One- and two- electron reductions in miniSOG and their implication in catalysis

Abstract

In the last years, the unconventional bioorthogonal catalytic activation of anticancer metal complexes by flavin and flavoproteins photocatalysis has been described [Alonso-de Castro et al., Angew. Chem.,Int. Ed., 2018, 57, 3143]. The reactivity is based on a two-electron redox reaction of the photoactivated flavin. Furthermore, when it comes to flavoproteins, we recently reported that site mutagenesis can modulate and improve this catalytic activity in miniSOG [Gurruchaga-Pereda et al., J. Phys. Chem. Lett., 2021, 12, 19, 4504]. In this paper, we analyze the reductive half-reaction in the different miniSOG environments by means of density functional theory. We observe that the redox properties of the flavin, and consequently, the reactivity of miniSOG changes upon selected mutations, unveiling the physico- chemical fundamentals of this modulation: the competition between the single and double reduction of the flavin, and the electron transfer probability from the protein to the flavin, which are both ultimately related to the stability of the electron accepting orbitals of the flavin in the different coordination modes. Both factors alter the reactivity of miniSOG, in line with the experimental results in the literature.

One‐ and Two‐Electron Reductions in MiniSOG and their Implication in Catalysis**

“…Probably, the assumption that Gln103 plays a fundamental role in miniSOG's chemistry arises from its vicinity to this binding site. Nevertheless, in our works [11] (and others in the literature [6,12] ) we have observed that Gln103 does not interact with N3 in miniSOG, but with O2, and therefore its influence is not as determinant as expected. This becomes apparent if the reduction reaction energies of Gln103 and WT are compared: even if Gln103 is absent in Q103V, the energy balances studied are very similar to those of WT.…”

“…Nevertheless, posterior classical Molecular Dynamics (MD) simulations carried out on mutants Q50W and Q103V, [11] show that the coordination of the flavin moiety to the protein changes upon mutation, even when this takes place in a remote site. It is known that the protein environment and the interactions established with the residues in the binding pocket can tune FMN's physicochemical properties, [12] and consequently, its catalytic activity could vary upon mutation.…”