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Oxidation triggers extensive conjugation and unusual stabilization of two di-heme dication diradical intermediates: role of bridging group for electronic communication.

ABSTRACT: MauG is a diheme enzyme that utilizes two covalently bound c-type hemes to catalyse the biosynthesis of the protein-derived cofactor tryptophan tryptophylquinone. The two hemes are physically separated by 14.5 Å and a hole-hopping mechanism is proposed in which a tryptophan residue located between the hemes undergoes reversible oxidation and reduction to increase the effective electronic coupling element and enhance the rate of reversible electron transfer between the hemes in bis-Fe(iv) MauG. The present work describes the structure and spectroscopic investigation of 2e-oxidations of the synthetic diheme analogs in which two heme centers are covalently connected through a conjugated ethylene bridge that leads to the stabilization of two unusual trans conformations (U and P' forms) with different and distinct spectroscopic and geometric features. Unlike in MauG, where the two oxidizing equivalents are distributed within the diheme system giving rise to the bis-Fe(iv) redox state, the synthetic analog stabilizes two ferric hemes, each coupled with a porphyrin cation radical, a scenario resembling the binuclear dication diradical complex. Interestingly, charge resonance-transition phenomena are observed here both in 1e and 2e-oxidised species from the same system, which are also clearly distinguishable by their relative position and intensity. Detailed UV-vis-NIR, X-ray, Mössbauer, EPR and 1H NMR spectroscopic investigations as well as variable temperature magnetic studies have unraveled strong electronic communications between two porphyrin ?-cation radicals through the bridging ethylene group. The extensive ?-conjugation also allows antiferromagnetic coupling between iron(iii) centers and porphyrin radical spins of both rings. DFT calculations revealed extended ?-conjugation and H-bonding interaction as the major factors in controlling the stability of the conformers.

SUBMITTER: Sil D

PROVIDER: S-EPMC5975787 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Oxidation triggers extensive conjugation and unusual stabilization of two di-heme dication diradical intermediates: role of bridging group for electronic communication.

Sil Debangsu D Dey Soumyajit S Kumar Amit A Bhowmik Susovan S Rath Sankar Prasad SP

Chemical science 20151026 2

MauG is a diheme enzyme that utilizes two covalently bound c-type hemes to catalyse the biosynthesis of the protein-derived cofactor tryptophan tryptophylquinone. The two hemes are physically separated by 14.5 Å and a hole-hopping mechanism is proposed in which a tryptophan residue located between the hemes undergoes reversible oxidation and reduction to increase the effective electronic coupling element and enhance the rate of reversible electron transfer between the hemes in bis-Fe(iv) MauG. T ...[more]

PMID: 29910877

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Project description:p53 is a homotetrameric tumor suppressor protein that is found to be mutated in most human cancers. Some of these mutations, particularly mutations to R337, fall in the tetramerization domain and cause defects in tetramer formation leading to loss of function. Mutation to His at this site has been found to destabilize the tetramer in a pH-dependent fashion. In structures of the tetramerization domain determined by crystallography, R337 from one monomer makes a salt bridge with D352 from another monomer, apparently helping to stabilize the tetramer. Here we present molecular dynamics simulations of wild-type p53 and the R337His mutant at several different pH and salt conditions. We find that the 337-352 salt bridge is joined by two other charged side chains, R333 and E349. These four residues do not settle into a fixed pattern of salt bridging, but continue to exchange salt-bridging partners on the nanosecond time scale throughout the simulation. This unusual system of fluid salt bridging may explain the previous finding from alanine scanning experiments that R333 contributes significantly to protein stability, even though in the crystal structure it is extended outward into solvent. This extended conformation of R333 appears to be the result of a specific crystal contact and, this contact being absent in the simulation, R333 turns inward to join its interaction partners. When R337 is mutated to His but remains positively charged, it maintains the original interaction with D352, but the newly observed interaction with E349 is weakened, accounting for the reduced stability of R337H even under mildly acidic conditions. When this His is deprotonated, the interaction with D352 is also lost, accounting for the further destabilization observed under mildly alkaline conditions. Simulations were carried out using both explicit and implicit solvent models, and both displayed similar behavior of the fluid salt-bridging cluster, suggesting that implicit solvent models can capture at least the qualitative features of this phenomenon as well as explicit solvent. Simulations under strongly acidic conditions in implicit solvent displayed the beginnings of the unfolding process, a destabilization of the hydrophobic dimer-dimer interface. Computational alanine scanning using the molecular mechanics Poisson-Boltzmann surface area method showed significant correlation to experimental unfolding data for charged and polar residues, but much weaker correlation for hydrophobic residues.

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Oxidation triggers extensive conjugation and unusual stabilization of two di-heme dication diradical intermediates: role of bridging group for electronic communication.

Publications

Oxidation triggers extensive conjugation and unusual stabilization of two di-heme dication diradical intermediates: role of bridging group for electronic communication.

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