Deciphering the concentration-dependent modulation effect of CT16 on the human α7 nicotinic receptor: Insights from molecular dynamics simulation

Alzheimer's disease (AD) is closely linked to the accumulation of amyloid-beta peptides (Aβ), which impair synaptic plasticity and contribute to cognitive decline. Among the fragments of Aβ, the CT16 peptide (the equivalent of Aβ16, derived from soluble amyloid precursor protein α, sAPPα) has been shown to interact with the α7 nicotinic acetylcholine receptor (α7nAChR), potentially enhancing synaptic plasticity. However, the concentration-dependent modulation of CT16 on α7nAChR and its underlying mechanisms remain poorly understood. We employ molecular dynamics simulations to investigate how varying concentrations of CT16 affect the conformation and function of the α7nAChR, and establishes the proportional relationship between CT16 concentration and α7nAChR receptor function regulation at the molecular level, finding a stoichiometric ratio of 1:3 for maximum activation of α7nAChR by CT16, and establishing the first demonstration that the constriction geometry of the pore within extracellular domain (specifically its minimal cross-sectional area) serves as the dominant structural determinant for ion permeation pathways at stoichiometric CT16:α7nAChR binding (1:1 ratio), a phenomenon contrasting sharply with scenarios at higher ratios (CT16:α7nAChR > 1:1). The presence of CT16 not only induces significant conformational changes, stabilizes specific receptor regions, but also modulates the ion channel's pore geometry in a concentration-dependent manner. These findings shed light on the potential role of CT16 in regulating synaptic plasticity and offer theoretical insights into its dual role as a positive allosteric modulator at low concentrations and an inhibitor at higher concentrations, which may have implications for therapeutic strategies targeting α7nAChR in AD and other neurodegenerative diseases. Concentration-dependent binding of CT16 to the extracellular domain (ECD) of α7 nicotinic acetylcholine receptor (α7nAChR) induces biphasic modulation of the d1/d2 pore diameters, exhibiting the mechanism of a reversible symmetry transition.