Analysis of the Reaction Mechanism of Neuropsin Based on Dynamic Structure Sampling: MD×QM/MM Approach

Key Points

• The aim is to explore the enzymatic reaction mechanism of neuropsin using advanced computational methods.
• Utilized QM/MM calculations combined with molecular dynamics (MD) simulations.
• Analyzed the distortion of the amide bond in the substrate-binding complex.
• Examined the proton transfer process among the catalytic triad.
• Performed free energy analysis to identify rate-determining steps.
• The distortion of the amide bond reduces the activation barrier for the reaction.
• Nucleophilic attack by Ser195 Oγ initiates critical proton transfers.
• Formation of a tetrahedral intermediate was identified as the rate-determining step.
• Stabilization from the oxyanion hole plays a significant role in catalysis.