Our data suggest that the evolution of distinct protein-protein interfaces may use the same basic strategy under selection pressure to maintain interactions. exceptional high accuracy (>57%). One of the most striking findings in our present study is that PND-1186 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 PND-1186 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 fromin vivoantibody affinity maturation can be utilized as a powerful tool to improve the binding affinity of protein-protein complex with a high accuracy. Keywords:Evolution/Protein, Evolution/Theory, Methods/Computation, Protein, Protein/Molecular Dynamics, Protein/Protein-Protein Interactions, Protein/Drug Interactions == Introduction == 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 protein-protein complexes is a fundamental issue with high interest for appreciating and delineating the macromolecular complexes and PND-1186 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 protein folds (3), altered enzymatic activity (4), and altered protein-protein association rate (5). However, because of limits of conformational search and inaccuracies in the treatment of polar interactions in the energy function, the design of improved binding affinity has met with limited success (6,7). Previous investigations have extensively studied the evolution of antibody/antigen interface during affinity maturation. Recently, Liet al.(1) provided the first visualization of the maturation of antibodies to protein. By directly comparing the structures of four antibodies bound to the same site on hen egg white lysozyme (HEL) at different phases PND-1186 of affinity maturation, they exposed that antibody affinity maturation is the result of small structural changes, mostly limited to the periphery of the antibody-combining site. Moreover, assessment of the germline to mature sequences inside a structural region-dependent fashion allows insights into the methods that nature uses to adult antibodies (Abs)3during the somatic hypermutation process. Tomlinsonet al.(8) have previously analyzed the diversity of amino acids at specific positions in the germline and adult Ab sequences. They found that the rate of recurrence of somatic hypermutation and the diversity of the germline sequences are highest in the CDRs. Rather than focus on the mutation Rabbit Polyclonal to ZNF225 frequencies, Clarket al.(9) examined the type of mutation and its functional implications deduced from the location in the structure. Their results indicated that residue type changes during the somatic PND-1186 hypermutation process were significant and experienced underlying practical rationales. In the present study, several strategies incorporating the evolutionary info derived fromin vivoantibody affinity maturation with classical simulation techniques was used to investigate whether the development of protein-protein interface acts in a similar way as antibody affinity maturation. If the same evolutionary mechanism is used in all the protein-protein interfaces, antibody evolutionary info would help to improve the prediction success rate.
Our data suggest that the evolution of distinct protein-protein interfaces may use the same basic strategy under selection pressure to maintain interactions