Conformational Control over Proton-Coupled Electron Transfer in Metalloenzymes

From the reduction of dinitrogen to the oxidation of water, the chemical transformations catalyzed by metalloenzymes underlie global geo- and biochemical cycles. These reactions represent some of the most kinetically and thermodynamically challenging processes known. They require the complex choreography of nature’s fundamental building blocks: electrons and protons, to be carried out with utmost precision and accuracy; mistimed synchronicity can be fatal. Gated by macrostructural conformational changes, the rate-determining steps of catalysis in many of these enzymes consist of protein structural rearrangements. Accordingly, a pattern emerges in which it appears that nature has evolved to leverage changes in macromolecular protein structure to control changes in the metallocofactor microstructure. This critical review defines (where possible) and discusses the detailed molecular mechanisms of how metalloenzymes are able to efficiently convert allosteric binding energy into activation energy through conformational gating. Here, the proton-coupled electron transfer (PCET) mechanisms in biology stand as a paradigm for the interplay between molecular and electronic structural control. Taking nitrogenase, photosystem II, and ribonucleotide reductase as examples, we present the culmination of decades of study on each of these systems to clarify what is known regarding the interplay between structural changes and functional outcomes in these metalloenzyme linchpins.