Predicting the Mechanism and Kinetics of the Watson-Crick to Hoogsteen Base Pairing Transition

DNA duplexes predominantly contain Watson-Crick (WC) base pairs. Yet, a non-negligible number of base pairs converts to the Hoogsteen (HG) hydrogen bonding pattern, involving a 180° rotation of the purine base relative to Watson-Crick. These WC to HG conversions alter the conformation of DNA, and may play a role in several processes including recognition and replication. The transient nature of these processes hamper thorough experimental investigation. Molecular dynamics simulations can provide complementary insights to experiments at high spatial and temporal resolution. By using path sampling techniques, a framework that harvests molecular dynamics trajectories that undergo reactions of interest, we avoid long waiting times in stable states, thus focusing on the actual transition. Our results reveal that WC to HG conversion can proceed along different routes with a varying degree of exposure of the purine. Furthermore, we computed the rate constants for this transition using transition interface sampling.