Melting Free Energies of DNA Duplexes with oxidized Base Residues and Abasic sites: A Molecular Dynamics Characterization

Ionizing radiation alters DNA strands and mainly creates multiply damaged sites (MDS), e.g. two or more damaged sites within one or two turns of the DNA (10 to 20 base pairs). The thermodynamic behavior of DNA duplexes vary due to the altered stability induced by these lesions. In this work, we used the unrestrained molecular dynamics and thermodynamic integration free energy calculation methods to highlight the important thermodynamic characteristics of lesion-free DNA and DNA lesions: the free energy of melting. We focus on the oxidized base 8-oxoguanine lesion (8-oG) and on the abasic site lesions (AP). The results show a small free energy of mutation G 8-oG due to very small changes in hydrogen bonding interactions with the paired base and in structural reorganization induced by 8-oG. In contrast, AP cause substantial change in hydrogen bonding interactions and relaxation of the backbone giving rise to a much larger free energy of mutation G AP. Melting free energies are extracted through a thermodynamic cycle involving free energies of mutations. They show that the abasic site decreases severely the melting free energy of DNA duplex and hence induces a larger DNA destabilization than the 8-oG.