physiology and the pathology of multiple cellular functions. It is known that a small subset of residues (hot spot) accounts for most of the protein-protein binding free energy. Hotspots can be located at the protein-protein binding interface or can be an allosteric hotspot. However, it is important to identify the hotspots that would disrupt or enhance the protein-protein interaction. This would enable design of small molecules that disrupt the complex formation. We are developing computational alanine scanning methods to identify hotspots in protein-protein interaction. We have used molecular dynamics simulations and the alanine scanning method to identify allosteric druggable potential binding sites for drug design. We are in the process of testing these methods for various known protein-protein complexes.

Publications related to this project:

• Lin J, Buettner R, Yuan YC, Yip R, Horne D, Jove R, Vaidehi N. 2009, Molecular dynamics simulations of the conformational changes in signal transducers and activators of transcription Stat1 and Stat3. J Mol Graph Model. 28(4):347-56.
• Buettner R, Corzano R, Rashid R, Lin J, Senthil M, Hedvat M, Schroeder A, Mao A, Herrmann A, Yim J, Li H, Yuan YC, Yakushijin K, Yakushijin F, Vaidehi N, Moore R, Gugiu G, Lee TD, Yip R, Chen Y, Jove R, Horne D, Williams JC. 2011, Alkylation of Cys 468 in Stat3 defines a Novel site for therapeutic development,  ACS Chem Biol. E pub.
• Lin, J., Liu, P., Zhang, H and Vaidehi N., 2011, Computational prediction of hot spots in protein-protein complexes: factors that affect the hotspot predictions, communicated.