Structural effects of divalent calcium cations on the α7 nicotinic acetylcholine receptor: A molecular dynamics simulation study

The α7 subtype of neuronal nicotinic acetylcholine receptor (nAChR) is a ligand‐gated ion channel protein that is vital to various neurological functions, including modulation of neurotransmitter release. A relatively high concentration of extracellular Ca2+ in the neuronal environment is likely to exert substantial structural and functional influence on nAChRs, which may affect their interactions with agonists and antagonists. In this work, we employed atomistic molecular dynamics (MD) simulations to examine the effects of elevated Ca2+ on the structure and dynamics of α7 nAChR embedded in a model phospholipid bilayer. Our results suggest that the presence of Ca2+ in the α7 nAChR environment results in closure of loop C‐in the extracellular ligand‐binding domain, a motion normally associated with agonist binding and receptor activation. Elevated Ca2+ also alters the conformation of key regions of the receptor, including the inter‐helical loops, pore‐lining helices and the “gate” residues, and causes partial channel opening in the absence of an agonist, leading to an attendant reduction in the free energy of Ca2+ permeation through the pore as elucidated by umbrella sampling simulations. Overall, the structural and permeability changes in α7 nAChR suggest that elevated Ca2+ induces a partially activated receptor state that is distinct from both the resting and the agonist‐activated states. These results are consistent with the notion that divalent ions can serve as a potentiator of nAChRs, resulting in a higher rate of receptor activation (and subsequent desensitization) in the presence of agonists, with possible implications for diseases involving calcium dysregulation.