The Protein-Protein Interface Evolution Acts in a Similar Way to Antibody Affinity Maturation

Abstract

Understanding the evolutionary mechanism that acts at the interfaces of protein-protein complexes is a fundamental issue with high interest for delineating the macromolecular complexes and networks responsible for regulation and complexity in biological systems. To investigate whether the evolution of protein-protein interface acts in a similar way as antibody affinity maturation, we incorporated evolutionary information derived from antibody affinity maturation with common simulation techniques to evaluate prediction success rates of the computational method in affinity improvement in four different systems: antibody-receptor, antibody-peptide, receptor-membrane ligand, and receptor-soluble ligand. It was interesting to find that the same evolutionary information could improve the prediction success rates in all the four protein-protein complexes with an exceptional high accuracy (>57%). One of the most striking findings in our present study is that not only in the antibody-combining site but in other protein-protein interfaces almost all of the affinity-enhancing mutations are located at the germline hotspot sequences (RGYW or WA), indicating that DNA hot spot mechanisms may be widely used in the evolution of protein-protein interfaces. Our data suggest that the evolution of distinct protein-protein interfaces may use the same basic strategy under selection pressure to maintain interactions. Additionally, our data indicate that classical simulation techniques incorporating the evolutionary information derived from in vivo antibody affinity maturation can be utilized as a powerful tool to improve the binding affinity of protein-protein complex with a high accuracy.Protein-mediated interactions in biological systems are used to organize the macromolecular complexes and networks responsible for regulation and complexity. Understanding the evolutionary mechanism that acts at the interfaces of proteinprotein complexes is a fundamental issue with high interest for appreciating and delineating the macromolecular complexes and networks responsible for regulation and complexity in biological systems. Affinity maturation of antibodies is unique in being the only evolutionary mechanism known to operate on a molecule in an organism's own body (1). It is interesting to ask whether the evolution of distinct protein-protein interfaces may use the same basic strategy under selection pressure to maintain interactions as that of an antibody response to a protein antigen during affinity maturation. Unfortunately, archaeological records for tracing the evolutionary pathway of specific protein-protein interfaces are unavailable. Tools to rationally alter and manipulate protein interaction offer great promise for understanding and delineating the protein-protein interface evolution (2). Recent advances in computational sciences have led to novel sophisticated and refined computational methods, which have addressed some problems related to the design of protein-protein binding affinity improvements, such as the design of stable prot...

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