Symmetry-adapted Markov state models of closing, opening, and desensitizing in α7 nicotinic acetylcholine receptors

Abstract

7 nicotinic acetylcholine receptors (nAChRs) are homopentameric ligand-gated ion channels gated by acetylcholine. These receptors play crucial roles in controlling electrical signaling within the nervous system by facilitating the passage of cations across the membrane. Recent studies have resolved and functionally annotated closed, open, and desensitized states of 7 nAChRs, providing insight into ion permeation and lipid modulation. However, the process by which 7 nAChRs transition between states remains unclear. To understand gating and lipid modulation, we generated two ensembles of molecular dynamics simulations of the apo form of 7 nAChRs, with or without cholesterol. Using symmetry-adapted Markov state modeling, we developed a five-state gating model. Free energies recapitulated functional behavior, with the closed state dominating in the absence of agonists. Notably, the transition rate from open to a non-conductive intermediate (flipped) state corresponded to experimentally measured open durations around 0.1 ms. The introduction of cholesterol relatively stabilized the desensitized state and reduced barriers between desensitized and open states. These results establish plausible asymmetric transition pathways between functionally important states, they define lipid modulation effects in the 7 nAChR conformational cycle, and provide an ensemble of structural models that could be utilized for guiding rational design strategies to develop lipidic pharmaceuticals targeting these receptors.