Mechanism of Tyrosine-Driven Deprotonation in Photosystem II Revealed by Multiscale Simulations

Photosystem II (PSII) drives light-induced water oxidation via stepwise redox transitions of its oxygen-evolving complex (OEC), a Mn₄Ca cluster advancing through five intermediate S-states (S₀-S₄). The S₂ → S₃ transition involves a redox event in which a Mn ion donates an electron to the redox-active tyrosine Y_Z, coupled to deprotonation of an OEC-bound water ligand─yet the underlying coupling mechanism remains unresolved. Time-resolved serial femtosecond crystallography (TR-SFX) has revealed transient electron density shifts near the redox-active tyrosine Y_Z, interpreted as sequential oxidation and reduction, with reduction initiating ∼1 μs after excitation and substantially progressed by 30 μs. However, this interpretation conflicts with kinetics from photothermal beam deflection (PBD), time-resolved X-ray absorption spectroscopy (TR-XAS), and electron paramagnetic resonance (EPR), which place electron transfer at 190-400 μs and proton transfer around 30 μs. Here, we reconcile these discrepancies using quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) simulations. We show that oxidation of P680 and Y_Z breaks the symmetry of the nearby hydrogen bonds involving water molecule W4, displacing Y_Z and replicating the TR-SFX features of Y_Z and Q165 observed at 1 μs. This local perturbation propagates through a hydrogen-bond network, transmitting the electrostatic signal from Y_Z to the E65-E312 dyad and triggering redox-coupled deprotonation via the Cl1 channel. By 30 μs, the hydrogen-bond symmetry is restored through deprotonation of W2 (or alternatively W1), reproducing the disappearance of TR-SFX density differences around Y_Z and Q165 without requiring Y_Z reduction. Our proposed mechanism also gives molecular insights into the O6* density, assigning it to water reorganization rather than a discrete Ca-bound hydroxide species. Our results reveal a detailed atomistic mechanism linking Y_Z oxidation to long-range proton release and suggest a functional role for the nearby Cl^- ion in proton transfer. More broadly, this study underscores the importance of hydrogen-bond dynamics in mediating redox-driven proton transport and demonstrates how integrative simulations can resolve mechanistic ambiguities.