Axial and equatorial ligand effects on biomimetic cysteine dioxygenase model complexes

Abstract

Density functional theory (DFT) calculations are presented on biomimetic model complexes of cysteine dioxygenase and focus on the effect of axial and equatorial ligand placement. Recent studies of one of us [Y. M. Badiei, M. A. Siegler and D. P. Goldberg, J. Am. Chem. Soc. 2011, 133, 1274] gave evidence of a nonheme iron biomimetic model of cysteine dioxygenase using an i-propyl-bis(imino)pyridine, equatorial tridentate ligand. Addition of thiophenol, an anion – either chloride or triflate – and molecular oxygen, led to several possible stereoisomers of this cysteine dioxygenase biomimetic. Moreover, large differences in reactivity using chloride as compared to triflate as the binding anion were observed. Here we present a series of DFT calculations on the origin of these reactivity differences and show that it is caused by the preference of coordination site of anion versus thiophenol binding to the chemical system. Thus, stereochemical interactions of triflate and the bulky iso-propyl substituents of the ligand prevent binding of thiophenol in the trans position using triflate. By contrast, smaller anions, such as chloride, can bind in several ligand positions and give isomers with similar stability. Our calculations explain the observance of thiophenol dioxygenation by this biomimetic system and give details of the reactivity differences of ligated chloride versus triflate.

Structure and Mechanism Leading to Formation of the Cysteine Sulfinate Product Complex of a Biomimetic Cysteine Dioxygenase Model

“…Clearly, direct attack of O 2 on sulfur is a high‐energy pathway that cannot compete with the formation of an iron(III)‐superoxo structure. Previous calculations on CDO model complexes as well as synthetic model complexes for intradiol catechol dioxygenases established similar conclusions that O 2 needs to bind the iron first 12b. 19…”

Structure-Based Insights into the Role of the Cys–Tyr Crosslink and Inhibitor Recognition by Mammalian Cysteine Dioxygenase

“…For C93A (Figure 2A and S1A), the active site iron was penta-coordinate with the three His ligands plus one peak with even higher electron density than the sulfurs of Met and Cys residues (~17 ρ rms vs. ~15 ρ rms ), and another with density appropriate for a water/hydroxide. The strong density is well modeled as a chloride ion, which is present at 15 mM in the crystallization buffer, is known to bind to iron, 41; 42; 43; 44 and was also recently similarly modeled in a crystal structure of a CDO Cys164Ser mutant. 45 The fully occupied water/hydroxide ligand is opposite to His140, and both the chloride and water appear stabilized by reasonably well-aligned bifurcated hydrogen-bonds from the Tyr157 hydroxyl (Figure 2A).…”

Applications of density functional theory to iron-containing molecules of bioinorganic interest

“…Theoretical studies of such biomimetic models may not only identify the key elements that determine their chemical reactivities, but may also provide insight into intermediates and reactivities of parent enzymes (Shaik et al, 2007a; de Visser et al, 2013). To date, DFT calculations have been applied extensively to various types of non-heme iron species (Scheme 1) (Bassan et al, 2002, 2005a,b; Roelfes et al, 2003; Decker and Solomon, 2005; Kumar et al, 2005; Quinonero et al, 2005; Berry et al, 2006; Bernasconi et al, 2007, 2011; de Visser, 2006, 2010; Hirao et al, 2006a, 2008a,b, 2011; Rohde et al, 2006; Decker et al, 2007; de Visser et al, 2007, 2011; Johansson et al, 2007; Noack and Siegbahn, 2007; Sastri et al, 2007; Sicking et al, 2007; Bernasconi and Baerends, 2008, 2013; Comba et al, 2008; Dhuri et al, 2008; Fiedler and Que, 2009; Klinker et al, 2009; Wang et al, 2009a, 2013b; Cho et al, 2010, 2012a, 2013; Geng et al, 2010; Chen et al, 2011; Chung et al, 2011b; Seo et al, 2011; Shaik et al, 2011; Vardhaman et al, 2011; Wong et al, 2011; Ye and Neese, 2011; Gonzalez-Ovalle et al, 2012; Gopakumar et al, 2012; Latifi et al, 2012; Mas-Ballesté et al, 2012; McDonald et al, 2012; Van Heuvelen et al, 2012; Ansari et al, 2013; Kim et al, 2013; Lee et al, 2013; Sahu et al, 2013; Tang et al, 2013; Ye et al, 2013; Hong et al, 2014; Sun et al, 2014). The intriguing reactivity patterns of these complexes are the result of active involvement of electrons in d-type MOs, which gives rise to multi-state scenarios (Shaik et al, 1998; Schröder et al, 2000; Schwarz, 2011).…”