Force Field Dependent DNA Breathing Dynamics: A Case Study of Hoogsteen Base Pairing in A6-DNA

Abstract

The Hoogsteen (HG) base pairing (bp) conformation, commonly observed in damaged and mutated DNA helix, facilitates DNA repair mechanism and DNA recognition by proteins and small molecules. The free energy difference of HG and Watson-Crick (WC) base pairs has been computed in previous computational studies. But, the mechanism of the conformational transition is not well understood. A detailed understanding of the process of WC to HG base pair transition can provide deeper understanding of DNA repair and recognition. In an earlier study, we explored the free energy landscape for this process using extensive computer simulation with CHARMM36 force field for the nucleic acid. In this work, we study the impact of force field models in describing the WC to HG base pairing transition using the meta-eABF enhanced sampling, quasi-harmonic entropy calculation, and non-bonded energy analysis. The secondary structures of the both base pairing forms and the topology of the free energy landscapes were consistent over different force field models, although the relative free energy, entropy and the interaction energies tend to vary. The relative stability of WC and HG conformation is dictated by a delicate balance between the enthalpic stabilization and the reduced entropy of the structurally rigid HG structure. These findings provide a holistic view on the impact of force fields on the DNA base pair dynamics leading to the formation of HG conformation and will facilitate future computational investigations of DNA repair and recognition mechanism in physiologically relevant conditions.