Allosteric Response Is both Conserved and Variable across Three CheY Orthologs

Abstract

A computational method to identify residues likely to initiate allosteric signals has been developed. The method is based on differences within stability and flexibility profiles between wild-type and perturbed structures as computed by a distance constraint model. Application of the approach to three bacterial chemotaxis protein Y (CheY) orthologs provides a comparison of allosteric response across protein family divergence. Interestingly, we observe a rich mixture of both conservation and variability within the identified allosteric sites. While similarity within the overall response parallels the evolutionary relationships, >50% of the best scoring putative sites are only identified in a single ortholog. These results suggest that detailed descriptions of intraprotein communication are substantially more variable than structure and function, yet do maintain some evolutionary relationships. Finally, structural clusters of large response identify four allosteric hotspots, including the β4/α4 loop known to be critical to relaying the CheY phosphorylation signal.

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

“…For example, one of us has recently demonstrated using computational modeling that, while residue-specific differences within CheY allostery are large and frequent, there is a general tendency for residues that initiate allostery to be structurally clustered (61). Furthermore, we also observe stronger correlation within allostery across two closely related Escherichia coli and Salmonella typhimurium CheY orthologs, whereas there is greater diversity when compared to the more divergent Thermotoga maritima ortholog.…”

An Interfacial Thermodynamics Model for Protein Stability

“…Moreover, the DCM predicts substructures within a protein that are rigid or flexible, and identifies sets of atoms that are co-rigid or co-flexible within a correlated motion. Many studies on proteins using a minimal DCM (mDCM) have elucidated stability/flexibility relationships important to function [Livesay & Jacobs, 2006;Livesay, et al 2008;Mottonen, et al 2009;Verma, et al 2010] including the study of allostery [Mottonen, et al 2010]. The DCM provides a good estimate for conformational entropy in simple loop systems compared to exact calculations .…”

A visual analytics approach to exploring protein flexibility subspaces

“…Example 1.1: An example now illustrates how some of the above functions are able to aid scientists in exploring subspace data sets. Mottonen et al [15] found that allosteric response is both conserved and variable across the CheY protein. To investigate this further using the added subspace functions, each plot is divided into eight grid cells along both the width and length.…”

“…For example, Figure 1 shows a set of flexibility plots representing the output of the Distance Constraint Model (DCM) [15], [13], a computational model used to calculate a protein's ability to change shape based on the relationship between energy and mechanical constraints. In this case, the plots convey the allosteric response of the CheY protein under a variety of parameter sets, one plot for each parameter set.…”

“…WaveMap was primarily tested on allosteric data resulting from the DCM [15], [13] and used wavelet analysis within a highly interactive framework to reduce the data to localized neighborhoods where flexibility behavior abruptly changed. Users were allowed an overview of the features across the data set, neighborhood analysis for a small number of plots, and a detailed contextual setting considering only one, fixed height column for each plot.…”