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

Abstract

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 Ca 2+ 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 Ca 2+ on the structure and dynamics of α7 nAChR embedded in a model phospholipid bilayer. Our results suggest that the presence of Ca 2+ 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 Ca 2+ 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 Ca 2+ permeation through the pore as elucidated by umbrella sampling simulations. Overall, the structural and permeability changes in α7 nAChR suggest that elevated Ca 2+ 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. K E Y W O R D S divalent calcium ions, molecular dynamics simulations, nicotinic acetylcholine receptors, permeation, umbrella sampling

Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptor

“…Although the conformational changes due to calcium binding are likely smaller than those due to agonist binding (Li et al, 2011), these smaller changes may prime the receptor so that changes elicited by agonist are either more stable or occur more rapidly. A recent study in which MD simulations were applied to a model of the full-length α7 nAChR also revealed conformational changes in the presence of calcium that were consistent with a partially activated state (Suresh and Hung, 2019).…”

Key role of the TM2-TM3 loop in calcium potentiation of the α9α10 nicotinic acetylcholine receptor

“…Blockage of α9 and α9α10 nAChRs occurs in the millimolar range, is voltage-dependent, and proposed to occur as a result of Ca 2+ permeation [18,47]. On the other hand, potentiation of α9α10 receptors is voltage-independent [18], suggesting that, similar to that proposed for α7 receptors [17,21,[48][49][50], Ca 2+ most likely interacts at an extracellular binding site to allosterically modulate coupling between ligand-binding and gating [18].…”

“…In this regard, extracellular calcium (Ca 2+ ) has been reported to increase macroscopic currents and change the kinetic properties of several native and recombinant nAChRs and has been classi ed as an allosteric modulator of these receptors [13][14][15][16][17][18][19]. Moreover, previous studies revealed that Ca 2+ binding leads to similar but smaller conformational changes than those due to agonist binding, that are consistent with a partially activated state [20,21].…”

Paired Simulations and Experimental Investigations into the Calcium-Dependent Conformation of Albumin

“…On the other hand, computational modeling and simulation offer the ability to study protein at the atomistic level, albeit at the expense of some accuracy. 23,24 One such computational approach is molecular dynamics (MD) simulations that can provide atomistic details of the protein structure and dynamics and validate experimental observations. 25,26 However, atomistic MD simulations can be very computationally expensive, especially if large-scale conformational changes are being studied.…”

“…Despite the success of experimental techniques to determine the structural features of proteins, − the experimental study of dynamic transitions between conformations remains extremely challenging. On the other hand, computational modeling and simulation offer the ability to study protein at the atomistic level, albeit at the expense of some accuracy. , One such computational approach is molecular dynamics (MD) simulations that can provide atomistic details of the protein structure and dynamics and validate experimental observations. , However, atomistic MD simulations can be very computationally expensive, especially if large-scale conformational changes are being studied. Such simulations are typically able to capture dynamics at the nanosecond to microsecond (ns to μs) timescales. , To increase these timescales, coarse-grained (CG) MD models can be used. , In CG models, a mapping scheme is used to represent a group of atoms as beads, leading to a reduction in the degrees of freedom and hence longer simulation timescales.…”