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Ligand-Induced Conformational Change in the 7 Nicotinic Receptor Ligand Binding Domain

Richard H. Henchman ^*, Hai-Long Wang , Steven M. Sine , Palmer Taylor  and J. Andrew McCammon ^* 

^* Howard Hughes Medical Institute, NSF Center for Theoretical Biophysics, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California; Receptor Biology Laboratory, Department of Physiology and Biophysics, Mayo Foundation, Rochester, Minnesota; and Department of Pharmacology, University of California, San Diego, La Jolla, California

Correspondence: Address reprint requests to Richard H. Henchman, Dept. of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093. Tel.: 858-822-1469; Fax: 858-534-4974; E-mail: rhenchma{at}mccammon.ucsd.edu.

Molecular dynamics simulations of a homology model of the ligand binding domain of the 7 nicotinic receptor are conducted with a range of bound ligands to induce different conformational states. Four simulations of 15 ns each are run with no ligand, antagonist d-tubocurarine (dTC), agonist acetylcholine (ACh), and agonist ACh with potentiator Ca²⁺, to give insight into the conformations of the active and inactive states of the receptor and suggest the mechanism for conformational change. The main structural factor distinguishing the active and inactive states is that a more open, symmetric arrangement of the five subunits arises for the two agonist simulations, whereas a more closed and asymmetric arrangement results for the apo and dTC cases. Most of the difference arises in the lower portion of the ligand binding domain near its connection to the adjacent transmembrane domain. The transfer of the more open state to the transmembrane domain could then promote ion flow through the channel. Variation in how subunits pack together with no ligand bound appears to give rise to asymmetry in the apo case. The presence of dTC expands the receptor but induces rotations in alternate directions in adjacent subunits that lead to an asymmetric arrangement as in the apo case. Ca²⁺ appears to promote a slightly greater expansion in the subunits than ACh alone by stabilizing the C-loop and ACh positions. Although the simulations are unlikely to be long enough to view the full conformational changes between open and closed states, a collection of different motions at a range of length scales are observed that are likely to participate in the conformational change.

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