Towards a hybrid method for detecting critical protein residues

Some regions in proteins play a critical role in determining their structure and function. Examples include flexible regions such as hinges which allow domain motions, and highly conserved functional interfaces which allow interactions with other proteins. Detecting these regions facilitates the analysis and simulation of protein rigidity and conformational changes and aids in characterizing protein-protein binding. We present an analysis of critical residues in proteins using a combination of two complementary methods. One method performs rigidity analysis to find rigid clusters of amino acids in a protein and the other method uses evolutionary conservation to find functional interfaces in proteins. We applied both methods to a dataset of proteins, including proteins with experimentally known critical residues. The results show that the combination of the two methods can detect the vast majority of critical residues in tested proteins.