Conserved-Potential-Driven Molecular Dynamics Deciphers Formose Reaction Mechanisms

The formose reaction, in which formaldehyde reacts to form sugars under alkaline conditions, is a leading candidate for prebiotic sugar synthesis, with ribose as a particularly significant though minor product. Despite the simplicity of its starting material (formaldehyde), the reaction involves intricate mechanistic steps and generates a complex product mixture, hindering full mechanistic elucidation even after decades of study. Here, we develop an efficient, mechanism-free molecular dynamics (MD) approach to simulate the formose reaction, using our recently proposed roto-translationally invariant potential (RTIP) to drive the molecular system toward reactive configurations for potential reactions. High-resolution RTIP-MD trajectories reveal a comprehensive reaction network, elucidating previously elusive mechanistic details for formaldehyde self-condensation, aldose-ketose tautomerization, and ribose synthesis. Based on the Gibbs free energy landscape, the microkinetic simulation conclusively settles the autocatalytic cycle debate, demonstrating that autocatalysis occurs predominantly at low glycolaldehyde concentrations, as evidenced by the reverse aldotetrose retroaldol cleavage. This proof-of-concept study demonstrates RTIP-MD's capability to simulate complex, multistep reactions, suggesting potential applicability to challenging systems such as enzyme catalysis.