MutS
recognizes base–base mismatches and base insertions/deletions
(IDLs) in newly replicated DNA. Specific interactions between MutS
and these errors trigger a cascade of protein–protein interactions
that ultimately lead to their repair. The inability to explain why
different DNA errors are repaired with widely varying efficiencies <i>in vivo</i> remains an outstanding example of our limited knowledge
of this process. Here, we present single-molecule Förster resonance
energy transfer measurements of the DNA bending dynamics induced by <i>Thermus aquaticus</i> MutS and the E41A mutant of MutS, which
is known to have error specific deficiencies in signaling repair.
We compared three DNA mismatches/IDLs (T-bulge, GT, and CC) with repair
efficiencies ranging from high to low. We identify three dominant
DNA bending states [slightly bent/unbent (<b>U</b>), intermediately
bent (<b>I</b>), and significantly bent (<b>B</b>)] and
find that the kinetics of interconverting among states varies widely
for different complexes. The increased stability of MutS–mismatch/IDL
complexes is associated with stabilization of <b>U</b> and lowering
of the <b>B</b> to <b>U</b> transition barrier. Destabilization
of <b>U</b> is always accompanied by a destabilization of <b>B</b>, supporting the suggestion that <b>B</b> is a “required”
precursor to <b>U</b>. Comparison of MutS and MutS-E41A dynamics
on GT and the T-bulge suggests that hydrogen bonding to MutS facilitates
the changes in base–base hydrogen bonding that are required
to achieve the <b>U</b> state, which has been implicated in
repair signaling. Taken together with repair propensities, our data
suggest that the bending kinetics of MutS–mismatched DNA complexes
may control the entry into functional pathways for downstream signaling
of repair