How Oxygen Binding Enhances Long‐Range Electron Transfer: Lessons From Reduction of Lytic Polysaccharide Monooxygenases by Cellobiose Dehydrogenase

Abstract

Long‐range electron transfer (ET) in metalloenzymes is a general and fundamental process governing O2 activation and reduction. Lytic polysaccharide monooxygenases (LPMOs) are key enzymes for the oxidative cleavage of insoluble polysaccharides, but their reduction mechanism by cellobiose dehydrogenase (CDH), one of the most commonly used enzymatic electron donors, via long‐range ET is still an enigma. Using multiscale simulations, we reveal that interprotein ET between CDH and LPMO is mediated by the heme propionates of CDH and solvent waters. We also show that oxygen binding to the copper center of LPMO is coupled with the long‐range interprotein ET. This process, which is spin‐regulated and enhanced by the presence of O2, directly leads to LPMO−CuII−O2−, bypassing the formation of the generally assumed LPMO−CuI species. The uncovered ET mechanism rationalizes experimental observations and might have far‐reaching implications for LPMO catalysis as well as the O2‐ or CO‐binding‐enhanced long‐range ET processes in other metalloenzymes.

Conformational Motion of Ferredoxin Enables Efficient Electron Transfer to Heme in the Full-Length P450TT

“…Organized solvent water molecules were found to be important in mediating electron tunneling across protein–protein interfaces as demonstrated theoretically − and experimentally. − Indeed, we found that interface regions between the heme domain and ferredoxin domain are highly hydrophilic and populated by plenty of solvent water molecules (Figure a). It is expected that the solvent water molecules can not only mediate the H-bond interactions between the heme domain and ferredoxin domain but also form new ET pathways as exemplified in Figure b.…”

Critical Roles of Exchange and Superexchange Interactions in Dictating Electron Transfer and Reactivity in Metalloenzymes

“…Therefore, the spin-regulated ET in the quartet state is remarkably favored over that in the doublet state. 38 Outlook. This Perspective discusses and highlights the critical roles of exchange and superexchange interactions in reactivities of metalloenzymes.…”

“…39−43 The heme of CDH can reduce Cu(II) to Cu(I), whereby the reduced Cu(I) can bind and activate O 2 . In the presence of O 2 , our QM/MM-MD metadynamics reveal that the binding of oxygen to Cu(II) triggers a long-range electron transfer from Fe(II) to Cu(II), 38 which is spin-regulated. Though both the doublet and quartet states are degenerate in energies in the reactant complex, we find that the electron transfer in the quartet state is remarkably favored over the one in the double state, which may not be rationalized by the thermodynamic advantage of ∼5 kcal/mol in the quartet state.…”

“…Because of the Pauli exclusion principle, the spin-down electron from CYT cannot be efficiently transferred via the Cu bridge to O 2 in the doublet state, which is in contrast to the case of the quartet state. 38 In addition, the shifting spin-down electron from CYT may have some superexchange interactions with the spinup electron of the Cu bridge in the quartet state, which may dynamically enhance the electronic coupling for ET. Therefore, the spin-regulated ET in the quartet state is remarkably favored over that in the doublet state.…”

Emergence of Function from Nonheme Diiron Oxygenases: A Quantum Mechanical/Molecular Mechanical Study of Oxygen Activation and Organophosphonate Catabolism Mechanisms by PhnZ

“…As Fe2 has five parallel electrons, IC4′ will obtain maximum exchange interactions (see Figure c) . Thus, such an inner sphere electron transfer is spin-regulated and exchange-enhanced. ,, …”