title: 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.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla 92093-0365, USA. stara@ucsd.edu
authors.forename: S
authors.initials: S
authors.lastname: Tara
authors.forename: A H
authors.initials: AH
authors.lastname: Elcock
authors.forename: P D
authors.initials: PD
authors.lastname: Kirchhoff
authors.forename: J M
authors.initials: JM
authors.lastname: Briggs
authors.forename: Z
authors.initials: Z
authors.lastname: Radic
authors.forename: P
authors.initials: P
authors.lastname: Taylor
authors.forename: J A
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D002412:Cations / Q000737:chemistry*; D003198:Computer Simulation; D004058:Diffusion; D004791:Enzyme Inhibitors / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D051379:Mice; D009154:Mutation; D011485:Protein Binding; D055672:Static Electricity
chemical_list: D002412:Cations; D004791:Enzyme Inhibitors; D008024:Ligands; D000110:Acetylcholinesterase