Invariant-Potential-Driven Molecular Dynamics Unravels Formose Reaction Kinetics

The formose reaction, a base-catalyzed formaldehyde polymerization in alkaline aqueous solution, is a prominent pathway for prebiotic sugar synthesis, notably ribose. Despite its simple starting materials (formaldehyde), the reaction involves intricate mechanistic steps and generates a complex mixture of products, hindering a complete mechanistic understanding even after decades of study. Here, we develop an efficient molecular dynamics (MD) approach to simulate the formose reaction, leveraging our recently proposed roto-translationally invariant potential (RTIP) to steer molecules toward reactive configurations for potential reactions. RTIP-MD trajectories reveals a new mechanism for the elusive self-condensation of formaldehyde, mediated by formyl anion nucleophilic attack, and maps a comprehensive reaction network including aldose-ketose tautomerization and ribose synthesis. Based on the Gibbs free energy landscape, we further perform a microkinetics simulation to investigate the debated autocatalytic cycle, and elucidate that the retroaldol cleavage of aldotetrose occurs only at low glycolaldehyde concentrations, primarily via enolization rather than a direct hydride shift. As demonstrated in this proof-of-concept study, our RTIP-MD method shows promising potential for accurately simulating complex reaction processes.