Persistently conserved positions in structurally similar, sequence dissimilar proteins: Roles in preserving protein fold and function

Abstract

Many protein pairs that share the same fold do not have any detectable sequence similarity, providing a valuable source of information for studying sequence‐structure relationship. In this study, we use a stringent data set of structurally similar, sequence‐dissimilar protein pairs to characterize residues that may play a role in the determination of protein structure and/or function. For each protein in the database, we identify amino‐acid positions that show residue conservation within both close and distant family members. These positions are termed “persistently conserved”. We then proceed to determine the “mutually” persistently conserved (MPC) positions: those structurally aligned positions in a protein pair that are persistently conserved in both pair mates. Because of their intra‐ and interfamily conservation, these positions are good candidates for determining protein fold and function. We find that 45% of the persistently conserved positions are mutually conserved. A significant fraction of them are located in critical positions for secondary structure determination, they are mostly buried, and many of them form spatial clusters within their protein structures. A substitution matrix based on the subset of MPC positions shows two distinct characteristics: (i) it is different from other available matrices, even those that are derived from structural alignments; (ii) its relative entropy is high, emphasizing the special residue restrictions imposed on these positions. Such a substitution matrix should be valuable for protein design experiments.