From Synthetic to Biological Fe₄S₄ Complexes: Redox Properties Correlated to Function of Radical S‐Adenosylmethionine Enzymes

Abstract

In memory of Professor Rudolf Zahradník, the father of the Czech school of quantum chemistry, our great teacher and friend. By employing the computational protocol for calculation of reduction potentials of the Fe 4 S 4-containing species validated using a representative series of well-defined synthetic complexes, we focused on redox properties of two prototypical radical SAM enzymes to reveal how they transform SAM into the reactive 5'-deoxyadenosyl radical, and how they tune this radical for its proper biological function. We found the reduction potential of SAM is indeed elevated by 0.3-0.4 V upon coordination to Fe 4 S 4 , which was previously speculated in the literature. This makes a generation of 5'-deoxyadenosyl radical from SAM less endergonic (by ca. 7-9 kcal mol À 1) and hence more feasible in both enzymes as compared to the identical process in water. Furthermore, our calculations indicate that the enzyme-bound 5'-deoxyadenosyl radical has a significantly lower reduction potential than in referential aqueous solution, which may help the enzymes to suppress potential side redox reactions and simultaneously elevate its proton-philic character, which may, in turn, promote the radical hydrogen-atom abstraction ability. * via homolytic cleavage of the FeÀ C5' bond. [17] Recent experiments on the synthetic [Fe 4 S 4 ]

Local Electric Fields As a Natural Switch of Heme-Iron Protein Reactivity

“…In more detail, the BDFE(O−H) change with the OEEF is, in fact, a product of the uneven effect of the OEEF on E°C pdI and pK A,CpdII (Figure 8); note that BDFE(O−H) = 23.06 × We expect that this differential tuning of E°C pdI and pK A,CpdII by the LEF could also be utilized by the enzymes, to steer the asynchronicity in the H atom abstraction between the proton and electron transfers, to achieve a higher reactivity/ selectivity. 13,55 Finally, we note that the computed properties of all three models (E°C pdI , E°H ,CpdI , and pK A,CpdII ) respond similarly to positive F z (Figure 8). However, DFT fails dramatically for E°C pdI and pK A,CpdII in the negative F z , for the His-ligated model.…”

“…Finally, we suggest that proteins' selectivity can be steered by regulating the disparity between E°C pdI and pK A,CpdII via introducing the asynchronicity in the proton/electron transfer in the H atom abstraction. 13,55 ■ CONCLUSIONS When a number of computational approaches were utilized on the small model systems, it was previously recognized that relatively large oriented electric fields could significantly contribute to the heme-iron reactivity and selectivity. However, a comprehensive association with the field magnitudes inside the proteins' active sites was missing, and the true accessibility of such fields in nature remained unquestioned.…”

Local Electric Fields as a Natural Switch of Heme-Iron Protein Reactivity

“…We expect that this differential tuning of E°CpdI and pKA,CpdII by the LEF could also be utilized by the enzymes, to steer the asynchronicity in the H-atom abstraction between the proton and electron transfers, to achieve a higher reactivity/selectivity. 13,55 Finally, we note that the computed properties of all three models (E°CpdI, E°H,CpdI, and pKA,CpdII) respond similarly to positive Fz (Figure 8). However, DFT fails dramatically for E°CpdI and pKA,CpdII in the negative Fz, for the His-ligated model.…”

“…Finally, we suggest that proteins' selectivity can be steered by regulating the disparity between E°CpdI and pKA,CpdII via introducing the asynchronicity in the proton/electron transfer in the H-atom abstraction. 13,55…”

Probing the Origins of Puzzling Reactivity in Fe/Mn–Oxo/Hydroxo Species toward C–H Bonds: A DFT and Ab Initio Perspective

“…The Lewis acidity (p K a ) of the M–O/OH moiety decreases as Mn III O > Fe III O > Fe II –OH > Mn II –OH > Mn IV O > Fe IV O > Mn III –OH > Fe III –OH > Mn V O > Mn V O > Fe IV –OH > Mn IV –OH in the DMA medium, while the calculated one-electron reduction potential values ( E 1/2 ) of the corresponding half-reaction for each species follows the order Fe IV –OH > Fe V O > Mn IV –OH > Mn V O > Fe IV –OH > Mn IV O > Fe III –OH > Mn III –OH > Fe III O > Mn III O > Mn II –OH > Fe II –OH against the Fc + /Fc couple (Table S1b and Figure S7). We have also estimated the error bars in the redox potentials, as well as the p K a value, as suggested earlier, and this is estimated to be 0.165 V and ±5, respectively.…”