Free Energy Calculation for Base Pair Dissociation in a DNA Duplex

Abstract

DNA is the main genetic material for living organisms including many viruses. DNA duplex, coded with A=T and G=C base pairs, is well suited for biological information storage. The interactions between two bases in a base pair contribute to the stability of DNA duplex, and are further related to gene replication and transcription. In this study, we use all-atom Molecular dynamics (MD) simulations combined with Umbrella sampling (US) method to determine the free energy profiles and explore the molecular details for base pair dissociations. Four groups of DNA duplexes with different sequences have been constructed and a total of 4.3 mu s MD simulations have been carried out. In the potential of mean force (PMF) profile for G equivalent to C base pair dissociation (denoted as PMF-PGC), we observed three peaks, which correspond to the three moments G equivalent to C base pair loses its three hydrogen bonds respectively. Differently, A=T base pair loses its two hydrogen bonds within a very short time. As a result, only one hydrogen bond rupture peak was observed in its PMF curve (denoted as PMF-PAT). Compared with PMF-PAT, the overall free energy barrier in PMF-PGC is higher, which is due to the better stability of G equivalent to C than A=T. In the latter sections of both PMFs, free energies are still increasing, which is mainly resulted from the rigidity of DNA duplex backbone. We have also investigated the impact of neighboring base pairs on the stability of middle one. It is found that neighboring G equivalent to C base pairs increase the stability of A=T base pair while neighboring C equivalent to G base pairs reduce the stability of A=T base pair. Additionally, neighboring T=A base pairs have little influence on the stability of A=T base pair.