Structural Categorization and identification of electrostatic interactions in two proposed Human Serum Albumin dimerization patterns and dipyridamole interaction.

Abstract

Human serum albumin (HSA) is a ubiquitous, multifunctional protein responsible for the systemic distribution of both endogenous metabolites and exogenous pharmaceuticals. Its inherent properties, mainly its ability to seep into the tissues and multiple ligand-binding sites, have rendered HSA an attractive vehicle in nanoparticle-based drug delivery systems, particularly in cancer targeting. In this study, we present high-resolution crystallographic data revealing two distinct dimerization patterns of HSA (PDB ID: 9V61), obtained under high-concentration crystallization conditions, in addition to results from dipyridamole dockings. Both dimer types demonstrate extensive interface areas and a significant number of electrostatic interactions. Comparative analysis with previously reported dimer structure (PDB ID: 3JQZ) and other high-interface-area structures, (PDB ID: 5Z0B, PDB ID: 8CKS) indicates similarities in contact regions, but unique residue-level differences in bonding interactions. Interface surface area distribution and space group histograms further support the rarity and potential physiological relevance of the identified dimer forms. Importantly, these dimer configurations do not disrupt Sudlows drug-binding sites, which is important as the dipyridamole docking analysis presents strong affinity to Sudlow site I and Sudlow site III, not affecting their utility in engineered drug delivery. Our findings open new avenues for structure-based mutagenesis and nanoparticle design strategies centered on HSA dimerization dynamics.