Conformational Transitions in Protein-Protein Association: Binding of Fasciculin-2 to Acetylcholinesterase
Jennifer M. Bui 1*, Zoran Radic 2, Palmer Taylor 2 and J. Andrew McCammon 2
1 University of California San Diego
2 University of California - San Diego
* To whom correspondence should be addressed. E-mail: jbui{at}mccammon.ucsd.edu.
Submitted on October 6, 2005
Revised on November 7, 2005
Accepted on 24 January 2006
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Abstract |
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The neurotoxin fasciculin-2, FAS2, is a pico-molar protein inhibitor of synaptic acetylcholinesterase, AChE. The dynamics of binding between FAS2 and AChE is influenced by conformational fluctuations both before and after protein encounter. Sub-microsecond molecular dynamics trajectories of apo forms of fasciculin, corresponding to different conformational substates, are reported here with reference to the conformational changes of the loop I of this three-finger toxin. This highly flexible loop exhibits an ensemble of conformations within each substate corresponding to its functions. The high energy barrier found between the two major substates leads to transitions that are slow on the time scale of the diffusional encounter of non-interacting FAS2 and AChE. The more stable of the two apo substates may not be the one observed in the complex with AChE. It seems likely that the more stable apo form binds rapidly to AChE and conformational re-adjustments then occur in the resulting encounter complex.
Key Words:
Conformational Conversions, Conformational Dynamics, Conformational Rearrangements, Molecular Dynamics, Protein-Protein Assocation, Protein-Protein Interactions
