Abstract:

Protein-protein interactions (PPI) play essential roles in biological processes. Understanding PPI from a structural, thermodynamic, and kinetic point of view gives us a better understanding about these building blocks of living systems. This review summarizes the recent progresses in PPI research, including the basic properties of the interfaces, different methods for the calculation of binding free energies, key determinants in the kinetic process of PPI, and successful examples of PPI design. Interfaces of specific biological protein complexes are distinct from non-specific crystal packing interfaces in many aspects, such as the interfacial size, the conservation of amino acid residues, and structural dynamic properties. Hotspots, hot regions, and modular structures can be found at the biological PPI interface. The binding free energy of PPI can be calculated using different approaches, such as MM-PBSA, potential of mean force, and various free energy models, based on structures of protein complexes. Various approaches and successes have been reported for new PPI design based on current knowledge, however, much needs to be done to further improve the manipulation of diverse PPI. We propose that the protein association/dissociation kinetic process should be considered in future PPI design studies, which may provide more options for the manipulation and engineering of PPI.

Key words: Protein-protein interactions, Basic property of protein-protein interfaces, Structural feature of protein-protein interfaces, Binding free energy calculation, Protein-protein interaction design, Protein-protein association/dissociation