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Nanosecond-Timescale Conformational Dynamics of the Human 7 Nicotinic Acetylcholine Receptor

Xiaolin Cheng ^*, Ivaylo Ivanov ^* , Hailong Wang , Steven M. Sine  and J. Andrew McCammon ^* 

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

Correspondence: Address reprint requests to Xiaolin Cheng, Dept. of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093. Tel.: 858-822-0169; Fax: 858-534-4974; E-mail: xcheng{at}mccammon.ucsd.edu.

We explore the conformational dynamics of a homology model of the human 7 nicotinic acetylcholine receptor using molecular dynamics simulation and analyses of root mean-square fluctuations, block partitioning of segmental motion, and principal component analysis. The results reveal flexible regions and concerted global motions of the subunits encompassing extracellular and transmembrane domains of the subunits. The most relevant motions comprise a bending, hinged at the ß10-M1 region, accompanied by concerted tilting of the M2 helices that widens the intracellular end of the channel. Despite the nanosecond timescale, the observations suggest that tilting of the M2 helices may initiate opening of the pore. The results also reveal direct coupling between a twisting motion of the extracellular domain and dynamic changes of M2. Covariance analysis of interresidue motions shows that this coupling arises through a network of residues within the Cys and M2-M3 loops where Phe¹³⁵ is stabilized within a hydrophobic pocket formed by Leu²⁷⁰ and Ile²⁷¹. The resulting concerted motion causes a downward shift of the M2 helices that disrupts a hydrophobic girdle formed by 9' and 13' residues.

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