In silico analysis of paraoxon binding by human and bovine serum albumin

Albumin is known to be able to cleave ether bonds in organophosphates (OPs). Amino acids responsible for esterase and pseudo-esterase albumin activity towards OPs are not yet finally identified. Presumably, Sudlow’s site I with the Tyr150 residue shows a “true” esterase activity, while Sudlow’s II site with the Tyr411 residue—a pseudo-esterase one. Both human (HSA) and bovine (BSA) serum albumins were used in in vitro studies of albumin (pseudo)esterase activity towards OPs. There is a body of evidence that the efficiency of interaction of different xenobiotics differs for these two proteins. Using paraoxon as an example, the aim of this study was to conduct an in silico study of the OP interaction with the previously identified potential sites of HSA and BSA (pseudo)esterase activity, to estimate the possibility of enzymatic reactions at these sites, to comparatively analyze these proteins from the evolutionary viewpoint, and to assess the possibility of extrapolating the experimental data obtained on BSA to a human organism. Molecular docking of paraoxon into the sites of HSA and BSA potential (pseudo)esterase activity has been performed. Conformational changes occurring in the resultant complexes with time have been studied by molecular dynamics simulation. It has been shown that Sudlow’s site II is less liable to evolutionary changes. Binding of modulators at other sites is not required for productive sorption of OPs and the phosphorylation reaction at Sudlow’s site II. It has been concluded that simi lar results for HSA and BSA could be expected for the irreversible binding of OPs at Sudlow’s site II. Since Sudlow’s site I is less conservative, diff erent binding efficiency could be expected for rigid molecules or optically active compounds. Both for HSA and BSA, productive binding of OPs at Sudlow’s site I is possible only after changes in the albumin molecule structure induced by binding of modulators at other sites.