Mismatch Recognition Cycle in MutS and MSH2-MSH6 from Normal Mode Analysis and Simulations

Abstract

Post-replication DNA mismatch repair (MMR) is crucial in ensuring genetic fidelity in prokaryots and eukaryots. The initial step of MMR is recognition of defective DNA by MutS or its eukaryotic homologs. Binding of MutS to mismatched DNA, the subsequent initiation of repair, and eventual recovery to a mismatch scanning mode is coupled to ATPase activity in MutS. Crystal structures of MutS and the eukaryotic MSH2:MSH6 system place the ATPase domain far away from the DNA binding domains, implicating a complex allosteric mechanism.Normal mode calculations and molecular dynamics simulations of MutS and MSH2:MSH6 structures were carried out to explore the coupling between DNA binding and ATPase activity. The mode analysis reveals conserved dynamics between the bacterial and eukaryotic complexes. Individual modes correlate ATPase activity with the probing of DNA kinking that is characteristic of mismatched DNA. Furthermore, differential ATPase activity between the MutS dimer moieties as observed experimentally is coupled to release of MutS from the mismatch during repair. Based on the calculations and consistent with available experimental data, a detailed mechanistic model of the allosteric conformational changes during DNA mismatch recognition by MutS is proposed.View Large Image | View Hi-Res Image | Download PowerPoint Slide