Domain motions and electron transfer dynamics in 2Fe-superoxide reductase

Abstract

Superoxide reductases are non-heme iron enzymes that represent valuable model systems for the reductive detoxification of reactive oxygen species. In the present study, we applied different theoretical methods to study the structural dynamics of a prototypical 2Fe-superoxide reductase and its influence on electron transfer towards the active site. Using normal mode and essential dynamics analyses, we could show that enzymes of this type are capable of well-defined, electrostatically triggered domain movements, which may allow conformational proofreading for cellular redox partners involved in intermolecular electron transfer. Moreover, these global modes of motion were found to enable access to molecular configurations with decreased tunnelling distances between the active site and the enzyme's second iron centre. Using all-atom classical molecular dynamics simulations and the tunnelling pathway model, however, we found that electron transfer between the two metal sites is not accelerated under these conditions. This unexpected finding suggests that the unperturbed enzymatic structure is optimized for intramolecular electron transfer, which provides an indirect indication of the biological relevance of such a mechanism. Consistently, efficient electron transfer was found to depend on a distinct route, which is accessible via the equilibrium geometry and characterized by a quasi conserved tyrosine that could enable multistep-tunnelling (hopping). Besides these explicit findings, the present study demonstrates the importance of considering both global and local protein dynamics, and a generalized approach for the functional analysis of these aspects is provided.

Iron Hydroperoxide Intermediate in Superoxide Reductase: Protonation or Dissociation First? MM Dynamics and QM/MM Metadynamics Study

“…Although the active site is identical in all the SORs characterized so far, some enzymes like those from Desulfoarculus baarsii and Desulfovibrio vulgaris possess a second mononuclear iron center localized in an additional N-terminal domain. , This center is of desulforedoxin type (DX) with an iron chelated by four sulfurs from cysteines in a rubredoxin-distorted manner ([FeS 4 ]) . It is located at 22 Å from the active site, and up to now when present in SOR, its function in catalysis has not been yet definitively established, although it has been proposed to act as an electron relay toward the active site. − …”

A high-spin alkylperoxo–iron(iii) complex with cis-anionic ligands: implications for the superoxide reductase mechanism

“…The current study provides a basis to discuss the function of the high-spin {Fe II (His) 4 (Cys)} active site of SOR. Although the putative O 2 -binding site is considered trans - to the axial thiolate ligand, 6,8,9 the redox induced structural changes at the level of the peptide bond(s), as previously demonstrated by one of us and others, 37,38 may lead to the formation of a HS cis -[Fe III (OOH)(Cys)] + moiety. The O–O bond cleavage to produce the undesired high-valent oxo–iron species is presumably prevented by the high-spin iron( iii ) center and the presence of the equatorial thiolate ligand.…”

Conformational H-bonding modulation of the iron active site cysteine ligand of superoxide reductase: absorption and resonance Raman studies

“…20 It is located 22 Å away from the active site and its function in catalysis is not clearly established yet. [21][22][23] Class II SORs, like in Pyrococcus…”