The Quantum Cliff: A Critical Proton Tunneling Threshold Determines Clinical Severity in RPE65-Mediated Retinal Disease

TL;DR

This study demonstrates that mutations in the human visual isomerase RPE65 are governed by a quantum-mechanical threshold effect arising from proton tunneling in the active site, and establishes quantum tunneling as a predictive mechanistic link between atomic structure and clinical phenotype, proposing a general framework for quantum-structural disease modeling.

Abstract

Predicting clinical severity from genotype remains a fundamental challenge in molecular medicine, particularly for enzymes whose function depends on sub-atomic-scale geometry. Mutations in the \textit{RPE65} isomerohydrolase cause Leber Congenital Amaurosis (LCA) and related retinal diseases; however, the kinetic mechanisms connecting sub-atomic-scale perturbations to blindness remain unclear. In this study, we demonstrate that mutations in the human visual isomerase RPE65 are governed by a quantum-mechanical threshold effect arising from proton tunneling in the active site. We established a hybrid quantum-classical structure-to-phenotype pipeline combining AlphaFold structure prediction with \textit{ab initio} quantum simulation using the Variational Quantum Eigensolver (VQE) to analyze minimal proton-coupled electron transfer in the visual cycle. Our analysis reveals that many pathogenic mutations do not merely occlude the active site, but rather strongly reduce the quantum probability of proton tunneling. We observed a sharp non-linear effect, termed the "Quantum Cliff," where minute structural changes (below 0.1 Å) reduce the reaction rate by multiple orders of magnitude. Based on these findings, we introduce a dimensionless Relative Quantum Activity Score (RQAS) that isolates the geometry-controlled exponential sensitivity of the reaction rate and successfully distinguishes between mild and severe patient phenotypes. These results suggest that RPE65 operates near a quantum-critical point, where sub-Angstrom structural perturbations induce a catastrophic loss of function. Furthermore, our findings establish quantum tunneling as a predictive mechanistic link between atomic structure and clinical phenotype, proposing a general framework for quantum-structural disease modeling.

Figures (5)

• Figure 1: Overview of the RPE65 proton-transfer workflow. The active site is modelled as a minimal O-H-O system. A variational quantum eigensolver (VQE) scans the proton coordinate to generate a one-dimensional potential energy surface. Barrier heights and widths are extracted and used to compute transfer probabilities via a combined quantum tunnelling and thermal activation model. Mutation-induced changes in donor-acceptor distance produce an exponential decrease in tunnelling probability, giving rise to a "quantum cliff" that explains the abrupt loss of activity in severe variants.
• Figure 2: Comparing Healthy vs. Broken Engines. (a) 3D Active Site Geometry. The reconstructed coordination sphere of the Iron cofactor (orange). The green dashed line represents the reaction coordinate vector. (b) Ab-Initio Potential Energy Surface. The relative energy profile calculated via VQE. The Wild Type (blue) exhibits a narrow barrier; the R91W mutant (red) exhibits a wide barrier.
• Figure 3: The Quantum Cliff. Scatter plot showing the dependence of Relative Quantum Activity (RQAS) on the Active Site Distance ($d_{OO}$). The linear trend on this semi-logarithmic scale confirms the exponential decay characteristic of quantum tunneling.
• Figure 4: Clinical Validation Regression. A scatter plot comparing experimentally measured activity (X-axis) against predicted quantum activity (Y-axis). The strong correlation ($R^2=0.93$) indicates robust ranking capability.
• Figure 5: Mutation Severity Ranking. A logarithmic comparison of predicted residual activity. Note the massive drop for severe variants.