Hybrid MC/QC simulations of water-assisted proton transfer in nucleosides. Guanosine and its analog acyclovir.
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-1for guanosine and 11.16 kcal mol-1for acyclovir, and the respective rate constants (k = 1.5 × 101s-1, guanosine and k = 4.09 × 101s-1, 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.
a Institute of Organic Chemistry , Bulgarian Academy of Sciences , 1113 Sofia , Bulgaria.
Nadezhda
N
Markova
b Faculty of Natural Sciences and Mathematics , Institute of Chemistry , Skopje , Macedonia.|c Research Centre for Environment and Materials , Macedonian Academy of Sciences and Arts , Krste Misirkov 2, 1000 Skopje , Macedonia.
Ljupco
L
Pejov
a Institute of Organic Chemistry , Bulgarian Academy of Sciences , 1113 Sofia , Bulgaria.
Nina
N
Stoyanova
a Institute of Organic Chemistry , Bulgarian Academy of Sciences , 1113 Sofia , Bulgaria.
Venelin
V
Enchev
D000212:Acyclovir / Q000737:chemistry; D006151:Guanosine / Q000737:chemistry; D006860:Hydrogen Bonding; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009010:Monte Carlo Method; D009705:Nucleosides / Q000737:chemistry*; D011522:Protons; D011789:Quantum Theory; D014867:Water / Q000737:chemistry*
D009705:Nucleosides; D011522:Protons; D014867:Water; D006151:Guanosine; D000212:Acyclovir
Monte Carlo simulation; ab initio; acyclovir; guanosine; nucleosides; proton transfer; tautomerism