Structural and Dynamic Alteration of Glycated Human Serum Albumin in Schiff Base and Amadori Adducts: A Molecular Simulation Study

Human serum albumin (HSA) is a protein carrier in bloodtransportingmetabolites and drugs. Glycated HSA (GHSA) acts as a potential biomarkerfor diabetes. Thus, many attempts have been made to detect GHSA. Glycationwas reported to damage the structure and ligand binding capability,where no molecular detail is available. Recently, the crystal structureof GHSA has been solved, where two glucose isomers (pyranose/GLC andopen-chain/GLO) are located at Sudlow's site I. GLO was foundto covalently bind to K195, while GLC is trapped by noncontact interactions.GHSA exists in two forms (Schiff base (SCH) and Amadori (AMA) adducts),but how both disrupt albumin activity microscopically remains unknown.To this end, molecular dynamics simulations were performed here toexplore the nature of SCH and AMA. Both forms are found to alter themain protein dynamics, resulting in (i) the widening of Sudlow'ssite I entrance, (ii) the size reduction of nine fatty acid-bindingpockets, (iii) the enlargement of Sudlow's site I and the shrinkingof Sudlow's site II, (iv) the enhancement of C34 reactivity,and (v) the change in the W214 microenvironment. These unique characteristicsfound here can be useful for understanding the effect of glycationon the albumin function in more detail and designing specific andselective GHSA detection strategies.

Automated summary

Human serum albumin (HSA) is a protein carrier in blood for transporting metabolites and drugs. Glycated HSA (GHSA) acts as a potential biomarker for diabetes, and efforts have been made to detect GHSA. The crystal structure of GHSA has been recently solved, revealing the location of glucose isomers and their binding capabilities. Molecular dynamics simulations were performed to explore the effect of different forms of glycated HSA on protein dynamics and function.