Proton transfer during DNA strand separation as a source of mutagenic guanine-cytosine tautomers

Abstract

Proton transfer between the DNA bases can lead to mutagenic Guanine-Cytosine tautomers. Over the past several decades, a heated debate has emerged over the biological impact of tautomeric forms. Here, we determine that the energy required for generating tautomers radically changes during the separation of double-stranded DNA. Density Functional Theory calculations indicate that the double proton transfer in Guanine-Cytosine follows a sequential, step-like mechanism where the reaction barrier increases quasi-linearly with strand separation. These results point to increased stability of the tautomer when the DNA strands unzip as they enter the helicase, effectively trapping the tautomer population. In addition, molecular dynamics simulations indicate that the relevant strand separation time is two orders of magnitude quicker than previously thought. Our results demonstrate that the unwinding of DNA by the helicase could simultaneously slow the formation but significantly enhance the stability of tautomeric base pairs and provide a feasible pathway for spontaneous DNA mutations.

How proton transfer impacts hachimoji DNA

“…We take k heli , representing the timescale of the helicase separation, to be 1.0 ps. 21 The authors of ref. 21 used ensemble MD to model the DNA strand separation process.…”

“… 21 The authors of ref. 21 used ensemble MD to model the DNA strand separation process. A schematic representation of the reactions is given in Fig.…”

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

“…However, as proposed by Florian and Leszczynski, 7 the tautomeric state must be stable enough to survive the DNA cleavage within the mitosis scheme; hence, the separation of DNA strands must be considered in order to validate proton transfer between bases as a genetic mutation mechanism. In a recent letter by Winokan et al, 18 tautomerization of the G-C base pair while undergoing DNA strand separation was investigated using DFT and molecular dynamics (MD) approaches. The conclusions of the DFT investigations determined that the tautomerization energy barrier increases as the strands move away from one another, as would be expected.…”

Quantum Tunnelling Effects in the Guanine-Thymine Wobble Misincorporation via Tautomerism

“…However, using a quantum interpretation, the tunnelling proton’s wave function evolve on a shorter time scale, so two probability distributions (in the canonical and tautomeric configuration) emerge. As previously demonstrated, once the tautomer is formed and the DNA is opened, it is stabilized and unlikely to revert to its canonical form due to a prohibitively large reaction barrier. , However, the degree to which environmental effects play a role in destabilizing the tautomer still needs to be determined. Some initial evidence suggests that the DNA environment reduces the reverse barrier, but it is unclear for the DNA and helicase complex.…”