Dynamic Coarse-Graining of DNA Melting Kinetics: Enthalpic and Entropic Effects of Cooperative Base-Pair Dynamics

Abstract

Thermodynamics and kinetics are two fundamental aspects of DNA melting and annealing. The thermodynamics of DNA duplex melting, dominated by states involving either strongly bound duplexes or widely separated strands, are well characterized and can be described by two-state models. On the other hand, kinetics involve the rarely visited intermediate states and are therefore harder to understand. Melting kinetics involve large enough time scales to prevent meaningful studies through all-atom molecular dynamics (MD) simulations, leading to the need to develop coarse-grained models. Existing coarse-grained models described well the thermodynamic melting temperature and near-equilibrium phenomena such as bubble formation and sharp phase transitions. However, the predicted kinetic rates were off by several orders of magnitude because they do not capture non-equilibrium cooperative dynamics near the transition state such as coupling among base unstacking, hydration cage vibration/breakup, and the untwisting of the helix. In this work, an MD dynamic coarse-graining approach is developed to analyze the correct melting kinetics of short DNA sequences. By projecting the dynamics onto the one-dimensional cooperative reaction coordinate based on time-scale separation, we decipher the sequential triggering of several key events that determine the successive changes in enthalpy, vibrational entropy, and configurational entropy towards the melting barrier. This results in a Fick-Jacobs “inverted-funnel” transition state theory which allows us to use all-atom MD simulations, principal component analysis, and elastic homogenization theory to identify the enthalpies and entropies at strategic locations along the reaction coordinate and to estimate the melting rate in agreement with experimental results.