Studying enzyme binding specificity in acetylcholinesterase using a combined molecular dynamics and multiple docking approach

Jeremy Kua, Yingkai Zhang, J. Andrew McCammon

Research output: Contribution to journalArticle

Abstract

A combined molecular dynamics simulation and multiple ligand docking approach is applied to study the binding specificity of acetylcholinesterase (AChE) with its natural substrate acetylcholine (ACh), a family of substrate analogues, and choline. Calculated docking energies are well correlated to experimental kcat/KM values, as well as to experimental binding affinities of a related series of TMTFA inhibitors. The "esteratic" and "anionic" subsites are found to act together to achieve substrate binding specificity. We find that the presence of ACh in the active site of AChE not only stabilizes the setup of the catalytic triad but also tightens both subsites to achieve better binding. The docking energy gained from this induced fit is 0.7 kcal/mol for ACh. For the binding of the substrate tailgroup to the anionic subsite, both the size and the positive charge of the tailgroup are important. The removal of the positive charge leads to a weaker binding of 1 kcal/mol loss in docking energy. Substituting each tall methyl group with hydrogen results in both an incremental loss in docking energy and also a decrease in the percentage of structures docked in the active site correctly set up for catalysis.

Original languageEnglish (US)
Pages (from-to)8260-8267
Number of pages8
JournalJournal of the American Chemical Society
Volume124
Issue number28
DOIs
StatePublished - Jul 17 2002

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Molecular Dynamics Simulation
Acetylcholinesterase
Acetylcholine
Molecular dynamics
Enzymes
Catalytic Domain
Substrates
Substrate Specificity
Choline
Catalysis
Hydrogen
Ligands
Computer simulation

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Studying enzyme binding specificity in acetylcholinesterase using a combined molecular dynamics and multiple docking approach. / Kua, Jeremy; Zhang, Yingkai; McCammon, J. Andrew.

In: Journal of the American Chemical Society, Vol. 124, No. 28, 17.07.2002, p. 8260-8267.

Research output: Contribution to journalArticle

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