Recognition and signaling in DNA mismatch repair: interdomain communication in T. Aquaticus Muts proteins

Abstract

Allosteric communication events involving multifaceted protein architectures are critical in complex biological processes, including DNA mismatch repair (MMR). MutS and its homologs, highly conserved proteins in both prokaryotes and eukaryotes, initiate MMR by recognizing mispaired DNA and signaling downstream repair. DNA binding is allosterically coupled to ATPase activity at the nucleotide binding sites ~70 Å away. Modern theories on allosteric communication include analysis of energy landscapes and network models. These models are not independent and molecular dynamics (MD) can provide knowledge of both. In this study, thermally populated substates on the free energy surface of MutS proteins are defined using all-atom MD simulations and principle component analysis (PCA). Our investigation reveals that DNA binding facilitates both, adjustment of thermal populations and major reshaping of the surface. Analysis of the collective atomic fluctuations within the protein framework of MutS establishes possible allosteric networks, which are highly dependent on the substate.