Effect of Cys34 Oxidation State of Albumin on Its Interaction with Paraoxon according to Molecular Modeling Data

Abstract

The effect of the Cys34 oxidation state in human serum albumin on its binding and catalytic activity towards paraoxon was investigated using molecular modeling methods. Three levels of the cysteine oxidation were considered: (1) Cys34 is reduced, (2) Cys34 is oxidized to sulfenic acid, and (3) Cys34 is oxidized to sulfinic acid. The conformational characteristics of the complexes of albumin with paraoxon bound in Sudlow sites I and II were studied by the molecular dynamics method. The possibility of a phosphorylation reaction was estimated by the distance between the phosphorus atom of paraoxon and the hydroxyl oxygen atom of the catalytic tyrosines in Sudlow sites I and II. The values of free binding energy of the albumin–paraoxon complexes were estimated using the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) approach. According to the data obtained, cysteine oxidation does not affect the possibility of an esterase reaction in Sudlow site I. Modification of Cys34 changes the conformation of Sudlow site I and the position of paraoxon within the site but does not affect the affinity of the ligand to the site. It has been hypothesized that lack of dependence of binding efficiency on the conformation of the site may be due to the small size and conformational mobility of paraoxon molecule, and such an effect will not be observed for more massive and rigid molecules. Modification of Cys34 has no significant effect on the conformation of Sudlow site II. In the oxidized forms of albumin, the productive conformation of the paraoxon molecule in Sudlow site II is more stable, therefore, the probability of the phosphorylation reaction is higher. The oxidation of Cys34 does not have a significant effect on the binding activity of Sudlow site II towards paraoxon.