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

Area of Science:

• Biochemistry
• Computational Chemistry
• Molecular Dynamics

Background:

• Quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations are crucial for understanding biochemical reactions.
• Existing enhanced sampling methods have limitations in computational cost, sampling completeness, and require predefined reaction coordinates.

Purpose of the Study:

• To develop a novel simulation strategy, Parallel Cascade Selection QM/MM MD (PaCS-Q), to overcome limitations of conventional methods.
• To enable efficient exploration of reaction pathways without predefined biases or external constraints.

Main Methods:

• PaCS-Q simulation iteratively identifies high-potential structures for configurational transitions.
• The method directly tracks changes in bond distances to identify transition states and intermediates.
• PaCS-Q was validated using the Claisen rearrangement in chorismate mutase and a peptidyl aldehyde reaction in Zika virus protease.

Main Results:

• PaCS-Q accurately captured reaction pathways for tested enzymatic mechanisms.
• The novel method demonstrated reduced computational costs compared to conventional approaches.
• Efficient sampling of reaction pathways was achieved.

Conclusions:

• PaCS-Q provides a robust and efficient tool for studying enzymatic mechanisms.
• The user-friendly workflow of PaCS-Q enhances accessibility for researchers.
• This method offers high accuracy and efficiency in elucidating complex biochemical reaction mechanisms.