On the Structural Space of Protein-Protein Interfaces

Abstract

All major cellular processes in living cells are dependent on protein-protein interactions. At the heart of protein-protein interactions are protein-protein interfaces where the direct physical interactions occur. One may view the collection of all possible protein interface structures as a structural space. Understanding the nature of this space not only advances our fundamental knowledge about proteins but has profound implications for protein-protein interaction prediction and design. Can one explain the observed space of structures just by the principles of physics or does evolution need to be invoked as well? Here, we focus on interface structures of dimers, i.e., a complex formed by two protein monomers. By developing and applying an efficient structural alignment method, iAlign, we study the structural similarity of >1000 representative protein-protein interfaces. We present results of comparing experimental (native) interface structures formed by proteins whose monomers adopt different structures and show that most native interfaces have a close structural neighbor with similar backbone C geometry and interfacial contact pattern. To understand the possible origin of this interface similarity, we build artificial complexes from a library of randomly generated, compact homopolymeric structures and compare the structure of their interfaces to native interfaces. We show that most of native complexes can find an artificial counterpart, and vice versa. Moreover, from protein-like sequences further designed to be thermodynamically compatible with the artificial structures, native-like artificial protein complexes with strong favorable interactions emerge, albeit at a small probability.