Quantum-topological simulation of Berry phase-induced fentanyl-μ-opioid receptor dissociation via terahertz vortex...

Fentanyl's sub-nanomolar affinity and ultra-slow dissociation from the μ-opioid receptor (μOR) limit the efficacy of pharmacological antagonists like naloxone in acute overdose. We propose a non-pharmacological strategy in which structured terahertz (THz) vortex fields imprint a geometric (Berry) phase on the ligand-receptor complex to selectively bias unbinding pathways without bulk heating. This approach targets the quantum-coherent control of the dissociation coordinate through topological phase engineering.

We formulated the quantum dynamics on a curved 2D reaction manifold $(r,\theta )$ encoding proton transfer distance and ligand torsion. The system was driven by a near-field THz vortex (topological charge ℓ ≠ 0) and evolved via the covariant time-dependent Schrödinger equation, solved with a Crank-Nicolson propagator and absorbing boundaries. Berry phases were computed on adiabatic $(\theta ,\Phi )$ cycles, and dissociation rate enhancement was quantified through probability flux analysis incorporating solvent recapture effects. The model parameters were derived from cryo-EM and QM/MM data to ensure biochemical realism. Simulations indicate an effective torsional barrier reduction of 0.06 eV ( $\approx 2.3k_{B}T$ at 300 K) within the 1-1.5 THz band, sufficient to accelerate μOR-fentanyl escape by∼10x   at fixed temperature. A value consistent with non-thermal, frequency-addressable biasing of dissociation pathways. These findings provide a quantum-coherent, non-pharmacological strategy for disengaging potent opioid ligands, offering a new pathway for photonic control of Biochemical interactions with sub-molecular precision.