Evaluation of the regioselective delactonization of tri-sialic acid lactone by in-solution molecular dynamics simulation

Abstract

An approximate model for the delactonization of tri-sialic acid lactone is presented with two water-layers that led to neutral hydrolysis of δ-lactone. The hydrolytic reactivity was studied with a 10-ns in-solution molecular dynamics simulation. The initial step of this hydrolysis involves a reactant water nucleophile complex via a proton transfer with another water molecule. Therefore, the probability of water molecules localized at the hydrolytic center correlates to the hydrolysis of δ-lactone. The stepwise delactonization of α2,8-(NeuAc)3 lactone results/resulted from water concentration discrepancy near the carbonyl carbon of lactones in two water oxygen⋯carbonyl carbon shells, and the distances of OC⋯Owater layers were 2.8Å and 5.1Å. Based on in-solution molecular dynamics study, the motion of water molecules over the re-face of the carbonyl groups was used for the quantitative description of the residence probability, p, whose value is 0.11 for lactone I and 0.33 for lactone II. The geometric criteria used to determine the residence statistics are (1) the distance of water–oxygen⋯carbonyl carbon in less than 5.1Å and (2) the cone angle, θ, of carbonyl OC⋯Owater in the range of 85–115°. As expected, a higher residence probability at lactone II led to its faster hydrolysis. Both the radial g(r) and angular p(θ) pair distribution functions of water oxygen and carbonyl groups of lactones ensure a better surrounding hydration encounter for lactone II. In contrast, water molecules around lactone I are deduced due to a steric hindrance by the turn structure of α2,8-(NeuAc)3 lactone.