DNA base mismatch (MM) is a defect in canonical DNA base pairing when two non-complementary bases are aligned in the same base-pair step of a duplex DNA. Such incorrect incorporation of bases, if unrepaired, generates mutations in somatic cells and cancer in various tissues. Interestingly, the mismatch repair (MMR) enzymes do not repair all types of mismatches with equal efficiency, suggesting differences in the intrinsic structural and dynamical properties of different base mismatches. Recent molecular dynamics (MD) simulation however, suggested that it is rather difficult to find a simple correlation between the structural changes of different MM base-pairs and efficiencies of MM-recognition by MMR enzymes, except that MM bases induce significant alteration in the surrounding ion and hydration environment which may allow transfer of base-specific signal to repair enzyme. In the present study, we show that different types of base mismatches indeed induce different local (solvation) dynamic signatures in the minor groove AT-rich DNA, probed by a minor groove binder, DAPI. The dynamics is measured by monitoring the time-dependent fluorescence Stokes shift (TDFSS) of the probe, DAPI over five decades of time from ~100 fs to 10 ns. Experimental results show that in all cases the underlying Stokes shift dynamics in faster time-scale follow smooth power-law type relaxation, multiplied with single or double exponential relaxations in the slower nanoseconds time-scale. The relative variations of these exponential relaxations are found to correlate well with the general trend of differential recognition of mismatches and repair efficiencies by enzymes. Direct comparison of experimental Stokes shift data with all-atom MD simulations also show that the mismatch-specific dynamics arise from collective motions of mismatched base pair and the electrostatically perturbed water and ions near the mismatch site. Our data indicate that the altered hydration and ion motions, coupled with mismatch specific motions, define the collective dynamic environment which may be sensed by the repair enzymes to differentiate mismatched bases with varying efficiencies.

Dynamic signatures of DNA base mismatches

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.