Recognition and Signaling in DNA Mismatch Repair: MD Studies of MutS Complexes with DNA and ATP

Abstract

The MutS family of DNA binding proteins has been reported to play a critical role in mismatch repair (MMR). Crystal structures of MutS (Escherichia coli and Thermus aquaticus) as well MSH homologs including human MutSα reveal intricate and complex multi-domain protein structures comprised of greater than 1,500 residues. The DNA binding domain of these proteins recognizes mispaired or unpaired bases. It has been proposed that this recognition event results in the release of a signal that travels from the DNA binding domain to the ATPase site. While much has been learned from previous binding studies of MutS, the contribution of the protein dynamics on MutS complex formation and intraprotein communication events are not fully resolved at the atomic level. In this study, state-of-the-art molecular dynamics (MD) simulations are used to investigate the dynamical processes that occur during the interactions with DNA and ATP substrates. In particular, we are interested in how the DNA mismatch recognition/binding event is signaled, triggering the initiation of DNA repair. The computational challenge represented by the size and complexity of MutS-DNA complexes provides an opportunity to develop MD approaches for large multi-component biological systems.