Anharmonic Bending Of Dna Base-Pair Mismatch

In vivo, mismatched base pairs introduced by erroneous replication are sharply bent by the DNA mismatch repair system, but how bending stiffness of mismatches contribute to mismatch recognition and repair efficiency is not clear. To investigate the extreme bending mechanics of mismatches, we designed a series of 105-bp dsDNA molecules, each with a single base pair mismatch in the middle, and measured their looping and unlooping rates with single-molecule Fluorescent Resonance Energy Transfer (FRET). The measured looping rates varied up to 15-fold and correlated well with their predicted thermodynamic stabilities. The measured unlooping rates, however, showed little correlation with the looping rates, contrary to what would be expected of a harmonically bending chain. This result suggests that the stiffness parameter of a DNA mismatch is dependent on bending angle, reminiscent of buckling or kinking transition. We propose a simple anharmonic model for DNA mismatch bending, which would better serve to explain not only our data but also the bend-weakening seen in recent molecular dynamic simulations. Our study indicates that different mismatches can differentially affect both bending and unbending steps of the mismatch repair pathway, leading to a nontrivial sequence dependence of mismatch repair efficiency.