MISMATCH RECOGNITION BY MSH2-MSH6

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 复制后DNA错配修复是确保遗传保真度的重要且高度保守的机制。DNA错配修复的第一步是通过细菌中的MutS和真核生物中的MSH复合物识别DNA碱基错配和插入或缺失。MSH 2-MSH 6复合物识别碱基错配和短碱基插入的结构最近已从晶体学中获得，并将用作广泛计算研究的起点，以阐明启动错配修复机制的原子细节。一个目的是进行MSH 2-MSH 6在100 ns时间尺度上的分子动力学模拟，以研究错配识别和ATP酶活性之间的变构偶联，这将导致MSH 2-MSH 6的构象变化以信号修复启动。第二个目的是研究MSH 2-MSH 6和DNA之间的详细相互作用，以了解缺陷DNA与正常DNA的区别机制，通过采用具有新的偏压电位的偏压模拟，促进MSH 2-MSH 6沿着DNA的易位。开发账户的近期目标是确定模拟软件和TeraGrid平台的最佳选择，为MRAC提案做准备。

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 is 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 is 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.