Regional covariation and its application for predicting protein contact patches

Abstract

Correlated mutation analysis (CMA) is an effective approach for predicting functional and structural residue interactions from multiple sequence alignments (MSAs) of proteins. As nearby residues may also play a role in a given functional interaction, we were interested in seeing whether covarying sites were clustered, and whether this could be used to enhance the predictive power of CMA. A large-scale search for coevolving regions within protein domains revealed that if two sites in a MSA covary, then neighboring sites in the alignment also typically covary, resulting in clusters of covarying residues. The program PatchD(http://www.uhnres.utoronto.ca/labs/tillier/) was developed to measure the covariation between disconnected sequence clusters to reveal patch covariation. Patches that exhibit strong covariation identify multiple residues that are generally nearby in the protein structure, suggesting that the detection of covarying patches can be used in conjunction with traditional CMA approaches to reveal functional interaction partners.

Platinum/taxane‐based chemotherapy with or without radiation therapy favorably impacts survival outcomes in stage I uterine papillary serous carcinoma

“…However, the fact that these residues correlate with each other so strongly implies that these residue networks possess some evolutionary advantage, although they may not be necessary for the stability of the domain as a whole. This finding suggests that these covarying residues are instead important for function,45 the binding specificity of the constant domains to their respective variable domains, light chains, or other constant domains, and may therefore be manipulated when designing antibodies for therapeutic use. Sparse networks of co‐evolving residues have been shown to connect functional areas in other types of protein domains 46, 47.…”

A Coevolutionary Residue Network at the Site of a Functionally Important Conformational Change in a Phosphohexomutase Enzyme Family

“…This highlights a drawback of coevolutionary analyses in all proteins, which is the difficulty of evaluating (experimentally or otherwise) the roles of the many pairwise residue couplings, particularly in the case of a large protein such as PMM/PGM. As an alternative, some recent studies have chosen to focus on coevolving residue “networks” [6], [33], [34], i.e. groups of coupled residues all of which co-vary with each other.…”

Protein Sequence Alignment Analysis by Local Covariation: Coevolution Statistics Detect Benchmark Alignment Errors

“…Increased local covariation should not be confused with patch covariation, where two short contiguous segments of sequence coevolve with one another [19]. Increased local covariation is only concerned with covariation that occurs within a short segment of an alignment, not between segments.…”

“…Coevolving residues are thought to arise by a mechanism of constrained amino acid change [9], [17], [18]. Many covariation statistics predict contacting pairs with high accuracy [13]–[15], [19]. If this dependency between positions is due to some evolutionary process, like structural or functional constraints, then it is often defined as coevolution [20].…”