title: Identifying Allosteric Hotspots with Dynamics: Application to Inter- and Intra-species Conservation.
abstract: The rapidly growing volume of data being produced by next-generation sequencing initiatives is enabling more in-depth analyses of conservation than previously possible. Deep sequencing is uncovering disease loci and regions under selective constraint, despite the fact that intuitive biophysical reasons for such constraint are sometimes absent. Allostery may often provide the missing explanatory link. We use models of protein conformational change to identify allosteric residues by finding essential surface pockets and information-flow bottlenecks, and we develop a software tool that enables users to perform this analysis on their own proteins of interest. Though fundamentally 3D-structural in nature, our analysis is computationally fast, thereby allowing us to run it across the PDB and to evaluate general properties of predicted allosteric residues. We find that these tend to be conserved over diverse evolutionary time scales. Finally, we highlight examples of allosteric residues that help explain poorly understood disease-associated variants.
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520, USA.
authors.forename: Declan
authors.initials: D
authors.lastname: Clarke
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, 260/266 Whitney Avenue, PO Box 208114, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, 260/266 Whitney Avenue, PO Box 208114, New Haven, CT 06520, USA.
authors.forename: Anurag
authors.initials: A
authors.lastname: Sethi
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, 260/266 Whitney Avenue, PO Box 208114, New Haven, CT 06520, USA; Department of Computer Science, Yale University, 260/266 Whitney Avenue, PO Box 208114, New Haven, CT 06520, USA.
authors.forename: Shantao
authors.initials: S
authors.lastname: Li
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, 260/266 Whitney Avenue, PO Box 208114, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, 260/266 Whitney Avenue, PO Box 208114, New Haven, CT 06520, USA.
authors.forename: Sushant
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Yale College, 260/266 Whitney Avenue, PO Box 208114, New Haven, CT 06520, USA.
authors.forename: Richard W F
authors.initials: RWF
authors.lastname: Chang
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, 260/266 Whitney Avenue, PO Box 208114, New Haven, CT 06520, USA; Integrated Graduate Program in Physical and Engineering Biology, Yale University, 260/266 Whitney Avenue, PO Box 208114, New Haven, CT 06520, USA.
authors.forename: Jieming
authors.initials: J
authors.lastname: Chen
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, 260/266 Whitney Avenue, PO Box 208114, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, 260/266 Whitney Avenue, PO Box 208114, New Haven, CT 06520, USA; Department of Computer Science, Yale University, 260/266 Whitney Avenue, PO Box 208114, New Haven, CT 06520, USA. Electronic address: mark@gersteinlab.org.
authors.forename: Mark
authors.initials: M
authors.lastname: Gerstein
mesh_terms: D000495:Allosteric Site; D000818:Animals; D017124:Conserved Sequence; D006801:Humans; D020543:Proteome / Q000737:chemistry; D020539:Sequence Analysis, Protein / Q000379:methods*; D012984:Software
chemical_list: D020543:Proteome