title: Large-Scale First-Principles Molecular Dynamics Simulations with Electrostatic Embedding: Application to Acetylcholinesterase Catalysis.
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.
authors.affiliation: Center for Applied Scientific Computing, Lawrence Livermore National Laboratory , Livermore, California 94550, United States.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Fattebert
authors.affiliation: Physical and Life Sciences, Lawrence Livermore National Laboratory , Livermore, California 94550, United States.
authors.forename: Edmond Y
authors.initials: EY
authors.lastname: Lau
authors.affiliation: Physical and Life Sciences, Lawrence Livermore National Laboratory , Livermore, California 94550, United States.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bennion
authors.affiliation: Physical and Life Sciences, Lawrence Livermore National Laboratory , Livermore, California 94550, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Huang
authors.affiliation: Physical and Life Sciences, Lawrence Livermore National Laboratory , Livermore, California 94550, United States.
authors.forename: Felice C
authors.initials: FC
authors.lastname: Lightstone
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000215:Acylation; D001665:Binding Sites; D055162:Biocatalysis; D020134:Catalytic Domain; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D011789:Quantum Theory; D055672:Static Electricity; D013696:Temperature; D013816:Thermodynamics
chemical_list: D000110:Acetylcholinesterase; D000109:Acetylcholine