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

Abstract

Gibbs free energy profiles of the cytosine deamination assisted by a water molecule in a discrete aqueous medium were obtained by the application of Steered Molecular Dynamic (SMD) simulations. Two pathways were considered to explain the mechanism of this process, where the water molecule attacks the C–N bond to give an intermediate (an amino–hydroxy–oxo structure in the A-path, and a hydroxy–oxo in the B-path) as the determinant step of reaction. Stationary structures along both energy profiles were analyzed at molecular dynamics level, obtaining states with higher free energies than those from electronic calculations in the gas phase and in solution described as a continuous medium. From the results obtained, the more complex A-pathway, with five steps, was kinetically the most favorable (with an endergonic reaction energy of 7.41 kcal mol⁻¹, a high barrier of 67.53 kcal mol⁻¹, and a small velocity constant k₂ = 1.80 × 10⁻³⁷ s⁻¹), concluding that the uracil base can participate in a spontaneous genetic mutation since the uracil–ammonia complex has a long lifetime of 6.10 × 10²⁷ s. This process turns out exergonic and faster when carried out in gas phase simulation or electronic calculation with a continuous medium, due to the disappearance of explicit water molecules that can compete with the assistant molecule.