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Dynamics of the Acetylcholinesterase Tetramer

Alemayehu A. Gorfe ^* , Chia-en A. Chang ^* , Ivaylo Ivanov ^*  and J. Andrew McCammon ^*   

^* Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, Howard Hughes Medical Institute, and Department of Pharmacology, University of California at San Diego, La Jolla, California 92093-0365

Correspondence: Address reprint requests to Alemayehu A. Gorfe, Tel.: 858-822-0255; E-mail: abebe{at}mccammon.ucsd.edu; or Chia-en A. Chang, Tel.: 858-822-1469; E-mail: cchang{at}mccammon.ucsd.edu.

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-based coarse-grained Brownian dynamics simulations was carried out to investigate the large-scale intersubunit dynamics in AChEt. We sampled the ns-µs 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.