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

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 study the enzymatic reaction catalyzed by acetylcholinesterase. We carried out Density functional theory calculations for a quantum mechanical (QM) sub- system consisting of 612 atoms with an O(N) complexity finite-difference approach. The QM sub-system 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 shows two energies barriers along the reaction coordinate for the enzyme catalyzed acylation of acetylcholine. In conclusion, the second barrier (8.5 kcal/mole) is rate-limiting for the acylation reaction and in good agreement with experiment.
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [1]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Publication Date:
OSTI Identifier:
1241999
Report Number(s):
LLNL-JRNL--673806
Journal ID: ISSN 1549-9618
Grant/Contract Number:
AC52-07NA27344
Type:
Accepted Manuscript
Journal Name:
Journal of Chemical Theory and Computation
Additional Journal Information:
Journal Volume: 11; Journal Issue: 12; Journal ID: ISSN 1549-9618
Publisher:
American Chemical Society
Research Org:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 97 MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE