Theoretical thermodynamic study of the adenine-thymine tautomeric equilibrium: Electronic structure calculations and steered molecular dynamic simulations

Abstract

Free energy of the tautomeric equilibrium A-T ! A*-T* between the canonical and noncanonical DNA base equilibrium in aqueous solution was theoretically determined by applying electronic structure methods (at the M06-2X-PCM/6-31111G(d,p) level) and steered molecular dynamic simulations. Concerted and stepwise mechanisms were considered for the double proton transfer in an effort to explain the anomalous behavior of this system where an unfavorable process without a transition state can be observed depending on the level of calculation used. Of the different mechanisms used in the simulations, the stepwise mechanism, in which the first step implies the transference of a proton from thymine to adenine, and a second step with the transference of a different proton from adenine to thymine, was the only one that showed two transition states and a reaction intermediate. However, a concerted and stepwise mechanism has similar kinetic and thermodynamic behavior, with similar reaction and activation energies. Simple proton transfer was more favorable for the transference of the hydrogen from the adenine to the thymine. The inclusion of an aqueous medium in this study only slightly modified these energies, but the barrier energy was higher when the solvent was described as a discrete medium. Transition states and intermediate structures were analyzed at molecular dynamic level. K E Y W O R D Sadenine-thymine, electronic structure calculation, proton transfer in solution, steered molecular dynamic simulations, tautomeric equilibrium, thermodynamic properties

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

“…During the geometry optimization of the double proton transfer tautomer product (A*:T*), either one or two of the transferred protons were observed to revert back to their original nucleobases, which led to either no overall reaction or single proton transfer. The glaring instability of the A*:T* tautomer is a previously well agreed upon subject, whereby several researchers have instead reported on a metastable A + :T − zwitterion intermediate and a highly unstable double proton transfer transition state [ 10 , 12 , 30 , 74 ]. In all our cases of single proton transfer in A:T, the same zwitterion product (A + :T − ) was formed.…”

“…Therefore, the B3LYP/aug-cc-pvdz with XDM dispersion correction was selected as the QM method in this study, based on its ability to accurately reproduce the binding energies and geometries of both the hydrogen bonded and stacked base pairs (as shown in electronic supplementary material, S2). royalsocietypublishing.org/journal/rsfs Interface Focus 10: 20190120 of the QM method, by the size of the explicit base pair environment and by the accessible time scale of simulation [44,73,74]. The impracticality and cost of performing multiple ab initio MD simulations is obviated by the use of a multiscale ensemble based on the QM/MM method [75].…”

“…The Gibbs free energy modifies the single proton transfer reaction coordinate shape (figure 9), by stabilizing the transition state approximately 3 kcal mol −1 more than the A + :T − zwitterion product (ΔG rxn ). Several studies have calculated the reverse Gibbs free energy barrier to be 0.5 and 3 kcal mol −1 when using the M05-2X/6-311++G** and the M06-2X/6-311++G** methods, respectively, and in conjunction with the PCM solvent approximation [16,74]. Our work is partially in agreement with an earlier study by Céron-Carrasco et al [30], who used the BP86/6-311++G** method and a micro-hydrated A:T model to predict the reverse free energy barrier to be approximately −1 kcal mol −1 .…”

“…Previous base pair proton transfer studies that use ab initio MD are limited by the expense (and therefore the accuracy) of the QM method, by the size of the explicit base pair environment and by the accessible time scale of simulation [ 44 , 73 , 74 ]. The impracticality and cost of performing multiple ab initio MD simulations is obviated by the use of a multiscale ensemble based on the QM/MM method [ 75 ].…”

Theoretical study of mechanisms for the hydrolytic deamination of cytosine via steered molecular dynamic simulations

“…The standard Gibbs energies of activation (DG ‡ ) and reaction (DG) can be determined by following the time evolution of the process, as previously shown in several works, [66][67][68][69][70][71] i.e., from the conguration of the reactant to the product (or vice versa) in elementary steps focusing on the reaction coordinate. In a previous work, 66 several calculations at different postequilibrium simulation times (200, 400, 600, 800, and 1000 ps) were performed to verify the Gaussian distribution of W in eqn (2).…”