Conformers of Cysteine and Cysteine Sulfenic Acid and Mechanisms of the Reaction of Cysteine Sulfenic Acid with 5,5-Dimethyl-1,3-cyclohexanedione (Dimedone)

Abstract

Equilibrium and molecular structures, relative energies of conformers of gaseous cysteine (Cys, C, Cys-SH) and gaseous cysteine sulfenic acid (Cys-SOH), and the mechanisms of the reaction of Cys-SOH with 3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one, the enol tautomer of 5,5-dimethyl-1,3-cyclohexadione (dimedone), have been studied using BD(T), CCSD(T), and QCISD(T) with the cc-pVTZ basis set and using MP2 and the density functionals B3LYP, B3PW91, PBE1PBE, PBEh1PBE, M062X, CAM-B3LYP, and WB97XD with the 6-311+G(d,p) basis set. The structures of the six lowest energy conformers of gaseous Cys-SOH are compared with the six lowest energy conformers of gaseous cysteine (Cys-SH). The relative stability of the six lowest energy conformers of Cys-SH and Cys-SOH are influenced by the interplay among many factors including dispersive effects, electronic effects, electrostatic interactions, hydrogen bonds, inductive effects, and noncovalent interactions. The mechanism of the addition of the lowest energy conformer of cysteine sulfenic acid (Cys-SOH) to dimedone may proceed through a six-membered ring transition state structure and through cyclic hydrogen-bonded transition state structures with one water molecule (8-membered ring), with two water molecules (10-membered ring), and with three water molecules (12-membered ring). Inclusion of one and two water molecules in the transition state structures lowers the activation barrier, whereas inclusion of a third water molecule raises the activation barrier.

Mechanism of the cysteine sulfenic acid O-sulfenylation of 1,3-cyclohexanedione

“…1) to form sulfides (thioethers). [1][2][3] In this manuscript, the investigation of an alternative reaction that leads to sulfenic ester formation through O-sulfenylation is presented and supported (Fig. 1).…”

“…1) is reasonable. 2 It is known that electrophilic sulfenyl sulfur reacts with nucleophiles such as alkenes, enamines, and enols. Owing to the vital importance and significance of the chemoselectivity of 1,3-cyclohexanedione (1) and 5,5-dimethyl-1,3-cyclohexanedione (2) in detecting protein sulfenic acids, it is important to understand the fundamental mechanisms and products of the sulfenylation reactions.…”

“…We are using computational quantum chemistry (see ESI †) to investigate the fundamental chemistry, properties, and structures of sulfenic acids and their reactions with (1) and ( 2) in order to acquire data and information to assist in elucidating the nature of the chemistry of protein thiols and protein sulfenic acids. 2,4,5 Amino acids exist as zwitterions in aqueous solution and in the crystalline state and in the neutral (nonionized) forms in the gas phase. In the gas phase, the lowest energy conformer of cysteine sulfenic acid (Cys-SOH, 5, Fig.…”

“…2). 2 The energy barriers for the O-sulfenylation reaction of cysteine sulfenic acid (5) with the s-cis-ketoenol (1b) tautomer S2 in the ESI. † It is seen that the inclusion of water molecules in the transition state structures lowers the activation barrier.…”

Biological chemistry and functionality of protein sulfenic acids and related thiol modifications

“…In addition to steric and electrostatic interactions mentioned above, these include intrinsic protein motions and dynamic structural changes induced by oxidation. Computational studies, for example, found that the lowest energy conformer of cysteine -SOH harbors four hydrogen-bonding interactions, which were proposed to impact both -SOH formation and stability [16]. Similar to small molecule -SOH, protein -SOH species can exist as stable products of thiol oxidation or can react with other moieties to produce disulfides (e.g., reaction with free or protein thiols, -SSR), thiosulfinate (reaction with other -SOH, -S(=O)SCys), sulfinic or sulfonic states (hyperoxidation, -SO 2/3 H), and sulfenyl amides (-SN).…”