Reaction Mechanism Path Sampling Based on Parallel Cascade Selection QM/MM Molecular Dynamics Simulation: PaCS-Q.

Abstract

Quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations are essential for elucidating complex biochemical reaction mechanisms. However, conventional enhanced sampling methods, such as umbrella sampling and metadynamics, often face limitations in computational cost, sampling completeness, and reliance on predefined reaction coordinates. To address these challenges, we developed Parallel Cascade Selection QM/MM MD (PaCS-Q) simulation, a novel strategy that efficiently explores reaction pathways by iteratively identifying high-potential structures for configurational transitions without predefined biases or external constraints. PaCS-Q directly tracks changes in bond distances over time, enabling the identification of transition states and intermediates. Validation of the Claisen rearrangement in chorismate mutase and the peptidyl aldehyde reaction in the Zika virus NS2B/NS3 serine protease demonstrated accurate pathway capture, reduced computational costs, and efficient sampling. With its user-friendly workflow, PaCS-Q broadens accessibility for computational and experimental researchers, offering a robust tool for studying enzymatic mechanisms with high accuracy and efficiency.