Ultrafast terahertz-induced torque disruption of fentanyl's μ-opioid receptor binding for precision overdose reversal.

Abstract

Context: This study establishes a quantum-biophysical framework for non-invasive opioid overdose reversal by demonstrating ultrafast terahertz (THz) torque-mediated disruption of fentanyl-μ-opioid receptor (μOR) binding. By targeting the vibrational modes of the fentanyl-μOR complex with resonant THz pulses (1-1.5 THz, ≥ 100 kV/cm), the study examines two key binding configurations: the Asp147 salt bridge (D147) and His297 hydrogen bond (H297). The model reveals that THz-induced torque reduces the dissociation barrier by 3.2-3.8 kcal/mol through mechanical disruption of the N-H⁺···O⁻ interaction, achieving 50% unbinding within 1.2 ps at optimal frequencies. The H297 configuration dissociates 40% faster than D147, indicating a pharmacologically preferable site for intervention. A sigmoidal dose-response is observed in the 100-150 kV/cm range, enabling > 90% dissociation efficacy under non-thermal conditions. These findings offer a novel electromagnetic approach for modulating opioid pharmacodynamics and inform the development of receptor-targeted antidotes via precision bioelectromagnetic strategies. While this study demonstrates the theoretical feasibility of THz-induced dissociation, future experimental work is needed to address translational challenges such as tissue penetration and biological specificity.

Methods: The study employs a quantum-classical hybrid framework combining time-dependent Schrödinger equation simulations with classical electrodynamics. Fentanyl is modeled as a confined asymmetric rotor interacting with a µOR-like potential landscape under circularly polarized THz radiation. Quantum torque is derived from angular momentum operators coupled to the electric field vector. Site-specific binding configurations (D147 and H297) are simulated with field-driven vibrational excitation and potential energy surface deformation. Dissociation dynamics and barrier modulation are quantified using Fermi's Golden Rule and time-evolved wavepacket propagation. Numerical computations were performed in Wolfram Mathematica 13.1, with molecular input parameters validated against DFT-based dipole moments, mass tensors, and force-field data extracted from experimental literature.