Mutations in human genes can be responsible for inherited genetic disorders and cancer. It has been shown that certain DNA sequences are more prone to mutate [1]. These sites are termed hotspots and exhibit a higher mutation frequency than expected by chance. In contrast, DNA sequences with lower mutation frequencies than expected by chance are termed coldspots. Mutation hotspots are usually derived from a mutation spectrum, which however often reflects particular population where an effect of a common ancestor plays a role. To detect coldspots and hotspots unaffected by population bias we analysed presence of germline mutations obtained from HGMD database in the 5-nucleotide segments which repeatedly occurring in genes associated with common inherited disorders [2], particularly in PAH, LDLR, CFTR, F8, and F9 genes.
Using molecular dynamics simulations and free energy calculations we have analyzed global bending properties of selected coldspots and hotspots with G/T, G/A and A/C mismatch base pairs. Coldspots were observed to be inherently more flexible than hotspots. In addition, we observed that mismatch G/T pair opens more easily towards minor groove than a canonical G=C base pair in the bent DNA conformation. This property might be critical for effective mismatch repair as aberrant DNA recognized by MutSα protein is noticeably bent and mismatch base pair is disrupted and shifted towards minor groove where it is recognized by conserved amino acids from MutSa.