Unveiling the Cleavage Mechanism of an RNA Model Compound on the whole pH Scale: Computations Meet Experiments in the Determination of Reaction Rates

The knowledge of the mechanism of reactions occurring in solution is a primary research line both in the context of theoretical-computational chemistry and in the field of organic and bio-organic chemistry. Given the importance of the hydrolysis of nucleic acids in life-related phenomena, here we present a combined experimental and computational study on the cleavage of an RNA model compound. This phosphodiester features a cleavage rate strictly dependent on the pH with three different dependence domains. Such experimental evidence, highlighted by an in-depth kinetic investigation, unequivocally suggests a change in the reaction mechanism along the pH scale. In order to interpret the data and to explain the experimental behavior, we have applied a theoretical-computational procedure, involving a hybrid quantum/classical approach, able to model chemical reactions in complex environments, i. e. in solution. This study turns out to quantitatively reproduce the experimental data with accuracy and, in addition, provides useful mechanistic insight into the transesterification process of the investigated compound. The study indicates that the cleavage can occur through an ANDN ${A_N D_N }$ , an AN+DN ${A_N + D_N }$ , and a DNAN ${D_N A_N }$ mechanism depending on the pH values.An in-depth kinetic investigation highlights that the cleavage rate of an RNA model compound is strictly dependent on the pH with different dependence domains. A theoretical-computational procedure, based on a hybrid quantum/classical approach, quantitatively reproduce the experimental data with accuracy and provides mechanistic insight into the transesterification process. This method, for its generality, pave the way for a universal tool to investigate the mechanism of chemical reactions in solution. image