Frequency-selective and ligand-architecture-dependent modulation of nicotinic acetylcholine receptor-ligand binding using terahertz waves.

Abstract

External oscillating electric fields can perturb biomolecular interactions, but how the response depends on excitation frequency and ligand architecture remains unclear. Here, all-atom molecular dynamics simulations were used to examine four ligand-bound nicotinic acetylcholine receptor (nAChR)-related extracellular-domain complexes containing carbamylcholine, clothianidin, epibatidine, or encenicline. Ligand dipole-moment autocorrelation spectra guided the selection of excitation frequencies between 14.50 and 46.58 THz. Across the four systems, the largest changes occurred at the lowest tested frequencies, whereas the intermediate- and high-frequency fields produced comparatively small effects. Low-frequency excitation reduced ligand-pocket contact areas and weakened interaction energies most strongly for flexible carbamylcholine and monocyclic clothianidin; bicyclic epibatidine showed an intermediate response, and polycyclic encenicline remained comparatively stable. The response was associated with increased ligand displacement and reorientation, enhanced fluctuations of pocket-contact residues, and loss or rearrangement of hydrogen bonds and cation-π interactions. These observations support a mechanistic picture in which low-frequency collective motions couple more effectively to ligand-pocket coordinates, whereas conformational rigidity limits the propagation of field-induced perturbations. These findings provide a structure-response framework for frequency-selective modulation of receptor-ligand interactions.

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