Context <p>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.</p> Method <p>We formulated the quantum dynamics on a curved 2D reaction manifold <InlineEquation ID="IEq1"> <EquationSource Format="TEX">$(r,\theta )$</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <mo stretchy="false">(</mo> <mi>r</mi> <mo>,</mo> <mi>θ</mi> <mo stretchy="false">)</mo> </mrow> </math></EquationSource> </InlineEquation> 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 <InlineEquation ID="IEq2"> <EquationSource Format="TEX">$(\theta ,\Phi )$</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <mo stretchy="false">(</mo> <mi>θ</mi> <mo>,</mo> <mi mathvariant="normal">Φ</mi> <mo stretchy="false">)</mo> </mrow> </math></EquationSource> </InlineEquation> 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 (<InlineEquation ID="IEq3"> <EquationSource Format="TEX">$\approx 2.3 {k}_{B}T$</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <mo>≈</mo> <mn>2.3</mn> <msub> <mi>k</mi> <mi>B</mi> </msub> <mi>T</mi> </mrow> </math></EquationSource> </InlineEquation> 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.</p>

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

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发表日期：

2025年11月20日

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Moses G. Udoisoh

摘要

Context

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.

Method

We formulated the quantum dynamics on a curved 2D reaction manifold $(r,\theta )$ $(r, θ)$ 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 $(\theta ,\Phi )$ $(θ, Φ)$ 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 ( $\approx 2.3 {k}_{B}T$ $\approx 2.3 k_{B} T$ 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.