Rapid binding of a cationic active site inhibitor to wild type and mutant mouse acetylcholinesterase: Brownian dynamics simulation including diffusion in the active site gorge

It is known that anionic surface residues play a role in the long‐range electrostatic attraction between acetylcholinesterase and cationic ligands. In our current investigation, we show that anionic residues also play an important role in the behavior of the ligand within the active site gorge of ac...

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Bibliographic Details
Published in:BIOPOLYM 1998-12, Vol.46 (7), p.465-474
Main Authors: Tara, Sylvia, Elcock, Adrian H., Kirchhoff, Paul D., Briggs, James M., Radic, Zoran, Taylor, Palmer, McCammon, J. Andrew
Format: Article
Language:English
Subjects:
acetylcholinesterase
Acetylcholinesterase - chemistry
Acetylcholinesterase - genetics
active site gorge
Animals
Binding Sites
Brownian dynamics simulations
Brownian movement
Cations - chemistry
Computer Simulation
Diffusion
Electric potential
electrostatic attraction
Electrostatics
Enzyme Inhibitors - metabolism
Kinetics
Ligands
Mice
Molecular dynamics
Mutation
Protein Binding
Rate constants
Static Electricity
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Summary:It is known that anionic surface residues play a role in the long‐range electrostatic attraction between acetylcholinesterase and cationic ligands. In our current investigation, we show that anionic residues also play an important role in the behavior of the ligand within the active site gorge of acetylcholinesterase. Negatively charged residues near the gorge opening not only attract positively charged ligands from solution to the enzyme, but can also restrict the motion of the ligand once it is inside of the gorge. We use Brownian dynamics techniques to calculate the rate constant kon for wild type and mutant acetylcholinesterase with a positively charged ligand. These calculations are performed by allowing the ligand to diffuse within the active site gorge. This is an extension of previously reported work in which a ligand was allowed to diffuse only to the enzyme surface. By setting the reaction criteria for the ligand closer to the active site, better agreement with experimental data is obtained. Although a number of residues influence the movement of the ligand within the gorge, Asp74 is shown to play a particularly important role in this function. Asp74 traps the ligand within the gorge, and in this way helps to ensure a reaction. © 1998 John Wiley & Sons, Inc. Biopoly 46: 465–474, 1998
ISSN:0006-3525
1097-0282
DOI:10.1002/(SICI)1097-0282(199812)46:7<465::AID-BIP4>3.0.CO;2-Y