This journal is c The Royal Society of Chemistry 2012 Chem. Commun. Cite this: DOI: 10.1039/c2cc30529a Corrin ring-induced redox tuningw Manoj Kumar and Pawel M. Kozlowski* Received 23rd January 2012, Accepted 6th February 2012 DOI: 10.1039/c2cc30529a The density functional calculations suggest that the expansion of the corrin macrocycle’s N 4 core by 0.06–0.10 A ˚ leads to an appreciable lowering of 100–150 mV vs. saturated calomel electrode in the reduction potentials of two biologically important B 12 cofactors namely methylcobalamin and adenosylcobalamin respectively. This redox tuning of B 12 cofactors may encourage the electron transfer- based activation mechanism for B 12 -dependent enzymes. Almost three decades ago, it was demonstrated based on the electrochemical studies 1,2 that the addition of an electron to a B 12 cofactor leads to a significant reduction in the bond dissociation energy (BDE) of the Co–C bond that could explain the catalytic effect observed in the enzymatic environment. 3 Despite its potential relevance, the reductive cleavage mechanism 4 was initially ruled out as a possible mode of activation because of the inaccessible redox chemistry of B 12 cofactors (À1.20 V to À1.60 V vs. saturated calomel electrode (SCE)). 1,2 But recently published theoretical studies 5a,b suggest that the proton-coupled electron transfer (PCET)-based activation that proceeds via the reductive cleavage route may be a valid mechanistic proposal. It is well-documented in literature 6–13 that the complex inter- actions operative within the protein framework can significantly alter the redox potential of a cofactor or the active site. For example, a single residue (Gln), in the case of superoxide dismutase, has been found to induce a redox modulation of over 1 V range owing to changes in its local environment. 6 Similarly, low dielectric constants of the protein active site and the H-bond network have been suggested to modulate the redox potential of the tyrosine residue and P 680 + motif in the case of PS-II. 7 Even the hydro- phobic residues present in the binding pockets of myoglobin and cytochromes have been found to exert a redox tuning of B500 mV. 8–10 Variations in the ligation and spin states of the heme framework also impart a significant amount of modulation upon the redox behavior of hemoproteins. 11–13 Despite the growing body of evidence about the redox tuning of protein-encapsulated redox cofactors, the electrochemical behavior of B 12 cofactors, while accounting for the various aspects of the enzymatic environ- ment, has yet to be explored. B 12 cofactors are organocorrinoid cobalt complexes that contain the corrin nucleus as their equatorial ligand (Fig. 1). The corrin ring is considered to be more flexible than the porphyrin. The conformational flexibility of the corrin motif was initially suggested to be of significance with regard to enzyme catalysis. 14,15 Specifically, the corrin macrocycle was postulated to undergo a butterfly-type distortion in the presence of enzyme that could lead to the enhanced cleavage of the Co–C bond. 15–18 But this viewpoint was later on discarded based upon spectroscopic 19 and theoretical 20,21 studies. Interestingly, these corrin distortion modes, especially Co–N xx (xx = 21–24) and Co–N ax bond distances, although being energetically unfavorable, are conserved at least among B 12 -dependent methyltransferases, 22a,23 mutases 22b,24 and ATP:corrinoid adenosyltransferases 22b,25 (Table S1, ESIw), suggesting that these structural perturbations could serve an important biological function. Recently the distortion-induced redox alteration of the porphyrin systems has been demonstrated where 200–250 mV redox shift was noticed when the conformation of the porphyrin motif was perturbed. 26 Herein we illustrate that the slight perturbation in the Co–N xx and Co–N ax bond distances of corrin structure (Fig. 1) can significantly modulate the redox potential of a B 12 cofactor. This is because the four nitrogens of the corrin architecture (N xx ) are directly coordinated to the metal center (Co III ion) and any variation in the corrin geometry would strongly impact the metal coordination site and hence the electrochemical behavior of the cofactor. Though the corrin ring-based structural frustration would be induced due to the steric and electrostatic constraints imposed by the enzyme, modeling such an impact is not feasible taking into account the current state of computational methodology. The proper calibration of a theoretical methodology for such an investigation would demand the extensive sampling due to the large dimensionality involved which can only be Fig. 1 Corrin framework with labeled N 4 core. Department of Chemistry, University of Louisville, Louisville, Kentucky-40292, USA. E-mail: pawel@louisville.edu; Fax: +1 5028528149; Tel: +1 5028526609 w Electronic supplementary information (ESI) available: Tables containing key structural and calibration details, figures depicting variation of the reduction potentials of the model complexes as a function of the linear displacements and the angular distortions, SOMOs of the reduced complexes. See DOI: 10.1039/c2cc30529a ChemComm Dynamic Article Links www.rsc.org/chemcomm COMMUNICATION Downloaded by University of Louisville on 28 March 2012 Published on 08 March 2012 on http://pubs.rsc.org | doi:10.1039/C2CC30529A View Online / Journal Homepage