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Human serum albumin (HSA) is a protein carrier in blood transporting metabolites and drugs. Glycated HSA (GHSA) acts as a potential biomarker for diabetes. Thus, many attempts have been made to detect GHSA. Glycation was reported to damage the structure and ligand binding capability, where no molecular detail is available. Recently, the crystal structure of GHSA has been solved, where two glucose isomers (pyranose/GLC and open-chain/GLO) are located at Sudlow’s site I. GLO was found to 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 to explore the nature of SCH and AMA. Both forms are found to alter the main protein dynamics, resulting in (i) the widening of Sudlow’s site I entrance, (ii) the size reduction of nine fatty acid-binding pockets, (iii) the enlargement of Sudlow’s site I and the shrinking of Sudlow’s site II, (iv) the enhancement of C34 reactivity, and (v) the change in the W214 microenvironment. These unique characteristics found here can be useful for understanding the effect of glycation on the albumin function in more detail and designing specific and selective GHSA detection strategies.

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Diabetes mellitus is a chronic metabolic disease involving continued elevated blood glucose levels. It is a leading cause of mortality and reduced life expectancy. Glycated human serum albumin (GHSA) has been reported to be a potential diabetes biomarker. A nanomaterial-based aptasensor is one of the effective techniques to detect GHSA. Graphene quantum dots (GQDs) have been widely used in aptasensors as an aptamer fluorescence quencher due to their high biocompatibility and sensitivity. GHSA-selective fluorescent aptamers are first quenched upon binding to GQDs. The presence of albumin targets results in the release of aptamers to albumin and consequently fluorescence recovery. To date, the molecular details on how GQDs interact with GHSA-selective aptamers and albumin remain limited, especially the interactions of an aptamer-bound GQD (GQDA) with an albumin. Thus, in this work, molecular dynamics simulations were used to reveal the binding mechanism of human serum albumin (HSA) and GHSA to GQDA. The results show the rapid and spontaneous assembly of albumin and GQDA. Multiple sites of albumins can accommodate both aptamers and GQDs. This suggests that the saturation of aptamers on GQDs is required for accurate albumin detection. Guanine and thymine are keys for albumin-aptamer clustering. GHSA gets denatured more than HSA. The presence of bound GQDA on GHSA widens the entrance of drug site I, resulting in the release of open-chain glucose. The insight obtained here will serve as a base for accurate GQD-based aptasensor design and development.