Asymmetric mutation rates at enzyme-inhibitor interfaces: implications for the protein-protein docking problem.

We have carried out a thorough and systematic sequence-structure study on how the pattern of conservation at the interface differs from the noninteracting surface in seven proteases and their inhibitors. As expected, the interface of a protease could be easily distinguished from the noninteracting surface by a concentrated area of conservation. In contrast, there was less distinction to be made between the interface and the noninteracting surface of inhibitors, and in five of the seven cases, a higher proportion of the interface area was variable compared to the rest of the surface. This is likely to cause a problem for binding-site prediction methods that assume the largest cluster of highly conserved residues on the surface of a protein corresponds to the interface. We conclude that such methods would succeed when applied to our protease test cases, but complications could arise with the inhibitors. These results also impact on methods to solve the protein-protein docking problem that use conservation at the interface to provide the location of the two protein binding sites prior to application of the docking algorithm.