MISMATCH RECOGNITION BY MSH2-MSH6

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 复制后DNA错配修复是确保遗传保真度的一种基本且高度保守的机制。DNA错配修复的第一步是识别细菌中的MutS和真核生物中的MSH复合体中的DNA碱基错配和插入或缺失。MSH2-MSH6复合体的结构识别碱基错配和短碱基插入，最近从结晶学中获得了该结构，并将被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学细节。一个目的是在100 ns的时间尺度上对MSH2-MSH6进行分子动力学模拟，以研究错配识别和ATPase活性之间的变构耦合，从而导致MSH2-MSH6的构象变化来启动信号修复。第二个目标是研究MSH2-MSH6与DNA之间的详细相互作用，以了解缺陷DNA与正常DNA区分的机制，方法是使用具有新的偏置电位的偏置模拟，该偏置电位促进MSH2-MSH6沿DNA的移位。发展账户的直接目标是确定模拟软件和TeraGrid平台的最佳选择，以便为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.