title: Dynamics of the acetylcholinesterase tetramer.
abstract: Acetylcholinesterase rapidly hydrolyzes the neurotransmitter acetylcholine in cholinergic synapses, including the neuromuscular junction. The tetramer is the most important functional form of the enzyme. Two low-resolution crystal structures have been solved. One is compact with two of its four peripheral anionic sites (PAS) sterically blocked by complementary subunits. The other is a loose tetramer with all four subunits accessible to solvent. These structures lacked the C-terminal amphipathic t-peptide (WAT domain) that interacts with the proline-rich attachment domain (PRAD). A complete tetramer model (AChEt) was built based on the structure of the PRAD/WAT complex and the compact tetramer. Normal mode analysis suggested that AChEt could exist in several conformations with subunits fluctuating relative to one another. Here, a multiscale simulation involving all-atom molecular dynamics and C alpha-based coarse-grained Brownian dynamics simulations was carried out to investigate the large-scale intersubunit dynamics in AChEt. We sampled the ns-mus timescale motions and found that the tetramer indeed constitutes a dynamic assembly of monomers. The intersubunit fluctuation is correlated with the occlusion of the PAS. Such motions of the subunits "gate" ligand-protein association. The gates are open more than 80% of the time on average, which suggests a small reduction in ligand-protein binding. Despite the limitations in the starting model and approximations inherent in coarse graining, these results are consistent with experiments which suggest that binding of a substrate to the PAS is only somewhat hindered by the association of the subunits.
authors.affiliation: Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California 92093-0365, USA. cchang@mccammon.ucsd.edu
authors.forename: Alemayehu A
authors.initials: AA
authors.lastname: Gorfe
authors.forename: Chia-en A
authors.initials: CE
authors.lastname: Chang
authors.forename: Ivaylo
authors.initials: I
authors.lastname: Ivanov
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000648:ultrastructure*; D003198:Computer Simulation; D019281:Dimerization; D004789:Enzyme Activation; D004795:Enzyme Stability; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D021122:Protein Subunits
chemical_list: D021122:Protein Subunits; D000110:Acetylcholinesterase