Hydrogen-activation mechanism of [Fe] hydrogenase revealed by multi-scale modeling

When investigating the mode of hydrogen activation by [Fe] hydrogenases, not only is the chemical reactivity at the active site of importance but also the large-scale conformational change between the so-called open and closed conformations, which leads to a special spatial arrangement of substrate and iron cofactor. To study H-2 activation, a complete model of the solvated and cofactor-bound enzyme in complex with the substrate methenyl-H4MPT+ was constructed. Both the closed and open conformations were simulated with classical molecular dynamics on the 100 ns time scale. Quantum-mechanics/molecular-mechanics (QM/MM) calculations on snapshots then revealed the features of the active site that enable the facile H-2 cleavage. The hydroxyl group of the pyridinol ligand can easily be deprotonated. With the deprotonated hydroxyl group and the structural arrangement in the closed conformation, H-2 coordinated to the Fe center is subject to an ionic and orbital push-pull effect and can be rapidly cleaved with a concerted hydride transfer to methenyl-H4MPT+. An intermediary hydride species is not formed.