Coupled mutation finder: A new entropy-based method quantifying phylogenetic noise for the detection of compensatory mutations

Abstract

BackgroundThe detection of significant compensatory mutation signals in multiple sequence alignments (MSAs) is often complicated by noise. A challenging problem in bioinformatics is remains the separation of significant signals between two or more non-conserved residue sites from the phylogenetic noise and unrelated pair signals. Determination of these non-conserved residue sites is as important as the recognition of strictly conserved positions for understanding of the structural basis of protein functions and identification of functionally important residue regions. In this study, we developed a new method, the Coupled Mutation Finder (CMF) quantifying the phylogenetic noise for the detection of compensatory mutations.ResultsTo demonstrate the effectiveness of this method, we analyzed essential sites of two human proteins: epidermal growth factor receptor (EGFR) and glucokinase (GCK). Our results suggest that the CMF is able to separate significant compensatory mutation signals from the phylogenetic noise and unrelated pair signals. The vast majority of compensatory mutation sites found by the CMF are related to essential sites of both proteins and they are likely to affect protein stability or functionality.ConclusionsThe CMF is a new method, which includes an MSA-specific statistical model based on multiple testing procedures that quantify the error made in terms of the false discovery rate and a novel entropy-based metric to upscale BLOSUM62 dissimilar compensatory mutations. Therefore, it is a helpful tool to predict and investigate compensatory mutation sites of structural or functional importance in proteins. We suggest that the CMF could be used as a novel automated function prediction tool that is required for a better understanding of the structural basis of proteins. The CMF server is freely accessible at http://cmf.bioinf.med.uni-goettingen.de.

A Novel Sequence-Based Feature for the Identification of DNA-Binding Sites in Proteins Using Jensen–Shannon Divergence

“…For this purpose, we adopt the ideas from Capra et al [34] and our previous studies CMF [36] and QCMF [32]. Our approach is an information theoretic method that applies the Jensen-Shannon divergence (JSD) for amino acid distributions of each site in a protein in two different ways.…”

“…Only the non-binding sites of our training data are used to compute p nd . As we have seen in [32] and [36], transforming empirical amino acid distributions of MSA columns by a carefully designed doubly stochastic matrix is an effective way to integrate the binding site signals. To this end, we first set up a counting matrix C bind in a way similar to that of calculating the matrix C nd .…”

“…Compared with [32] and [36], we enhance the effect of transforming M's empirical column distributions by means of the doubly stochastic matrix D just defined. Let k be a column index of M. First, we compute the matrix product C (t) M k := C M k · D. Second, we add up all of C (t) M k 's rows.…”

“…In this study, following the line of Capra et al [34] we first quantify the divergence between the observed amino acid distribution of a site in a protein and the background distribution of non-binding sites by using JSD. After that, in analogy to our previous studies QCMF [32] and CMF [36], we incorporate biochemical signals of binding residues in the calculation of JSD that results in the intensification of the DNA-binding residue signals from the non-binding signals.…”

New Measurement for Correlation of Co-evolution Relationship of Subsequences in Protein

“…However, not all the predicted sites have high individual MI values with each other. Since top 75 pairwise sites using in connðkÞ is over-conservative [40], some co-evolved important sites are ranked lower than 75. In fact, a string of adjacent residues shows high similarity in secondary chemical shifts with a string of residues in a database, the central residues in the two strings are likely to have similar backbone torsion angles [41].…”