A kinetic study of dimethyl sulfoxide reductase based on density functional theory

Abstract

We present a density functional theory study on the oxygen atom transfer (OAT) reaction of dimethyl sulfoxide (DMSO) with model complexes resembling a functional synthetic analogue of the molybdoenzyme DMSO reductase. The good agreement between our calculated Gibbs free energy profile and data derived from experimental kinetic parameters supports the reaction mechanisms of the oxygen atom transfer proposed in this study. When the mechanism involves the formation of a DMSO-bound intermediate, the calculations on the free energy surface provide valuable information that explains the origin of the apparent contradiction between the experimental findings and previous theoretical calculations with respect to the rate-limiting step of the reaction mechanism. The enzymatic mechanism of the OAT reaction is more complex than the mechanism of any synthetic analogue, mainly due to the formation of an enzyme-substrate adduct prior to the appearance of the substrate-bound intermediate. This study also presents a possible mechanism for the formation of such an adduct and the subsequent oxygen atom transfer. The mechanism involves a proton transfer to and from the substrate.

Determination of Solubility Parameters of Ionic Liquids and Ionic Liquid/Solvent Mixtures from Intrinsic Viscosity

“…The transition structure corresponded to the (Me) 2 S=O double‐bond cleavage and is similar to the crystal structures of the enzyme in both the oxidized and reduced states 13. Later studies by Thapper,14 McNamara,15,16 Hernandez‐Marin and Ziegler,17 Solomon,18,19 Hofmann,20,21 and us22–24 have established a two‐step associative mechanism, in which DMSO first binds to the reduced active site, and the S–O bond is cleaved in the second step concomitant with the oxidization of the Mo ion to the Mo VI state (see Scheme ). The second step is rate limiting and has a predicted activation energy of 76,14 80,15 69,17 68,18,19 40,20,21 or 63 kJ/mol 24.…”

“…Later studies by Thapper,14 McNamara,15,16 Hernandez‐Marin and Ziegler,17 Solomon,18,19 Hofmann,20,21 and us22–24 have established a two‐step associative mechanism, in which DMSO first binds to the reduced active site, and the S–O bond is cleaved in the second step concomitant with the oxidization of the Mo ion to the Mo VI state (see Scheme ). The second step is rate limiting and has a predicted activation energy of 76,14 80,15 69,17 68,18,19 40,20,21 or 63 kJ/mol 24. The activation energy of the first step is appreciably lower and often close to that of the intermediate species (IM in Scheme ).…”

Effect of the protein ligand in DMSO reductase studied by computational methods

“…Thapper et al studied also the binding of DMSO and proposed a two-step mechanism, based on a slightly different model [20]. Subsequently, these findings were confirmed by several other groups [16,17,21,22,24,29,30]. The suggested reaction starts with DMSO binding to the Mo(IV) state of the active site to form an intermediate.…”

“…Seven models were employed to investigate the effect of the protein-derived ligand ( Figure 1). All models involve two molecules of dimethyldithiolene (DMDT, CH3SC=CSCH3), which is a common model of molybdopterin, both in experimental and computational studies [16,17,21,22,24,29,30]. CH3O -, CH3S -, and CH3Sewere used as models of serine, cysteine, and selenocysteine, respectively, whereas OH -, O 2-, SH -, and S 2were tested as models of oxo and sulfido groups observed in some enzymes [1,7,9,33].…”

“…The DMSOR reaction mechanism has also been thoroughly studied with computational methods [16][17][18][19][20][21][22][23][24][25][26][27]. In 2001, Webster and Hall used the B3LYP method to show that the energy barrier of OAT is 37 kJ/mol, starting from the DMSO-bound intermediate [19].…”