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Characterizing the Binding of Enzyme Inhibitors at the Molecular and Ensemble Levels
Author(s) -
Cao Samantha Midung,
Pham Benjamin,
Radcliffe Amethyst,
La Phuc,
Wang Richard,
An Yi,
Sorin Eric J.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb121
Subject(s) - butyrylcholinesterase , molecular dynamics , enzyme , chemistry , folding (dsp implementation) , enzyme inhibition , stereochemistry , binding affinities , computational biology , biochemistry , biophysics , acetylcholinesterase , computational chemistry , biology , aché , receptor , electrical engineering , engineering
Recent studies have shown that butyrylcholinesterase (BuChE) activity is increased in patients suffering from Alzheimer's disease (AD) and is one of the main enzyme targets necessary to treat Alzheimer's symptoms. As BuChE is a key enzyme that catalyzes the hydrolysis of the neurotransmitter acetylcholine, increased control over inhibition of this enzyme is highly sought. We employ molecular dynamics (MD) simulations to study the physics of the inhibitor‐enzyme complex and the chemical characteristics necessary to effectively target BuChE. One family of inhibitors is the dialkyl phenyl phosphates (DAPPs), which have been shown to specifically target BuChE. We studied the interactions and binding affinities of a number of DAPP's docked in the active site of BuChE. Using the Folding@Home Distributed Computing Network, 8,000 all‐atom molecular dynamics simulations were collected, including the enzyme sans inhibitor, which is used to evaluate the mechanism and energetics of ligand‐binding, as well as the equilibrium dynamics of the enzyme‐substrate complex. This work was made possible by the worldwide Folding@Home volunteers who contributed invaluable processor time; Women & Philanthropy, Kenneth L. Marsi, and James L. Jensen Student Scholarships; and a Research Corporation Cottrell College Science Award.