The influence of base pair tautomerism on single point mutations in aqueous DNA

Abstract

The relationship between base pair hydrogen bond proton transfer and the rate of spontaneous single point mutations at ambient temperatures and pressures in aqueous DNA is investigated. By using an ensemble-based multiscale computational modelling method, statistically robust rates of proton transfer for the A:T and G:C base pairs within a solvated DNA dodecamer are calculated. Several different proton transfer pathways are observed within the same base pair. It is shown that, in G:C, the double proton transfer tautomer is preferred, while the single proton transfer process is favoured in A:T. The reported range of rate coefficients for double proton transfer is consistent with recent experimental data. Notwithstanding the approximately 1000 times more common presence of single proton transfer products from A:T, observationally there is bias towards G:C to A:T mutations in a wide range of living organisms. We infer that the double proton transfer reactions between G:C base pairs have a negligible contribution towards this bias for the following reasons: (i) the maximum half-life of the G*:C* tautomer is in the range of picoseconds, which is significantly smaller than the milliseconds it takes for DNA to unwind during replication, (ii) statistically, the majority of G*:C* tautomers revert back to their canonical forms through a barrierless process, and (iii) the thermodynamic instability of the tautomers with respect to the canonical base pairs. Through similar reasoning, we also deduce that proton transfer in the A:T base pair does not contribute to single point mutations in DNA.

The influence of external electric fields on proton transfer tautomerism in the guanine–cytosine base pair

“…In addition, we will use QM/MM to investigate the influence external electric fields have on the rate of single point mutations in aqueous DNA via the proton transfer imino-enol tautomerism in the Watson-Crick GC base pair. We have shown in our previous work 6 that this combination of multiscale techniques yields activation energy barriers and rate coefficients for GC proton transfer that are in better agreement with recent NMR experiments 3,4 than alternative gas-phase QM models. The errors in our simulations are quantified by performing multiple replicas via the application of an ensemble-based methodology.…”

“…A total of 25 different configurations were chosen on a distance-based criterion between the nucleobases in the base pair of interest. As shown in our previous work, 6 an ensemble of 25 QM/MM replicas is more than enough to achieve a suitable convergence in base pair proton transfer energies, with associated errors as low as 0.25 kcal mol À1 .…”

“…Recent computational studies have calculated the kinetic and thermodynamic properties of the Watson-Crick base pair tautomers to be highly unstable using density functional theory (DFT) 5 and DFT quantum mechanical/molecular mechanical (QM/MM) techniques. 6 The simulations predict the G*C* tautomer to have a very small concentration at equilibrium (K = 10 À9 ) and the fast kinetics of the reverse reaction (G*C* -GC) promote the swift reverting of the tautomer to canonical GC. In addition, 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.…”

“…6 The simulations predict the G*C* tautomer to have a very small concentration at equilibrium (K = 10 À9 ) and the fast kinetics of the reverse reaction (G*C* -GC) promote the swift reverting of the tautomer to canonical GC. In addition, 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.…”

Computational biomedicine. Part 1: molecular medicine

“…Gheorghiu et al [11] have studied the role of quantum mechanical processes associated with proton hopping between base pairs within DNA double helices, using a combination of ensemble-based classical molecular dynamics coupled to quantum mechanics/molecular mechanics, in order to calculate the rates of these reaction processes, the barriers to the reverse reactions and thermodynamic aspects, which lead to the conclusion that the Löwdin mechanism for mutations is unlikely to play a significant role in causing mutations within human DNA.…”