Interaction of Glycated Albumin with Receptor for Glycation End Products According to Molecular Modeling Data

Abstract

In diabetes mellitus (DM) patients, the accumulation of advanced glycation end products (AGE) leads to inflammation and oxidative stress through the activation of specific receptors for AGE (RAGE). Glycated albumin (gHSA) makes a significant contribution to the overall level of AGE in human body and, as a result, to the pathogenesis of DM and concomitant diseases. The mechanism of interaction of gHSA with RAGE is practically not studied. The purpose of the present paper is to study the binding of gHSA to RAGE using molecular modeling methods, to find the main sites of interaction and structural features of glycation sites that determine the efficiency of complex formation with RAGE. Ten gHSA models were constructed using molecular docking and molecular dynamics (MD) methods; each model corresponded to one modified lysine residue (carboxymethyl-lysine): Lys64, Lys73, Lys137, Lys233, Lys262, Lys317, Lys378, Lys525, Lys573, Lys574. Complexes of gHSA with the V-domain of RAGE were constructed using the macromolecular docking method, and their stability was studied using MD simulation. In the constructed gHSA models, the carboxyl groups of glycated Lys317 and Lys525 form intramolecular salt bridges with surrounding amino acids; in other cases, the carboxyl groups of the modified lysines are free to interact with positively charged amino acid residues on the RAGE surface. According to the macromolecular docking data and subsequent MD simulation, the complex of RAGE with gHSA glycated at Lys233 is most effective in terms of strength and specificity. Specific RAGE complexes with gHSA glycated at Lys317 and Lys574 are not formed. The obtained data on the interaction of gHSA with RAGE will help to understand the role of albumin in the pathophysiology of DM and advance towards the prevention and development of effective therapy for this disease.