Investigation into the mechanism and dynamics of DNA association and dissociation utilizing kinetic Monte Carlo simulations

In this work, we present a kinetic Markov state Monte Carlo model designed to complement temperature-jump (T-jump) infrared spectroscopy experiments probing the kinetics and dynamics of short DNA oligonucleotides. The model is designed to be accessible to experimental researchers in terms of both computational simplicity and expense while providing detailed insights beyond those provided by experimental methods. The model is an extension of a thermodynamic lattice model for DNA hybridization utilizing the formalism of the nucleation-zipper mechanism. Association and dissociation trajectories were generated utilizing the Gillespie algorithm and parameters determined via fitting the association and dissociation timescales to previously published experimental data. Terminal end fraying, experimentally observed following a rapid T-jump, in the sequence 5′-ATATGCATAT-3′ was replicated by the model that also demonstrated that experimentally observed fast dynamics in the sequences 5′-C(AT)nG-3′, where n = 2-6, were also due to terminal end fraying. The dominant association pathways, isolated by transition pathway theory, showed two primary motifs: initiating at or next to a G:C base pair, which is enthalpically favorable and related to the increased strength of G:C base pairs, and initiating in the center of the sequence, which is entropically favorable and related to minimizing the penalty associated with the decrease in configurational entropy due to hybridization.