Residues surrounding the active centre of carbon monoxide dehydrogenase are key in converting [Formula: see text] to CO.

The enzyme carbon monoxide dehydrogenase is capable of efficiently converting [Formula: see text] to CO and, therefore, can enable an affordable [Formula: see text] recycling strategy. The reduction of [Formula: see text] occurs at a peculiar nickel-iron-sulfur cluster, following a mechanism that remains little understood. In this study, we have used ab initio molecular dynamics simulations to explore the free energy landscape of the reaction. We predict the existence of a COOH ligand that strongly interacts with the surrounding protein residues and favours a mechanism where a [Formula: see text] molecule is eliminated before CO. We have taken advantages of the insights offered by our simulations to revisit the catalytic mechanism and the role of the residues surrounding the active centre in particular, thus assisting in the design of inorganic catalysts that mimic the enzyme.