Book of Abstracts: Albany 2011
June 14-18 2011
©Adenine Press (2010)
Dynamical Allosterism in the Mechanism of Action of DNA Mismatch Repair Protein MutS
The multidomain protein T. aquaticus MutS and its prokaryotic and eukaryotic homologs recognize DNA replication errors and initiate mismatch repair (MMR). MutS actions are fueled by ATP binding and hydrolysis, which modulate its interactions with DNA and other proteins in the MMR pathway. The DNA binding and ATPase activities are allosterically coupled over a distance of ~70 Å, and the molecular mechanism of coupling has not been clarified. To address this problem, all-atom molecular dynamics (MD) simulations of ~150 ns including explicit solvent were performed on two key complexes—ATP-bound and ATP-free MutS•DNA(+T bulge). We used principal component analysis (PCA) in fluctuation space to assess ATP ligand-induced changes in MutS structure and dynamics. The MD calculated ensembles of thermally accessible structures showed markedly small differences between the two complexes. However, analysis of the covariance of dynamical fluctuations revealed a number of potentially significant inter-residue and inter-domain couplings. Moreover, PCA analysis revealed clusters of correlated atomic fluctuations linking the DNA and nucleotide binding sites, especially in the ATP-bound MutS•DNA(+T) complex. These results support the idea that allosterism between the nucleotide and DNA binding sites in MutS can occur via ligand-induced changes in motion, i.e., dynamical allosterism.
This work was supported by the NSF (MCB-1022203 to M.M.H) and the NIH (GM-076490 to D.L.B). S.N.P. was supported by a NIH NRSA Postdoctoral Fellowship (F32-GM-87101).
Susan N. Pieniazek
Department of Chemistry