Abstract
The Watson–Crick base pair proton transfer tautomers would be widely considered as a source of spontaneous mutations in DNA replication if not for their short lifetimes and thermodynamic instability. This work investigates the effects external electric fields have on the stability of the guanine–cytosine proton transfer tautomers within a realistic strand of aqueous DNA using a combination of ensemble-based classical molecular dynamics (MD) coupled to quantum mechanics/molecular mechanics (QM/MM). Performing an ensemble of calculations accounts for the stochastic aspects of the simulations while allowing for easier identification of systematic errors. The methodology applied in this work has previously been shown to estimate base pair proton transfer rate coefficients that are in good agreement with recent experimental data. A range of electric fields in the order of 104 to 109 V m−1 is investigated based on their real-life medicinal applications which include gene therapy and cancer treatments. The MD trajectories confirm that electric fields up to 1.00 × 109 V m−1 have a negligible influence on the structure of the base pairs within DNA. The QM/MM results show that the application of large external electric fields (1.00 × 109 V m−1) parallel to the hydrogen bonds increases the thermodynamic population of the tautomers by up to one order of magnitude; moreover, the lifetimes of the tautomers remain insignificant when compared to the timescale of DNA replication.
Highlights
The proton transfer tautomers are too short-lived to be thoroughly investigated by standard experimental techniques and for this reason, researchers have turned to theoretical techniques
This work investigates the effects external electric fields have on the stability of the guanine–cytosine proton transfer tautomers within a realistic strand of aqueous DNA using a combination of ensemblebased classical molecular dynamics (MD) coupled to quantum mechanics/molecular mechanics (QM/MM)
The QM/MM results show that the application of large external electric fields (1.00 Â 109 V mÀ1) parallel to the hydrogen bonds increases the thermodynamic population of the tautomers by up to one order of magnitude; the lifetimes of the tautomers remain insignificant when compared to the timescale of DNA replication
Summary
The proton transfer tautomers are too short-lived to be thoroughly investigated by standard experimental techniques and for this reason, researchers have turned to theoretical techniques. Owing to the extremely short lifetime of G*C*, i.e., in the range of femtoseconds to picoseconds,[6] the lifetime of the transient tautomer is approximately three to five orders of magnitude smaller than the nanoseconds it takes for DNA to unwind during the replication process.[7] As such, the contribution of base pair tautomerism towards the rates of spontaneous mutations in DNA is considered to be negligible at best.
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