Differential Mismatch Recognition Specificities of Eukaryotic MutS Homologs, MutSα and MutSβ

In eukaryotes, the recognition of the DNA postreplication errors and initiation of the mismatch repair is carried out by two MutS homologs: MutS alpha and Mut beta. MutS alpha recognizes base mismatches and 1 to 2 unpaired nucleotides whereas MutS beta recognizes longer insertion-deletion loops (IDLs) with 1 to 15 unpaired nucleotides as well as certain mismatches. Results from molecular dynamics simulations of native MutS beta:IDL-containing DNA and MutSa:mismatch DNA complexes as well as complexes with swapped DNA substrates provide mechanistic insight into how the differential substrate specificities are achieved by MutS alpha and MutS beta, respectively. Our simulations results suggest more extensive interactions between MutS beta and IDL-DNA and between MutS alpha and mismatch-containing DNA that suggest corresponding differences in stability. Furthermore, our simulations suggest more expanded mechanistic details involving a different degree of bending when DNA is bound to either MutS alpha or MutS beta and a more likely opening of the clamp domains when noncognate substrates are bound. The simulation results also provide detailed information on key residues in MutS beta and MutSa that are likely involved in recognizing IDL-DNA and mismatch-containing DNA, respectively.