What can be learned from the electrostatic environments within nitrogenase enzymes?

Nitrogen fixation is a fundamental, and yet challenging, chemical transformation due to the intrinsic inertness of dinitrogen. Whereas industrial ammonia synthesis relies on the energy-intensive Haber–Bosch process, nitrogenase enzymes achieve this transformation under ambient conditions—yet at the expense of a remarkably high ATP demand. Understanding their mode of operation could inspire the development of more efficient synthetic catalysts. In this study, we scrutinize the electrostatic environment surrounding nitrogenase’s active site, the so-called M-cluster. Strikingly, we observe that all types of M-clusters exhibit similar trends, with distinct patterns around the individual metal sites that have been proposed as potential N2-coordination sites. Specifically, a strong local electric field pointing away from the Fe2 site is identified, as well as a minor field pointing towards the Fe6 sites. Furthermore, a significant oriented long-range field along the Fe2–Fe6 axis is computed across the entire family of nitrogenases. In the final part of the manuscript, we discuss how the observed electrostatic patterns may impact chemical reactivity, and how they can be connected to previously made mechanistic hypotheses. Overall, this study provides further evidence for the ubiquitousness of local electric fields in enzyme catalysis, even when substrates that seemingly have only limited electrostatic susceptibility are involved.