Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors

Xiaolin Cheng, Hailong Wang, Barry Grant, Steven M Sine, J. Andrew McCammon

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

The initial coupling between ligand binding and channel gating in the human α7 nicotinic acetylcholine receptor (nAChR) has been investigated with targeted molecular dynamics (TMD) simulation. During the simulation, eight residues at the tip of the C-loop in two alternating subunits were forced to move toward a ligand-bound conformation as captured in the crystallographic structure of acetylcholine binding protein (AChBP) in complex with carbamoylcholine. Comparison of apo- and ligand-bound AChBP structures shows only minor rearrangements distal from the ligand-binding site. In contrast, comparison of apo and TMD simulation structures of the nAChR reveals significant changes toward the bottom of the ligand-binding domain. These structural rearrangements are subsequently translated to the pore domain, leading to a partly open channel within 4 ns of TMD simulation. Furthermore, we confirmed that two highly conserved residue pairs, one located near the ligand-binding pocket (Lys145 and Tyr188), and the other located toward the bottom of the ligand-binding domain (Arg206 and Glu45), are likely to play important roles in coupling agonist binding to channel gating. Overall, our simulations suggest that gating movements of the α7 receptor may involve relatively small structural changes within the ligand-binding domain, implying that the gating transition is energy-efficient and can be easily modulated by agonist binding/unbinding.

Original languageEnglish (US)
Pages (from-to)1173-1184
Number of pages12
JournalPLoS Computational Biology
Volume2
Issue number9
DOIs
StatePublished - 2006

Fingerprint

molecular dynamics
Nicotinic Receptors
Molecular Dynamics Simulation
Molecular Dynamics
Receptor
ligand
Molecular dynamics
Closure
Ligands
receptors
Acetylcholine
cholinergic receptors
simulation
acetylcholine
agonists
binding proteins
Carrier Proteins
Computer simulation
Rearrangement
carbachol

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Ecology
  • Molecular Biology
  • Genetics
  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Computational Theory and Mathematics

Cite this

Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors. / Cheng, Xiaolin; Wang, Hailong; Grant, Barry; Sine, Steven M; McCammon, J. Andrew.

In: PLoS Computational Biology, Vol. 2, No. 9, 2006, p. 1173-1184.

Research output: Contribution to journalArticle

Cheng, Xiaolin ; Wang, Hailong ; Grant, Barry ; Sine, Steven M ; McCammon, J. Andrew. / Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors. In: PLoS Computational Biology. 2006 ; Vol. 2, No. 9. pp. 1173-1184.
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