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

Jean Luc Fattebert, Edmond Y Lau, Brian J. Bennion, Patrick Huang, Felice C Lightstone

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Enzymes are complicated solvated systems that typically require many atoms to simulate their function with any degree of accuracy. We have recently developed numerical techniques for large scale first-principles molecular dynamics simulations and applied them to the study of the enzymatic reaction catalyzed by acetylcholinesterase. We carried out density functional theory calculations for a quantum-mechanical (QM) subsystem consisting of 612 atoms with an O(N) complexity finite-difference approach. The QM subsystem is embedded inside an external potential field representing the electrostatic effect due to the environment. We obtained finite-temperature sampling by first-principles molecular dynamics for the acylation reaction of acetylcholine catalyzed by acetylcholinesterase. Our calculations show two energy barriers along the reaction coordinate for the enzyme-catalyzed acylation of acetylcholine. The second barrier (8.5 kcal/mol) is rate-limiting for the acylation reaction and in good agreement with experiment.

Original languageEnglish (US)
Pages (from-to)5688-5695
Number of pages8
JournalJournal of Chemical Theory and Computation
Volume11
Issue number12
DOIs
StatePublished - Oct 22 2015
Externally publishedYes

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Computer Science Applications

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