LargeScale FirstPrinciples 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 FirstPrinciples 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 finitedifference 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 FirstPrinciples 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 ratelimiting for the acylation reaction and in good agreement with experiment.
 Authors:

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 Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
 Publication Date:
 Report Number(s):
 LLNLJRNL673806
Journal ID: ISSN 15499618
 Grant/Contract Number:
 AC5207NA27344
 Type:
 Accepted Manuscript
 Journal Name:
 Journal of Chemical Theory and Computation
 Additional Journal Information:
 Journal Volume: 11; Journal Issue: 12; Journal ID: ISSN 15499618
 Publisher:
 American Chemical Society
 Research Org:
 Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
 Sponsoring Org:
 USDOE
 Country of Publication:
 United States
 Language:
 English
 Subject:
 59 BASIC BIOLOGICAL SCIENCES; 97 MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE
 OSTI Identifier:
 1241999
Fattebert, JeanLuc, Lau, Edmond Y., Bennion, Brian J., Huang, Patrick, and Lightstone, Felice C.. LargeScale FirstPrinciples Molecular Dynamics Simulations with Electrostatic Embedding: Application to Acetylcholinesterase Catalysis. United States: N. p.,
Web. doi:10.1021/acs.jctc.5b00606.
Fattebert, JeanLuc, Lau, Edmond Y., Bennion, Brian J., Huang, Patrick, & Lightstone, Felice C.. LargeScale FirstPrinciples Molecular Dynamics Simulations with Electrostatic Embedding: Application to Acetylcholinesterase Catalysis. United States. doi:10.1021/acs.jctc.5b00606.
Fattebert, JeanLuc, Lau, Edmond Y., Bennion, Brian J., Huang, Patrick, and Lightstone, Felice C.. 2015.
"LargeScale FirstPrinciples Molecular Dynamics Simulations with Electrostatic Embedding: Application to Acetylcholinesterase Catalysis". United States.
doi:10.1021/acs.jctc.5b00606. https://www.osti.gov/servlets/purl/1241999.
@article{osti_1241999,
title = {LargeScale FirstPrinciples Molecular Dynamics Simulations with Electrostatic Embedding: Application to Acetylcholinesterase Catalysis},
author = {Fattebert, JeanLuc and Lau, Edmond Y. and Bennion, Brian J. and Huang, Patrick and Lightstone, Felice C.},
abstractNote = {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 FirstPrinciples 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 finitedifference 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 FirstPrinciples 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 ratelimiting for the acylation reaction and in good agreement with experiment.},
doi = {10.1021/acs.jctc.5b00606},
journal = {Journal of Chemical Theory and Computation},
number = 12,
volume = 11,
place = {United States},
year = {2015},
month = {10}
}