Modulation of the albumin–paraoxon interaction sites by fatty acids: Analysis by the molecular modeling methods


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Abstract

It is known that albumin can break the ester bonds in organophosphorus compounds (OPs). Amino acids responsible for esterase and pseudoesterase activity of albumin towards OPs are still not determined. It is assumed that Sudlow’s site I with residue Tyr150 exhibits the “true” esterase activity; and Sudlow’s site II containing residue Tyr411, a pseudoesterase one. Binding of fatty acids to albumin affects the efficiency of its interaction with xenobiotics; however, the effect of fatty acids on the interaction of albumin with OPs was not studied. The purpose of this work was to study the interaction of OPs with potential sites of albumin enzymatic activity and to examine the effect of fatty acids on the efficiency of such interaction using the molecular modeling methods by the example of paraoxon, a known inhibitor of acetylcholinesterase, and oleic acid. The structures of the protein complexes with paraoxon and oleic acid were determined by the molecular docking procedure; the conformational changes were calculated by the molecular dynamics method. It has been shown that sorption of oleic acid in one of the fatty acid-binding sites leads to the conformational changes in Sudlow’s sites I and II due to a “reversal” of the side chains of Arg410 and Arg257 residues by 90°. It has been found that this change in geometry reduces the affinity of Sudlow’s site I and increases the Sudlow’s site II affinity to paraoxon. The amino acid residue Ser193, which was previously identified as a site of possible albumin esterase activity, is not able to bind paraoxon efficiently. It is assumed that its activity can be affected by the interaction of the oleic acid molecules with other fatty acid-binding sites. It is hypothesized that the lesser toxicity of paraoxon compared to soman may be associated not only with its lower inhibitory activity against cholinesterases, but also with the increased affinity of paraoxon to albumin. It was concluded that albumin may serve as an alternative means of OP detoxification.

About the authors

D. A. Belinskaia

Sechenov Institute of Evolutionary Physiology and Biochemistry

Author for correspondence.
Email: d_belinskaya@mail.ru
Russian Federation, St. Petersburg, 194223

K. I. Taborskaya

Sechenov Institute of Evolutionary Physiology and Biochemistry

Email: d_belinskaya@mail.ru
Russian Federation, St. Petersburg, 194223

P. V. Avdonin

Koltsov Institute of Developmental Biology

Email: d_belinskaya@mail.ru
Russian Federation, Moscow, 119334

N. V. Goncharov

Sechenov Institute of Evolutionary Physiology and Biochemistry; Research Institute of Hygiene, Occupational Pathology, and Human Ecology

Email: d_belinskaya@mail.ru
Russian Federation, St. Petersburg, 194223; St. Petersburg, 118663

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