Biophysical Journal 74: 242-255 (1998)
© 1998 the Biophysical Society

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Biophys J, January 1998, p. 242-255, Vol. 74, No. 1

Kinked-Helices Model of the Nicotinic Acetylcholine Receptor Ion Channel and Its Complexes with Blockers: Simulation by the Monte Carlo Minimization Method

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia

A model of the nicotinic acetylcholine receptor ion channel was elaborated based on the data from electron microscopy, affinity labeling, cysteine scanning, mutagenesis studies, and channel blockade. A restrained Monte Carlo minimization method was used for the calculations. Five identical M2 segments (the sequence EKMTLSISVL¹⁰LALTVFLLVI²⁰V) were arranged in five-helix bundles with various geometrical profiles of the pore. For each bundle, energy profiles for chlorpromazine, QX-222, pentamethonium, and other blocking drugs pulled through the pore were calculated. An optimal model obtained allows all of the blockers free access to the pore, but retards them at the rings of residues known to contribute to the corresponding binding sites. In this model, M2 helices are necessarily kinked. They come into contact with each other at the cytoplasmic end but diverge at the synaptic end, where N-termini of M1 segments may contribute to the pore. The kinks disengage -helical H-bonds between Ala¹² and Ser⁸. The uncoupled lone electron pairs of Ser⁸ carbonyl oxygens protrude into the pore, forming a hydrophilic ring that may be important for the permeation of cations. A split network of H-bonds provides a flexibility to the chains Val⁹-Ala¹², the numerous conformations of which form only two or three intrasegment H-bonds. The cross-ectional dimensions of the interface between the flexible chains vary essentially at the level of Leu¹¹. We suggest that conformational transitions in the chains Val⁹-Ala¹² are responsible for the channel gating, whereas rotations of more stable -helical parts of M2 segments may be necessary to transfer the channel in the desensitized state.

Biophys J, January 1998, p. 242-255, Vol. 74, No. 1
© 1998 by the Biophysical Society   0006-3495/98/01/242/14  $2.00

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