Characterization of domain-peptide interaction interface: a generic structure-based model to decipher the binding specificity of SH3 domains.

Extensive efforts have been devoted to determining the binding specificity of Src homology 3 (SH3) domains usually in a case-by-case manner. A generic structure-based model is necessary to decipher the protein recognition code of the entire domain family. In this study, we have developed a general framework that combines molecular modeling and a machine learning algorithm to capture the energetic characteristics of the domain-peptide interactions and predict the binding specificity of the SH3 domain family. Our model is not trained for individual SH3 domains; rather it is a generic model for the entire domain family. Our model not only achieved satisfactory prediction accuracy but also provided structural insights into which residues are important for the binding specificity. The success of our framework on SH3 domains suggests that it is possible to establish a theoretical model to decipher the protein recognition code of any modular domain.