title: Base-flipping mechanism in postmismatch recognition by MutS.
abstract: DNA mismatch recognition and repair is vital for preserving the fidelity of the genome. Conserved across prokaryotes and eukaryotes, MutS is the primary protein that is responsible for recognizing a variety of DNA mismatches. From molecular dynamics simulations of the Escherichia coli MutS-DNA complex, we describe significant conformational dynamics in the DNA surrounding a G·T mismatch that involves weakening of the basepair hydrogen bonding in the basepair adjacent to the mismatch and, in one simulation, complete base opening via the major groove. The energetics of base flipping was further examined with Hamiltonian replica exchange free energy calculations revealing a stable flipped-out state with an initial barrier of ~2 kcal/mol. Furthermore, we observe changes in the local DNA structure as well as in the MutS structure that appear to be correlated with base flipping. Our results suggest a role of base flipping as part of the repair initiation mechanism most likely leading to sliding-clamp formation.
authors: Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, Michigan, USA.
authors: Sean M
authors: SM
authors: Law
authors: Michael
authors: M
authors: Feig
mesh_terms: D020137:Base Pair Mismatch; D020029:Base Pairing; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D004926:Escherichia coli; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D051719:MutS DNA Mismatch-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D029968:Escherichia coli Proteins; D004247:DNA; D051719:MutS DNA Mismatch-Binding Protein; C497175:MutS protein, E coli