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Direct Detection of the Acetate-forming Activity of the Enzyme Acetate Kinase
Published on: December 19, 2011
Dynamics of the acetylcholinesterase tetramer
Alemayehu A Gorfe1, Chia-en A Chang, Ivaylo Ivanov
1Department 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
Biophysical Journal
|October 9, 2007
Summary
Acetylcholinesterase tetramers dynamically assemble, with subunit fluctuations controlling access to peripheral anionic sites. This dynamic gating slightly reduces substrate binding, consistent with experimental findings.
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- Acetylcholinesterase (AChE) is crucial for neurotransmission, rapidly hydrolyzing acetylcholine in synapses.
- The tetrameric form is the most functionally significant for AChE.
- Previous crystal structures were low-resolution and lacked key C-terminal domains.
Purpose of the Study:
- To investigate the large-scale intersubunit dynamics of the complete acetylcholinesterase tetramer (AChEt).
- To understand how subunit dynamics influence ligand access to active sites.
- To bridge structural data with functional insights into AChE activity.
Main Methods:
- Construction of a complete AChEt tetramer model incorporating PRAD/WAT domains.
- Multiscale simulations: all-atom molecular dynamics and coarse-grained Brownian dynamics.
- Analysis of ns-μs timescale motions to characterize intersubunit dynamics.
Main Results:
- AChEt tetramers exhibit dynamic assembly, with subunits fluctuating relative to each other.
- Intersubunit motion correlates with the accessibility of peripheral anionic sites (PAS).
- Subunit motions act as "gates," influencing ligand-protein association, with gates open >80% of the time.
Conclusions:
- The AChE tetramer is a dynamic assembly, not a static structure.
- Dynamic gating of PAS by subunit fluctuations slightly hinders ligand binding, aligning with experimental observations.
- These findings provide a dynamic perspective on AChE function at the molecular level.
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