Orientation-Dependent Adsorption and Thermodynamics of Human Serum Albumin at Polyurethane Interfaces

Understanding how proteins adsorb at polymer-water interfaces is central to predicting and controlling biofouling in biomedical materials. Here, we use extensive all-atom molecular dynamics (MD) simulations combined with potential of mean force calculations to investigate the adsorption of human serum albumin (HSA) at a medical-grade polyether-based polyurethane interface. By systematically varying the initial orientation of HSA, we reveal a pronounced orientation dependence in adsorption behavior, despite the protein remaining structurally stable in all cases. Only a subset of orientations access strongly adsorbed states, characterized by localized interfacial patches enriched in aromatic and hydrophobic residues. These interactions are stabilized primarily by van der Waals forces, with interfacial water molecules frequently mediating hydrogen bonding between HSA and the polymer surface. Free energy profiles confirm that adsorption is thermodynamically favorable and predominantly enthalpy-driven, with the magnitude of the adsorption free energy strongly dependent on protein orientation. Comparison with previous simulations of HSA adsorption on poly(vinyl chloride) highlights the substantially weaker affinity of HSA for polyurethane, consistent with its higher polarity and reduced hydrophobic continuity. Together, these results provide molecular-level insight into orientation-dependent protein adsorption at soft polymer interfaces and offer guidance for the rational design of materials with reduced fouling propensity.