Semi-empirical metadynamics simulations for chemical glycosylation reactions.

Glycosylation, the formation of glycosidic bonds, is a central yet challenging step in the chemical synthesis of complex carbohydrates due to its intricate regio- and stereochemical control. This study explores explicitly solvated, semi-empirical molecular dynamics (MD) simulations combined with multiple walker well-tempered metadynamics to investigate the mechanistic landscape of glycosylation involving a constrained glucose donor and a series of simple alcohol nucleophiles varying in nucleophilicity: ethanol, 2-monofluoroethanol, 2,2-difluoroethanol, and 2,2,2-trifluoroethanol. Our simulations reveal several mechanistic pathways depending on the nucleophile and substitution site. Stronger nucleophiles favor concerted SN2 displacement, while weaker nucleophiles increasingly promote dissociative SN1-like mechanisms and frontside attack pathways. This study demonstrates how semi-empirical MD simulations, combined with explicit solvation, can provide insights to understand the glycosylation reaction pathways.