Book of Abstracts: Albany 2005
Protein-protein Interactions: What is the Preferred Way for Proteins to Interact?
Understanding and ultimately predicting protein associations is immensely important for functional genomics and drug design. We propose that binding sites have preferred organizations. First, the hot spots cluster within densely packed ?hot regions?. Within these regions, they form networks of interactions. Thus, hot spots located within a hot region contribute cooperatively to the stability of the complex. However, the contributions of separate, independent hot regions are additive. Moreover, hot spots are often pre-organized already in the unbound (free) protein states. Describing a binding site through independent local hot regions has implications to binding site definition, design and parameterization for prediction. The compactness and co-operativity emphasize the similarity between binding and folding. This proposition is grounded in computation and experiment. It explains why summation of the interactions may overestimate the stability of the complex. Furthermore, statistically, charge-charge coupling of the hot spots is disfavored. However, since within the highly packed regions the solvent is screened, the electrostatic contributions are strengthened. Thus, we propose a new description of protein binding sites: a site consists of (one or a few) self-contained cooperative regions. Since the residue hot spots are those conserved by evolution, proteins binding multiple partners at the same sites are expected to use all or some combination of these regions.
Eventually, protein-protein interactions should be viewed within the context of Systems Biology. Within the Systems framework, predicting which proteins interact and how they interact is an extremely significant goal. It assists in assigning function, in obtaining information relating to their regulation, and provides clues to the system dynamics. It yields clues to protein design and to competing pathways. And, it provides essential information on the system robustness and drug design. Thus, I shall present our perspective of protein-protein interactions, and in particular the application of these to predict protein-protein interactions toward Systems Biology.