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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
4
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pubmed:dateCreated |
2008-1-24
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:commentsCorrections |
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http://linkedlifedata.com/resource/pubmed/commentcorrection/17921202-9915834
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
1542-0086
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
94
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1144-54
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pubmed:dateRevised |
2011-3-17
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pubmed:meshHeading |
pubmed-meshheading:17921202-Acetylcholinesterase,
pubmed-meshheading:17921202-Computer Simulation,
pubmed-meshheading:17921202-Dimerization,
pubmed-meshheading:17921202-Enzyme Activation,
pubmed-meshheading:17921202-Enzyme Stability,
pubmed-meshheading:17921202-Kinetics,
pubmed-meshheading:17921202-Models, Chemical,
pubmed-meshheading:17921202-Models, Molecular,
pubmed-meshheading:17921202-Protein Conformation,
pubmed-meshheading:17921202-Protein Subunits
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pubmed:year |
2008
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pubmed:articleTitle |
Dynamics of the acetylcholinesterase tetramer.
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pubmed: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
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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