Mechanistic and Physiological Implications of the Interplay among Iron–Sulfur Clusters in [FeFe]-Hydrogenases. A QM/MM Perspective

Abstract

Key stereoelectronic properties of Desulfovibrio desulfuricans [FeFe]-hydrogenase (DdH) were investigated by quantum mechanical description of its complete inorganic core, which includes a Fe 6 S 6 active site (the H-cluster), as well as two ancillary Fe 4 S 4 assemblies (the F and F' clusters). The partially oxidized, active-ready form of DdH is able to efficiently bind dihydrogen, thus starting H 2 oxidation catalysis. The calculations allow us to unambiguously assign a mixed Fe(II)Fe(I) state to the catalytic core of the active-ready enzyme and show that H 2 uptake exerts subtle, yet crucial influences on the redox properties of DdH. In fact, H 2 binding can promote electron transfer from the H-cluster to the solvent-exposed F'-cluster, thanks to a 50% decrease of the energy gap between the HOMO (that is localized on the H-cluster) and the LUMO (which is centered on the F'-cluster). Our results also indicate that the binding of the redox partners of DdH in proximity of its F'-cluster can trigger oneelectron oxidation of the H 2 -bound enzyme, a process that is expected to have an important role in H 2 activation. Our findings are analyzed not only from a mechanistic perspective, but also in consideration of the physiological role of DdH. In fact, this enzyme is known to be able to catalyze both the oxidation and the evolution of H 2 , depending on the cellular metabolic requirements. Hints for the design of targeted mutations that could lead to the enhancement of the oxidizing properties of DdH are proposed and discussed.3

Probing the Effects of One‐Electron Reduction and Protonation on the Electronic Properties of the Fe‐S Clusters in the Active‐Ready Form of [FeFe]‐Hydrogenases. A QM/MM Investigation.

“…In particular, the average FeÀS Cys bond lengths are 0.06 longer in H ox À than in H ox [22] (2.37 vs. 2.31 ). On the other hand, the geometric features of the H-cluster do not differ significantly in the H ox À and H ox states, as is shown in Table 2.…”

“…A comparison between the latter and the geometry of the unprotonated parent complex H ox [22] can provide valuable insights into the structural modifications that would take place upon H ox protonation. It must be noted that, in agreement with experimental data, the structural features of the [2 Fe] H subcluster in the QM/MM H ox model indicated a quasi-symmetric disposition of the CO group bridging the Fe p and Fe d ions (Table 2).…”

“…It must be noted that, in agreement with experimental data, the structural features of the [2 Fe] H subcluster in the QM/MM H ox model indicated a quasi-symmetric disposition of the CO group bridging the Fe p and Fe d ions (Table 2). [22] However, analysis of the structural features of the protonated [2 Fe] H subcluster in H ox -H + reveals that the protonation would have a marked effect on the structural features of the diiron moiety, namely the bridging CO moves towards the Fe d atom. The FeÀS bonds in the [2 Fe] H assembly are strongly contracted in the H ox -H + state, in accordance with the oxidation of the iron atoms ( Figure 3 and Table 2).…”

“…1.2 eV), it has been suggested that electron transfer from the F'-to the H-cluster (and vice versa) could be triggered by protonation and/or one-electron reduction of the enzyme. [22] Prompted by the above observations, and with the aim of unravelling the effects of one-electron reduction and proton binding on the electronic properties of the metal clusters in the H ox -form of DdH, we carried out a computational study on a QM/MM model of the enzyme in which all three Fe-S clusters are simultaneously present in the QM system, together with a point-charge model of the surrounding protein and solvent. The optimization of the wavefunction of such a model automatically gives us the answer of where the electrons in the system prefer to be and how the electrons move when the system is reduced and/or protonated.…”

Dataset for Modelling Reaction Mechanisms Using Density Functional Theory: Mechanism of ortho‐Hydroxylation by High‐Valent Iron‐Oxo Species

“…Basis set LanL2DZ for Fe [21][22][23][24] and a 6-31 G [25] basis set for the other atoms like C, H, N, and O are employed. Accuracy of B3LYP has been well documented by the work of Neese, Shaik, Siegbahn, Solomon, and Ryde earlier [26][27][28][29][30][31][32]. Many reported density functionals have issues of obtaining correct spin ground state.…”