title: Evolutionary Covariance Combined with Molecular Dynamics Predicts a Framework for Allostery in the MutS DNA Mismatch Repair Protein.
abstract: Mismatch repair (MMR) is an essential, evolutionarily conserved pathway that maintains genome stability by correcting base-pairing errors in DNA. Here we examine the sequence and structure of MutS MMR protein to decipher the amino acid framework underlying its two key activities-recognizing mismatches in DNA and using ATP to initiate repair. Statistical coupling analysis (SCA) identified a network (sector) of coevolved amino acids in the MutS protein family. The potential functional significance of this SCA sector was assessed by performing molecular dynamics (MD) simulations for alanine mutants of the top 5% of 160 residues in the distribution, and control nonsector residues. The effects on three independent metrics were monitored: (i) MutS domain conformational dynamics, (ii) hydrogen bonding between MutS and DNA/ATP, and (iii) relative ATP binding free energy. Each measure revealed that sector residues contribute more substantively to MutS structure-function than nonsector residues. Notably, sector mutations disrupted MutS contacts with DNA and/or ATP from a distance via contiguous pathways and correlated motions, supporting the idea that SCA can identify amino acid networks underlying allosteric communication. The combined SCA/MD approach yielded novel, experimentally testable hypotheses for unknown roles of many residues distributed across MutS, including some implicated in Lynch cancer syndrome.
authors.affiliation: Molecular Biology and Biochemistry Department, ‡Molecular Biophysics Program, §Chemistry Department, and ∥Computer Science Department, Wesleyan University , Middletown, Connecticut 06459, United States.
authors.forename: Bharat
authors.initials: B
authors.lastname: Lakhani
authors.affiliation: Molecular Biology and Biochemistry Department, ‡Molecular Biophysics Program, §Chemistry Department, and ∥Computer Science Department, Wesleyan University , Middletown, Connecticut 06459, United States.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Thayer
authors.affiliation: Molecular Biology and Biochemistry Department, ‡Molecular Biophysics Program, §Chemistry Department, and ∥Computer Science Department, Wesleyan University , Middletown, Connecticut 06459, United States.
authors.forename: Manju M
authors.identifier: 0000-0003-3133-4495
authors.initials: MM
authors.lastname: Hingorani
authors.affiliation: Molecular Biology and Biochemistry Department, ‡Molecular Biophysics Program, §Chemistry Department, and ∥Computer Science Department, Wesleyan University , Middletown, Connecticut 06459, United States.
authors.forename: David L
authors.identifier: 0000-0003-2150-899X
authors.initials: DL
authors.lastname: Beveridge
mesh_terms: D053843:DNA Mismatch Repair; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D051719:MutS DNA Mismatch-Binding Protein / Q000737:chemistry*; D013824:Thermus / Q000737:chemistry
chemical_list: D051719:MutS DNA Mismatch-Binding Protein