Unraveling the dynamics and energetic events involved in the flipping process of thymine glycol lesion using computational approaches.
Tanashree Jaganade and U. Deva Priyakumar
Center for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad, 500032, India
Abstract
Our genome constantly gets exposed to some internal or external damages. To repair these damages caused by continuous environmental attacks and to preserve the genome integrity, DNA repair mechanisms are essential for cell survival. Thymine glycol (TG) is one of the principal damaging lesions produced by oxidation of thymine. To undergo repair mechanism TG lesion has to excise from the intrahelical state into the enzymes active site. Base-flipping process is the key step in DNA repair mechanism and it involves high free energy barrier. The primary aim of this study is to unravel the energetic events which drive lesion containing flipping process in absence and presence of the enzyme and to elucidate the effect of the lesion on structural perturbations and dynamics of the DNA. In the current study, employing atomistic simulations combined with efficient umbrella sampling method, we analyzed free energy profiles of thymine glycol (TG lesion) containing and lesion free DNA in the presence and absence of Mimivirus Nei1 endonuclease. Lowest energy barrier was obtained for TG in presence of enzyme followed by lesion containing free DNA in comparison to undamaged (THY containing) system. Base flips either via minor or major groove for THY or TG. W-C energies and distance between atoms strongly correlate with the obtained energy profiles for TG and THY. Change in solvation energies or SASA from closed to open states are more favorable for TG than THY. Free energy profiles in the absence and presence of enzyme showed a rapid rise in energies as moving from intrahelical to extrahelical state in all types of DNA duplexes. Lesion containing DNA was found to be happy in extrahelical conformation in presence of the enzyme. Difference between barrier heights is due to various factors such as base-pairing interactions, solvation effects, the potential energy of systems and stacking interactions. Solvation effect was found to be one of the major contributing factors which make the flipping process of the lesion favorable. With this study, we could discern the lesion containing repair mechanism at the molecular level.
References
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