Solvent-mediated mechanism and kinetics of glucose mutarotation from enhanced sampling simulations

Abstract

Understanding how solvent molecules participate in chemical reaction mechanisms remains a central challenge in molecular simulations. Here, we investigate the mechanism and kinetics of glucose mutarotation in aqueous solution using a combined well-tempered metadynamics and mean force integration approach, within the framework of canonical transition state theory. We compute free energy landscapes and kinetic rate coefficients for the α → β mutarotation in pure water, as well as in systems representative of water/methanol and water/acetone mixtures. Our simulations indicate that ring opening and closure occur via concerted, solvent-assisted pathways, with ring opening identified as the rate-determining step. The temperature dependence of the predicted kinetic constant is quantitatively consistent with experimental data, while the reactivity modulation by organic co-solvents is captured qualitatively. Overall, the results provide molecular-level insight into solvent-mediated carbohydrate chemistry, demonstrating that the solvent participates in all key reactive steps and highlighting how enhanced sampling techniques can yield mechanistic and kinetic information in explicitly solvated reactive systems.