Why the Flavin Adenine Dinucleotide (FAD) Cofactor Needs To Be Covalently Linked to Complex II of the Electron‐Transport Chain for the Conversion of FADH2 into FAD
dc.contributor.author
dc.date.accessioned
2018-10-25T10:38:02Z
dc.date.available
2018-10-25T10:38:02Z
dc.date.issued
2018-04-06
dc.identifier.issn
0947-6539
dc.identifier.uri
dc.description.abstract
A covalently bound flavin cofactor is predominant in the succinate-ubiquinone oxidoreductase (SQR; Complex II), an essential component of aerobic electron transport, and in the menaquinol-fumarate oxidoreductase (QFR), the anaerobic counterpart, although it is only present in approximately 10 % of the known flavoenzymes. This work investigates the role of this 8α-N3-histidyl linkage between the flavin adenine dinucleotide (FAD) cofactor and the respiratory Complex II. After parameterization with DFT calculations, classical molecular-dynamics simulations and quantum-mechanics calculations for Complex II:FAD and Complex II:FADH2, with and without the covalent bond, were performed. It was observed that the covalent bond is essential for the active-center arrangement of the FADH2/FAD cofactor. Removal of this bond causes a displacement of the isoalloxazine group, which influences interactions with the protein, flavin solvation, and possible proton-transfer pathways. Specifically, for the noncovalently bound FADH2cofactor, the N1 atom moves away from the His-A365 and His-A254 residues and the N5 atom moves away from the glutamine-62A residue. Both of the histidine and glutamine residues interact with a chain of water molecules that cross the enzyme, which is most likely involved in proton transfer. Breaking this chain of water molecules could thereby compromise proton transfer across the two active sites of Complex II
dc.description.sponsorship
The following organizations are thanked for financial support: A.T.P.C. is grateful to the Fundação para a Ciência e Tecnologia (FCT) for the grant IF/01272/2015. AGAUR for fellowship 2010 BP_B00238, the Ministerio de Ciencia e Innovación (MICINN, project number CTQ2011‐25086/BQU), and the DIUE of the Generalitat de Catalunya (project number 2009SGR528 and Xarxa de Referència en Química Teòrica i Computacional). Financial support from MICINN (Ministry of Science and Innovation, Spain) and the FEDER fund (European Fund for Regional Development) was provided by grant UNGI08‐4E‐003. With the support of the Secretary for Universities and Research of the Ministry of Economy and Knowledge of the Government of Catalonia and the Cofund programme of the Marie Curie Actions of the 7th R&D Framework Programme of the European Union. D.F.A.R.D. acknowledges the financial support from INVEST NI RD0314092
dc.format.mimetype
application/pdf
dc.language.iso
eng
dc.publisher
Wiley
dc.relation
info:eu-repo/grantAgreement/MICINN//CTQ2011-25086/ES/MODELIZACION MULTIESCALAR EN (BIO)QUIMICA/
dc.relation.isformatof
Reproducció digital del document publicat a: https://doi.org/10.1002/chem.201704622
dc.relation.ispartof
Chemistry - A European Journal, 2018, vol. 24, núm. 20, p. 5246-5252
dc.relation.ispartofseries
Articles publicats (D-Q)
dc.rights
Attribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.uri
dc.subject
dc.title
Why the Flavin Adenine Dinucleotide (FAD) Cofactor Needs To Be Covalently Linked to Complex II of the Electron‐Transport Chain for the Conversion of FADH2 into FAD
dc.type
info:eu-repo/semantics/article
dc.rights.accessRights
info:eu-repo/semantics/openAccess
dc.type.version
info:eu-repo/semantics/publishedVersion
dc.identifier.doi
dc.identifier.idgrec
027958
dc.contributor.funder
dc.type.peerreviewed
peer-reviewed
dc.relation.ProjectAcronym
dc.identifier.eissn
1521-3765