Redox leveling of the Kok cycle of photosystem II established by water ligand binding to the oxygen evolving complex

Photosystem II (PSII) produces dioxygen at the oxygen-evolving complex (OEC) by catalyzing light-driven water oxidation. The OEC Mn4CaO5 cluster cycles through a series of redox state intermediates Si (i = 0-4) along the Kok cycle, as the tyrosine Z radical oxidizes the cluster and accumulates multiple oxidizing equivalents. All S-state transitions occur within a narrow range of redox potentials and involve alternating oxidation and deprotonation steps. Here, we address the origin of the redox leveling mechanism as determined by the structure of hydrogen bonding surrounding the OEC and binding of water ligands to the OECs. We focus on the S2 to S3 transition to investigate the relative oxidation potential of the tyrosine radical as compared to the oxidation potential of high valent Mn centers regulated by water binding. Free energy calculations at the DFT QM/MM level of theory show that water binding lowers the free energy change for the S2/S3 transition by 13.7 kcal/mol, demonstrating the regulatory role of water binding on the reaction mechanism. The dynamics of water binding to the Mn is further analyzed by running molecular dynamics simulations where the interaction potential of water ligands to the Mn centers is parametrized at the DFT level. Our analysis demonstrates the capabilities of our simulations for studies of substrate water ligand exchange to the OEC that enables direct comparisons to time-resolved mass spectroscopic measurements.