Asymmetric Structural Motions of the Homomeric α7 Nicotinic Receptor Ligand Binding Domain Revealed by Molecular Dynamics Simulation

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

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

A homology model of the ligand binding domain of the α7 nicotinic receptor is constructed based on the acetylcholine-binding protein crystal structure. This structure is refined in a 10 ns molecular dynamics simulation. The modeled structure proves fairly resilient, with no significant changes at the secondary or tertiary structural levels. The hypothesis that the acetylcholine-binding protein template is in the activated or desensitized state, and the absence of a bound agonist in the simulation suggests that the structure may also be relaxing from this state to the activatable state. Candidate motions that take place involve not only the side chains of residues lining the binding sites, but also the subunit positions that determine the overall shape of the receptor. In particular, two nonadjacent subunits move outward, whereas their partners counterclockwise to them move inward, leading to a marginally wider interface between themselves and an overall asymmetric structure. This in turn affects the binding sites, producing two that are more open and characterized by distinct side-chain conformations of W54 and L118, although motions of the side chains of all residues in every binding site still contribute to a reduction in binding site size, especially the outward motion of W148, which hinders acetylcholine binding. The Cys loop at the membrane interface also displays some flexibility. Although the short simulation timescale is unlikely to sample adequately all the conformational states, the pattern of observed motions suggests how ligand binding may correlate with larger-scale subunit motions that would connect with the transmembrane region that controls the passage of ions. Furthermore, the shape of the asymmetry with binding sites of differing affinity for acetylcholine, characteristic of other nicotinic receptors, may be a natural property of the relaxed, activatable state of α7.

Original languageEnglish (US)
Pages (from-to)3007-3018
Number of pages12
JournalBiophysical Journal
Volume85
Issue number5
StatePublished - Nov 2003

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Nicotinic Receptors
Molecular Dynamics Simulation
Binding Sites
Acetylcholine
Ligands
Carrier Proteins
Ions
Membranes

ASJC Scopus subject areas

  • Biophysics

Cite this

Asymmetric Structural Motions of the Homomeric α7 Nicotinic Receptor Ligand Binding Domain Revealed by Molecular Dynamics Simulation. / Henchman, Richard H.; Wang, Hai Long; Sine, Steven M; Taylor, Palmer; McCammon, J. Andrew.

In: Biophysical Journal, Vol. 85, No. 5, 11.2003, p. 3007-3018.

Research output: Contribution to journalArticle

Henchman, Richard H. ; Wang, Hai Long ; Sine, Steven M ; Taylor, Palmer ; McCammon, J. Andrew. / Asymmetric Structural Motions of the Homomeric α7 Nicotinic Receptor Ligand Binding Domain Revealed by Molecular Dynamics Simulation. In: Biophysical Journal. 2003 ; Vol. 85, No. 5. pp. 3007-3018.
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