# Conserved-Potential-Driven Molecular Dynamics Deciphers Formose Reaction Mechanisms

## TL;DR

A new molecular dynamics approach reveals detailed mechanisms of the formose reaction, including how sugars like ribose are formed from formaldehyde.

## Contribution

An efficient mechanism-free MD approach using RTIP potential elucidates the complex formose reaction network and resolves the autocatalysis debate.

## Key findings

- RTIP-MD simulations reveal a comprehensive reaction network for the formose reaction.
- Autocatalysis occurs predominantly at low glycolaldehyde concentrations via reverse aldotetrose retroaldol cleavage.
- The method shows potential applicability to complex systems like enzyme catalysis.

## Abstract

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.