Hybrid MC/QC simulations of water-assisted proton transfer in nucleosides. Guanosine and its analog acyclovir

Abstract

To provide an in-depth insight into the molecular basis of spontaneous tautomerism in DNA and RNA base pairs, a hybrid Monte Carlo (MC)-quantum chemical (QC) methodology is implemented to map two-dimensional potential energy surfaces along the reaction coordinates of solvent-assisted proton transfer processes in guanosine and its analog acyclovir in aqueous solution. The solvent effects were simulated by explicit inclusion of water molecules that model the relevant part of the first hydration shell around the solute. The position of these water molecules was estimated by carrying out a classical Metropolis Monte Carlo simulation of dilute water solutions of the guanosine (Gs) and acyclovir (ACV) and subsequently analyzing solute-solvent intermolecular interactions in the statistically-independent MC-generated configurations. The solvent-assisted proton transfer processes were further investigated using two different ab initio MP2 quantum chemical approaches. In the first one, potential energy surfaces of the 'bare' finite solute-solvent clusters containing Gs/ACV and four water molecules (MP2/6-31+G(d,p) level) were explored, while within the second approach, these clusters were embedded in 'bulk' solvent treated as polarizable continuum (C-PCM/MP2/6-31+G(d,p) level of theory). It was found that in the gas phase and in water solution, the most stable tautomer for guanosine and acyclovir is the 1H-2-amino-6-oxo form followed by the 2-amino-6-(sZ)-hydroxy form. The energy barriers of the water-assisted proton transfer reaction in guanosine and in acyclovir are found to be very similar - 11.74 kcal mol for guanosine and 11.16 kcal mol for acyclovir, and the respective rate constants (k = 1.5 × 10 s, guanosine and k = 4.09 × 10 s, acyclovir), are sufficiently large to generate the 2-amino-6-(sZ)-hydroxy tautomer. The analysis of the reaction profiles in both compounds shows that the proton transfer processes occur through the asynchronous concerted mechanism.

Tautomerism of Inosine in Water: Is It Possible?

“…Therefore, the experimental IR and Raman spectra of inosine in water have no evidence of the enol tautomer presence but according to our theoretical predictions with regard to kinetics of tautomeric conversion in water of inosine, the enol form B should be presented in solution. We have shown ,− that the calculated barriers in the range of 12–17 kcal mol –1 for the water-assisted proton transfer reactions indicate that the tautomeric conversions are kinetically feasible processes. The detection of the rare tautomeric forms by spectroscopic methods is not possible and a probable exception might be fluorescence spectroscopy …”

“…To study tautomerism in aqueous solutions is more difficult because tautomerization is mediated by water molecules. This process leads to fast rates of the tautomeric equilibria and low abundance of minor tautomeric species …”

The Role of Proton Transfer on Mutations

“…Prof. Hovorun's group has carried out studies for the canonical A·T(WC) and G·C(WC) WC complexes (Löwdin, 1963; Gorb et al, 2004; Brovarets' et al, 2012; Brovarets' and Hovorun, 2014a,b, 2015e; Roßbach and Ochsenfeld, 2017), wobble pairs Padermshoke et al, 2008; Brovarets' et al, 2015, model protein–DNA complexes (Brovarets' et al, 2012), water-assisted proton transfer in nucleosides (Markova et al, 2017), and mutagenic tautomers (Kondratyuk et al, 2000; Samijlenko et al, 2004; Platonov et al, 2005) to search the reason for the spontaneous point mutations, and other important biological functions such as heredity, aging, and diseases (Löwdin, 1963). These mutations can be considered as “quantum jump” between the undamaged chromosomes and its mutated counterpart states.…”

Quantum Surprises from the Watson-Crick and Hoogsteen G·C Nucleobase Pairs: A Comprehensive QM/QTAIM Investigation

“…The topic of tautomerism is of paramount importance nowadays [1][2][3][4][5][6][7], since, from the one side, it enables to explain the chemical structure of the biomolecules, and, from the other sidetheir functioning in the living cell.…”