A comprehensive sequence alignment analysis and structure comparison of the SH3 domain family

grantor: University of TorontoTo take full advantage of the current wealth of protein sequence and structure data, rigorous methods for sequence analysis and structure comparison must be developed. In this study, a non-redundant alignment of 266 SH3 domain sequences was assembled. Henikoff weighting was used to reduce sequence bias and Shannon entropy was calculated at each position as a measure of residue conservation. Eighteen SH3 domain structures were aligned and a number of all-vs-all comparisons were performed to quantitate structural variation in the domain. No direct correlations between sequence identity or positional entropy and RMSD between structures were observed. However, conserved residues were found to consistently play important structural and/or functional roles in the SH3 domain. Several examples were noted of sequence conservation being mirrored by conservation of finer-grain structural features, such as residue burial by bound ligand or positioning in ß-turns. To further understand residue interactions in the SH3 domain, an algorithm for covariation analysis was developed. Because of its potential to aid in structure prediction, a focus of this work was on elimination of artifactual covariations and accurate prediction of residue contacts. (Abstract shortened by UMI.)M.Sc