Tautomerisation Mechanisms in the Adenine-Thymine Nucleobase Pair During DNA Strand Separation

Abstract

The adenine-thymine tautomer (A*-T*) has previously been discounted as a spontaneous mutagenesis mechanism due to the energetic instability of the tautomeric configuration. We study the stability of A*-T* while the nucleobases undergo DNA strand separation. Our calculations indicate an increase in the stability of A*-T* as the DNA strands unzip and the hydrogen bonds between the bases stretch. Molecular Dynamics simulations reveal the timescales and dynamics of DNA strand separation and statistical ensemble of opening angles present in a biological environment. Our results demonstrate that the unwinding of DNA, an inherently out-of-equilibrium process facilitated by helicase, will change the energy landscape of the adenine-thymine tautomerisation reaction. We propose that DNA strand separation allows the stable tautomerisation of adenine-thymine, providing a feasible pathway for genetic point mutations via proton transfer between the A-T bases.