Predicting kinetic constants of protein-protein interactions based on structural properties

Elucidating kinetic processes of protein-protein interactions (PPI) helps to understand how basic building blocks affect overall behavior of living systems. In this study, we used structure-based properties to build predictive models for kinetic constants of PPI. A highly diverse PPI dataset, protein-protein kinetic interaction data and structures (PPKIDS), was built. PPKIDS contains 62 PPI with complex structures and kinetic constants measured experimentally. The influence of structural properties on kinetics of PPI was studied using 35 structure-based features, describing different aspects of complex structures. Linear models for the prediction of kinetic constants were built by fitting with selected subsets of structure-based features. The models gave correlation coefficients of 0.801, 0.732, and 0.770 for k(off), k(on), and K(d), respectively, in leave-one-out cross validations. The predictive models reported here use only protein complex structures as input and can be generally applied in PPI studies as well as systems biology modeling. Our study confirmed that different properties play different roles in the kinetic process of PPI. For example, k(on) was affected by overall structural features of complexes, such as the composition of secondary structures, the change of translational and rotational entropy, and the electrostatic interaction; while k(off) was determined by interfacial properties, such as number of contacted atom pairs per 100 Ų. This information provides useful hints for PPI design.