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Biophys. J. BioFAST: First Published June 15, 2007. doi:10.1529/biophysj.107.109843
© 2007 by the Biophysical Society.

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BIOPHYSICAL THEORY AND MODELING

Nanosecond Time Scale Conformational Dynamics of the Human {alpha}7 Nicotinic Acetylcholine Receptor

Xiaolin Cheng 1*, Ivaylo Ivanov 1, Hailong Wang 2, Steven M Sine 2 and J. Andrew McCammon 3

1 HHMI/UCSD
2 Mayo Clinic
3 University of California - San Diego

* To whom correspondence should be addressed. E-mail: xcheng{at}mccammon.ucsd.edu.

Submitted on March 29, 2007
Revised on May 9, 2007
Accepted on 8 June 2007


  Abstract
We explore the conformational dynamics of a homology model of the human {alpha}7 nicotinic acetylcholine receptor (nAChR) using molecular dynamics (MD) simulation and analyses of root-mean-square fluctuations (RMSF), block partitioning of segmental motion and principal component analysis (PCA). 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 {beta}10-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 inter-residue 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.

Key Words: TLS model, allosteric mechanism, channel gating, correlation analysis, molecular dynamics, nicotinic receptor




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Copyright © 2007 by the Biophysical Society.