Report on the research conducted under the funding of the Sloan foundation postdoctoral fellowship in Computational Molecular Biology [Systematic study of protein-protein complexes] Final report

A central question in molecular biology is what structural features are common at protein-protein interfaces and what energetic factors define the affinity and specificity of protein-protein association. Analysis of structural and mutational data on protein-protein interfaces revealed that protein-protein interfaces of different functional classes contain many more energetically important charged and polar residues than was previously thought. Since, in the context of protein folding studies, polar interactions are believed to destabilize the folded proteins, this observation raised the question as to the forces that determine the stability of protein complexes. To investigate this issue in detail, the authors developed a number of partitioning schemes that allowed them to investigate the role of selected residues, ion pairs, and networks of polar interactions in protein-protein association. The methods developed were applied to the analysis of four different protein-protein interfaces: the ribonuclease barnase and its inhibitor barstar, the human growth hormone and its receptor, subtype N9 influenze virus neuraminidase and NC41 antibody, and the Ras Binding Domain of kinase cRaf and a Ras homologue Rap1A. The calculations revealed a surprising variability in how polar interactions affect the stability of different complexes. The finding that positions of charged and polar residues on protein-protein interfaces are optimized with respect to electrostatic interactions suggests that this property can be employed for the discrimination between native conformations and trial complexes generated by a docking algorithm. Analysis indicated the presence of SH2 domains in Janus family of non-receptor protein tyrosine kinases