An automatic method for assessing structural importance of amino acid positions

Buried residues, bends, cysteines, prolines and leucines were significantly more likely to occupy positions highly correlated with structural change than expected by chance. Some buried residues were found to be less informative than expected, particularly residues involved in active sites and the binding of small molecules.The correlation-based method generates predictions of structural importance for superfamily positions which agree well with previous results of manual analyses, and may be of use in automated residue annotation piplines. A PERL script which implements the method is provided.Over the course of evolutionary time proteins which retain a particular molecular function accumulate neutral mutations to their sequences; these mutations in turn generate functionally neutral changes to the structure of the protein [1].The location of an amino acid residue in the sequence and structure constrains its mutability according to how easily the mutation can be accommodated without disruption [2,3]. Thus buried positions generally accept mutations less readily than those exposed to solvent and where function is conserved it is extremely rare to find mutations to active site residues [4,5].These broad details of the relationship between protein sequence and structure are well established but more detailed patterns are difficult to assess on a global scale and it becomes necessary to examine superfamilies individually to determine which positions may be most important for maintaining structure and function.A large number of manual analyses have been published [e.g. [6-10]] which identify structurally important residues in particular protein families, however these are time-consuming, rely on extensive knowledge of the details of the family in question and may be subjective. A quantitative assessment of the importance of particular amino acid sites in a family of proteins by an automatic method would be an important step towards standardising such assessments.Such a m