This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Post-replication DNA mismatch repair is an essential and highly conserved mechanism to ensure genetic fidelity. The first step in DNA mismatch repair is recognition of DNA base mismatches and insertion or deletions by MutS in bacteria and MSH complexes in eukaryots. The structure for the MSH2-MSH6 complex which recognizes base mismatches and short base insertions has recently become available from crystallography and will be used as the starting point for extensive computational studies to elucidate atomistic details of the mechanism by which mismatch repair is initiated.
One aim i s to carry out molecular dynamics simulations of MSH2-MSH6 over 100 ns time scales to study allosteric coupling between mismatch recognition and ATPase activity that would lead to conformational changes in MSH2-MSH6 to signal repair initiation.
A second aim i s to examine the detailed interaction between MSH2-MSH6 and DNA to understand the mechanism by which defective DNA is distinguished from regular DNA by employing biased simulations with a new biasing potential that facilitates translocation of MSH2-MSH6 along DNA. The immediate goal of the development account is to determine the best choice of simulation software and TeraGrid platform in preparation for an MRAC proposal.
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