Photosystem II (PSII) uses solar energy to extract electrons and protons from water, liberating molecular oxygen as a by-product.  The reaction is exceptionally demanding from a thermodynamic perspective and the reaction mechanism is not yet fully understood.  Recent structural models of PSII are facilitating the development of both detailed mechanistic hypotheses and experiments designed to describe the roles of specific amino acid residues.  Many of these experiments involve Fourier Transform Infrared (FTIR) difference spectroscopy.  FTIR difference spectroscopy is an extremely sensitive tool for characterizing the dynamic structural changes that occur during an enzyme’s catalytic cycle, such as changes in molecular interactions, bonding, protonation states, and protein backbone conformations.  In PSII, the frequencies of numerous vibrational modes change as the Mn₄Ca cluster is oxidized through the catalytic cycle.  This seminar will describe isotopic labeling and mutagenesis studies that have been undertaken to identify these modes.  Their identification will help describe the structural changes that accompany the oxidations of the Mn₄Ca cluster and will provide insight into how the Mn₄Ca cluster’s reactivity is regulated by its protein environment to maximize the efficiency of water oxidation and minimize the release of toxic, highly reactive intermediates.  This work complements X-ray crystallographic, computational, synthetic bioinorganic, and many other spectroscopic studies designed to elucidate the mechanism of molecular oxygen production in PSII.