Mechanisms of the T-A to C-G transition studied by SMD simulations: Deamination vs tautomerisation

摘要

The T-A to C-G transition was obtained in gas and aqueous phases by applying steered molecular dynamic (SMD) simulations. Two different pathways were considered to explain the mechanism of the transition, which included water-molecule-assisted adenine deamination and tautomerisation of the T*-A* mispair via double proton transfer. In both pathways, the associations between nitrogenous bases of DNA, such as T-A, C-G, G-T* and C-A*, were also considered. In the gas phase, the transition via deamination was determined to be the most favourable (Delta G = 3.92 kcal.mol(-1)) while in solution tautomerisation was favoured (Delta G = 11.33 kcal.mol(-1)). The presence of solvent made the mutation more endergonic, slowed the reaction and increased its overall energy requirement and energy barrier. The lifetimes of T*-A* and C-G species formed in the tautomerisation pathway were very short, and C-G pair was only predicted to be capable of encoding the genetic sequence only when the transition followed the deamination path (t(gas) = 1.64.10(+36) s, t(solution) = 1.81.10(+25) s). Molecular structures involved in these mechanisms were analysed along the reaction path, which allowed us to visualise the energy profiles of the reactions over time and calculate their kinetic and thermodynamic properties. (C) 2020 Elsevier B.V. All rights reserved.