SeqStruct: A New Amino Acid Similarity Matrix Based on Sequence Correlations and Structural Contacts Yields Sequence-Structure Congruence

Abstract

SUMMARYProtein sequence matching does not properly account for some well-known features of protein structures: surface residues being more variable than core residues, the high packing densities in globular proteins, and does not yield good matches of sequences of many proteins known to be close structural relatives. There are now abundant protein sequences and structures to enable major improvements to sequence matching. Here, we utilize structural frameworks to mount the observed correlated sequences to identify the most important correlated parts. The rationale is that protein structures provide the important physical framework for improving sequence matching. Combining the sequence and structure data in this way leads to a simple amino acid substitution matrix that can be readily incorporated into any sequence matching. This enables the incorporation of allosteric information into sequence matching and transforms it effectively from a 1-D to a 3-D procedure. The results from testing in over 3,000 sequence matches demonstrate a 37% gain in sequence similarity and a loss of 26% of the gaps when compared with the use of BLOSUM62. And, importantly there are major gains in the specificity of sequence matching across diverse proteins. Specifically, all known cases where protein structures match but sequences do not match well are resolved.All rights reserved. No reuse allowed without permission.

New amino acid substitution matrix brings sequence alignments into agreement with structure matches

“…Our own group recently explored the approach of developing different substitution matrices for different structure families but obtained relatively small gains. 33 In a predecessor to this paper, we developed a new substitution matrix that combined BLOSUM62 matrix with the correlated pair information from multiple sequence alignments (MSAs) 34 to show in a proof of principle that this can bring structure matches and sequence matches into agreement. That substitution matrix permits too many substitutions and was found to give false positives in homolog detection.…”