Book of Abstracts: Albany 2009
June 16-20 2009
© Adenine Press (2008)
Recognition and Allosteric Signaling in DNA Mismatch Repair: MD and GNM Studies on MutS Complexes with DNA and ATP
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 over a distance of 70 Å 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 intra- and inter-domain communication events are not fully resolved at the atomic level. In this study, 50 ns 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 longer time frame aspect of the process is treated by a Gaussian Network Model normal mode analysis. The results for the free and bound forms of the protein are analyzed to determine which model of allostery - conformational pathway, energy landscape or vibrational coupling - best describes the process. The computational challenge represented by the size and complexity of MutS-DNA complexes provides an opportunity to develop multi-scale modeling approaches for the study of allostery in large, complex multi-component biological systems.