Molecular Mechanisms of Interaction of Human Serum Albumin with the CD36 Receptor: Insights from Molecular Dynamics Simulations.

The rate of fatty acid (FA) uptake by cells depends on the presence of the CD36 receptor on the cell surface. However, unesterified FAs cannot circulate freely in plasma; they are bound to serum albumin. The molecular mechanisms of FA transfer from albumin to CD36 remain poorly understood. This study used macromolecular docking and molecular dynamics methods to investigate the interaction of the CD36 receptor with human serum albumin (HSA) loaded with oleic acid at the FA1-7 fatty acid-binding sites, with the aim of identifying potential mechanisms of FA transfer from HSA to CD36. The data obtained indicate that the interaction of HSA with CD36 does not result in direct FA transfer, but rather causes a local weakening of the affinity of individual FA sites on HSA. A comparative analysis was performed between the interaction interfaces predicted by macromolecular docking and those generated by AlphaFold 3. To further evaluate the influence of ligand nature, an additional molecular docking of HSA loaded with saturated (palmitic, PALM) and polyunsaturated (arachidonic, ARA) acids to the CD36 receptor was performed. This revealed a marked sensitivity of the protein-protein interface architecture to the type of lipid ligand, with the effect of ARA being more pronounced than PALM. Conversely, an alternative structure prediction using the AlphaFold3 algorithm demonstrated the opposite trend, indicating high geometric invariance and reproducibility of the complex. Ultimately, the proposed dynamic mechanism expands our understanding of the multi-stage processes governing FA transport across the endothelium.