title: Mechanism of acetylcholinesterase inhibition by fasciculin: a 5-ns molecular dynamics simulation.
abstract: Our previous molecular dynamics simulation (10 ns) of mouse acetylcholinesterase (EC 3.1.1.7) revealed complex fluctuation of the enzyme active site gorge. Now we report a 5-ns simulation of acetylcholinesterase complexed with fasciculin 2. Fasciculin 2 binds to the gorge entrance of acetylcholinesterase with excellent complementarity and many polar and hydrophobic interactions. In this simulation of the protein-protein complex, where fasciculin 2 appears to sterically block access of ligands to the gorge, again we observe a two-peaked probability distribution of the gorge width. When fasciculin is present, the gorge width distribution is altered such that the gorge is more likely to be narrow. Moreover, there are large increases in the opening of alternative passages, namely, the side door (near Thr 75) and the back door (near Tyr 449). Finally, the catalytic triad arrangement in the acetylcholinesterase active site is disrupted with fasciculin bound. These data support that, in addition to the steric obstruction seen in the crystal structure, fasciculin may inhibit acetylcholinesterase by combined allosteric and dynamical means. Additional data from these simulations can be found at http://mccammon.ucsd.edu/.
authors.affiliation: Howard Hughes Medical Institute and Department of Chemistry, University of California, San Diego, La Jolla, California 92093-0365, USA.
authors.forename: Kaihsu
authors.initials: K
authors.lastname: Tai
authors.forename: Tongye
authors.initials: T
authors.lastname: Shen
authors.forename: Richard H
authors.initials: RH
authors.lastname: Henchman
authors.forename: Yves
authors.initials: Y
authors.lastname: Bourne
authors.forename: Pascale
authors.initials: P
authors.lastname: Marchot
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D003198:Computer Simulation; D004546:Elapid Venoms / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D002800:Cholinesterase Inhibitors; D004546:Elapid Venoms; C044937:fasciculin; D000110:Acetylcholinesterase