Quantum Tunneling-Gated Vesicle Fusion: Proton-Coupled Electron Transfer and Mechanical Barrier Softening Shape Neurotransmitter Release Latency

Neurotransmitter release in neurons requires synaptic vesicles to fuse rapidly with the presynaptic membrane after calcium entry, yet single-vesicle recordings show highly heterogeneous latency distributions with both fast events and long heavy tails. Most existing models fit these data empirically without mechanistic grounding. We introduce a quantum- mechanochemical model in which an initial proton-coupled electron transfer (PCET) step, governed by quantum tunneling, primes the vesicle for fusion, while a subsequent time-dependent mechanical barrier softening drives the final membrane merger. The scheme consists of three states: a closed SNARE complex that activates through PCET [Formula], a primed intermediate (P) that undergoes mechanical gating with an aging rate and forward rate k2(t), and a reversible slip-back process (k-1(t)) that sustains long-latency events. The PCET step is described by a Marcus-type tunneling expression with isotope-dependent mass terms, enabling direct prediction of the kinetic isotope effect (KIE) between protiated and deuterated conditions. Structural heterogeneity is included via a distribution of donor-acceptor distances. By calibrating the mechanochemical attempt frequency{gamma} to reproduce the typical early fusion probability (P [0- 5 ms]H{approx} 0.20), the model generates latency probability density functions (PDFs), cumulative distributions (CDFs), and hazard rates consistent with experimental observations. Parameter sweeps show how tunneling decay ({beta}tun) controls the KIE magnitude, while mechanical aging and back reaction redistribute early versus late events. This quantum-mechanical and force-activated framework provides a physically interpretable, testable alternative to purely empirical fits for single-vesicle fusion latency in neurons.