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PEDS Advance Access originally published online on June 26, 2007
Protein Engineering Design and Selection 2007 20(7):353-359; doi:10.1093/protein/gzm029
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Molecular dynamics studies of AChBP with nicotine and carbamylcholine: the role of water in the binding pocket

Shiva Amiri, Mark S.P. Sansom and Philip C. Biggin1

Structural Bioinformatics and Computational Biochemistry, Department of Biochemistry, The University of Oxford, South Parks Road, Oxford OX1 3QU, UK

1 To whom correspondence should be addressed. E-mail: philip.biggin{at}bioch.ox.ac.uk

The acetylcholine-binding protein (AChBP) is homologous to the ligand-binding domain of the nicotinic acetylcholine receptor (nAChR) and other members of the Cys-loop family of neurotransmitter receptors. The high-resolution X-ray structures of AChBP mean it has been used as a model from which to understand agonist and antagonist binding to nAChRs. We present here a molecular dynamics (MD) study of AChBP with nicotine and carbamylcholine bound. Our results suggest that the ligand imposes rigidity on the binding pocket residues. The simulations also suggest that the protein undergoes breathing motions with respect to the five-fold axis, a motion that has been postulated to be related to gating in the nAChR. We analyzed the behaviour of the water molecules in and around the binding site and found that they occupied five distinct sites within the binding pocket. Water occupied these sites in the absence of ligand, but the presence of ligand increased the probability that a water molecule would be found in these sites. Finally, we demonstrate how the positions of these waters might be used in the design of new ligands by comparing the positions of these sites with other recent structures.

Keywords: nicotinic acetylcholine receptor/computational/conformational change/cys-loop receptor/simulation

Received April 13, 2007; revised April 13, 2007; accepted April 26, 2007.


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