A Critical Evaluation of Correlated Mutation Algorithms and Coevolution Within Allosteric Mechanisms

Abstract

The notion of using the evolutionary history encoded within multiple sequence alignments to predict allosteric mechanisms is appealing. In this approach, correlated mutations are expected to reflect coordinated changes that maintain intramolecular coupling between residue pairs. Despite much early fanfare, the general suitability of correlated mutations to predict allosteric couplings has not yet been established. Lack of progress along these lines has been hindered by several algorithmic limitations including phylogenetic artifacts within alignments masking true covariance and the computational intractability of consideration of more than two correlated residues at a time. Recent progress in algorithm development, however, has been substantial with a new generation of correlated mutation algorithms that have made fundamental progress toward solving these difficult problems. Despite these encouraging results, there remains little evidence to suggest that the evolutionary constraints acting on allosteric couplings are sufficient to be recovered from multiple sequence alignments. In this review, we argue that due to the exquisite sensitivity of protein dynamics, and hence that of allosteric mechanisms, the latter vary widely within protein families. If it turns out to be generally true that even very similar homologs display a wide divergence of allosteric mechanisms, then even a perfect correlated mutation algorithm could not be reliably used as a general mechanism for discovery of allosteric pathways.

Decipher the Mechanisms of Protein Conformational Changes Induced by Nucleotide Binding through Free-Energy Landscape Analysis: ATP Binding to Hsp70

“…Most mechanistic information about hHsp70 was derived from comparisons with the highly homologous bacterial E. coli Hsp70 (DnaK) (see Table S1). It should be mentioned however that a high homology of sequence between two proteins does not guarantee that their allosteric mechanisms and residues involved are similar [60]. In the present work, the calculations and analysis were performed for DnaK because a large set of structural and biochemical data are available (see Results and Discussion sections for a comparison with the present results and their implications for hHsp70).…”

Structured States of Disordered Proteins from Genomic Sequences

“…By exploiting recent advances in predicting tertiary contacts and 3D structures from sequence alignments, we sought to uncover what evolutionary information from protein sequences alone could reveal about 2D and 3D structural states of low complexity sequences or proteins considered disordered (Hopf et al, 2012; Livesay et al, 2012; Marks et al, 2011; Morcos et al, 2013; Morcos et al, 2011; Thompson and Baker, 2011; Weinreb et al, 2016). We made no assumption that the proteins or regions take on any structural constraint in vivo and used co-evolutionary analysis of thousands of genomic sequences to predict the likelihood of structural constraints of the human disordered proteome.…”

Intramolecular allosteric communication in dopamine D2 receptor revealed by evolutionary amino acid covariation

“…Covariation can also involve distal residues, but the function of these at-a-distance couplings is elusive and has been attributed to background noise, alternative protein conformations, or subunit interactions of protein homooligomers (5,7,12). Alternately, distal covarying residue pairs could indicate allosteric couplings (6,(13)(14)(15)(16)(17)(18).The possibility of capturing intramolecular allosteric communication by amino acid covariation analysis of protein family sequences has not been extensively explored. Nonproximal thermodynamic coupling between correlated residue pairs was noted in 274 PDZ domains (14), but the relationship to allostery is still debated (19,20).…”

“…Covariation can also involve distal residues, but the function of these at-a-distance couplings is elusive and has been attributed to background noise, alternative protein conformations, or subunit interactions of protein homooligomers (5,7,12). Alternately, distal covarying residue pairs could indicate allosteric couplings (6,(13)(14)(15)(16)(17)(18).…”

“…Nonproximal thermodynamic coupling between correlated residue pairs was noted in 274 PDZ domains (14), but the relationship to allostery is still debated (19,20). It may be that distinctive allosteric mechanisms, even among close homologs, limit the extraction of allosteric couplings from sequences (13). Our previous identification of residues important for allosteric signaling within G protein-coupled receptors (GPCRs) using Evolutionary Trace (ET) (21-24) and strong conservation of some of the residues implicated led us to ask whether ET could also uncover couplings among protein sequence positions not in direct contact.…”