Terahertz wave targeting modulates the dedocking of neurotransmitters with receptors

Abstract

Neurotransmitters are essential in regulating the functions of the nervous, cardiovascular, endocrine, and various other tissue systems. Neurodegenerative diseases such as Parkinson's disease, depression, and Alzheimer's disease involve the loss of catecholamine neurons. One of the main challenges is the accumulation of catecholamine (CA) metabolites. Reducing the metabolic aggregation toxicity of the transmitter molecules remains an open question. In this work, we proposed a novel physical method, terahertz-triggered dedocking, to unbind ligand molecules that accumulate around receptor proteins, potentially alleviating neurodegenerative diseases. We found that electromagnetic stimulation at 44.5 THz successfully dissociates the DA ligand from the binding sites at the receptor by breaking weak hydrogen bonds. Using molecular docking, we identified multiple binding sites for CA neurotransmitter molecules within the dopamine receptor D2 (DRD2). We also characterized the terahertz fingerprints and theoretical spectra of CAs across the 0.5 to 50 THz range, revealing their microscopic vibrational modes at characteristic peak positions and elucidating how specific vibrations influence molecular conformational changes. This finding highlights the potential of terahertz radiation in regulating the nervous system and provides new theoretical support for neural drug discovery and the intervention of neurological disorders.

Keywords: Conformation; Dedocking; Neurotransmitters; Terahertz irradiation; Terahertz waves.

Graphical abstract

Fig. 1

Schematic diagram of CAs and their interconversion process through dopamine beta hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT).

Fig. 2

Analysis of hydrogen bonds and hydrophobic interactions between DRD2 receptor and CAs (DA (a1, a2, a3), A/E (a4), and NE (a5)). The black, red, and dark blue spheres represent C, O, and N atoms, respectively. The green dotted line represents hydrogen bonds.

Fig. 3

(a) Structural diagram of DRD2 with DA ligand. The black, white, red, and dark blue spheres represent C, H, O and N atoms, respectively. The dark blue dotted line represents hydrogen bonds. (b) Absorption spectra of the bulk water (dark blue curve) and the DA-DRD2 receptor groups (orange curve), respectively. (c) (d) Comparisons of the center of mass distance (Dm) (upper) of the H-bond distance for each base pair between the D2 receptor and DA ligand, for cases without (w/o) and with THz-EW stimulus.

Fig. 4

(a) Terahertz experimental (solid line) and theoretical simulation (dashed line) spectra of CAs in the range of 0.5 to 50 THz. (b) The vibration modes and contact angles of CAs molecules near the DA-DRD2 complex sensitive frequency of 44.5 THz are shown. The black, white, red, and blue spheres represent C, H, O and N atoms, respectively. In every substance, two molecules are identical.