Large-Scale First-Principles Molecular Dynamics Simulations with Electrostatic Embedding: Application to...

Area of Science:

• Computational chemistry
• Biophysics
• Enzyme kinetics

Background:

• Enzymes are complex systems requiring accurate simulation for functional studies.
• Simulating enzymatic reactions demands significant computational resources.

Purpose of the Study:

• To apply novel numerical techniques for large-scale first-principles molecular dynamics simulations.
• To study the enzymatic reaction catalyzed by acetylcholinesterase.

Main Methods:

• Density functional theory (DFT) calculations for a 612-atom quantum-mechanical (QM) subsystem.
• An O(N) complexity finite-difference approach for QM calculations.
• Embedding the QM subsystem within an external potential field representing the environment.
• First-principles molecular dynamics for finite-temperature sampling of the acylation reaction.

Main Results:

• Identified two energy barriers along the reaction coordinate for acetylcholine acylation.
• Determined the second energy barrier to be 8.5 kcal/mol.
• The calculated rate-limiting barrier showed good agreement with experimental values.

Conclusions:

• The developed numerical techniques enable accurate simulation of complex enzymatic systems.
• The study provides detailed insights into the mechanism of acetylcholinesterase catalysis.
• Computational findings correlate well with experimental observations for enzyme-catalyzed reactions.