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Substrate Binding Specifically Modulates Domain Arrangements in Adenylate Kinase
Fabian Zeller1, Martin Zacharias1
1Physics Department, Technical University Munich, Garching, Germany.
Biophysical Journal
|November 5, 2015
Summary
Adenylate kinase (ADK) uses large domain movements for catalysis. Substrate binding controls these movements, with ATP binding to one site closing the enzyme to prevent unproductive states.
Area of Science:
- Biochemistry
- Enzymology
- Structural Biology
Background:
- Adenylate kinase (ADK) is crucial for cellular energy homeostasis.
- ADK possesses two substrate-binding domains that undergo significant conformational changes during catalysis.
- The enzyme exists in an open apo state, transitioning to a closed holo state upon substrate binding for efficient catalysis.
Purpose of the Study:
- To investigate how individual domain motions in ADK are modulated by substrate binding.
- To elucidate the role of substrate type and binding site on ADK's conformational dynamics.
- To understand the mechanism preventing unproductive enzyme-substrate states.
Main Methods:
- Molecular dynamics (MD) simulations were employed to study ADK dynamics.
- Two-dimensional free-energy landscapes were calculated for apo and holo states.
- Simulations analyzed the effects of single natural substrate binding to specific sites.
Main Results:
- Substrate binding significantly influences ADK's conformational ensemble.
- The two lid domains exhibit non-symmetric behavior in response to substrate binding.
- Initial substrate binding to one site allows the other site to remain open for subsequent binding.
Conclusions:
- ADK's conformational states are highly dependent on substrate identity and binding location.
- ATP binding to the AMP-lid site induces a global domain closure.
- This mechanism likely prevents the formation of stable, non-productive enzyme-substrate complexes.
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