Molecular Interactions between Styrene Oligomers and Human Serum Albumin: A Multiscale Computational Study of a Plastic-Derived Environmental Contaminant

Abstract Micro- and nanoplastics are pervasive environmental pollutants known to accumulate in human organs. While the hazards of larger plastic particles are under intense investigation, the toxicological impact of molecular-level plastic oligomers with dimensions around 1 nm is a critical and underexplored area. This study provides a comprehensive molecular-level in silico characterization of the binding interactions between styrene oligomers (1–7 units) and HSA, characterizing their molecular basis and its potential relevance to HSA’s ligand transport function. A multilevel computational approach was employed, integrating molecular docking, MD simulations, DFT, MM/PBSA binding free energy calculations, and ProLIF interaction fingerprinting. FA1 accommodated 82–95% of the most favorable docking poses for oligomers containing three to seven styrene units and exhibited the lowest docking scores, reaching −11.9 kcal·mol–1, compared with −6.4 kcal·mol–1 for the monomer. MD simulations confirmed the structural stability of oligomer-HSA complexes, further supported by dynamic cross-correlation, principal component, and solvent-accessible surface area analyses. Quantum biochemistry analyses further confirmed FA1 as the most energetically favorable binding pocket, with an average interaction energy of −117.47 kcal·mol–1 compared with −73.96 kcal·mol–1 for FA6, a hierarchy independently reproduced by MM/PBSA calculations (R = 0.82). For the hexamer and heptamer, FA1 exhibited energetic advantages of 27.39 and 21.84 kcal·mol–1, respectively. These findings indicate that HSA binds styrene oligomers with high stability and affinity at FA1, providing a molecular basis for further investigation of their potential relevance to ligand transport and systemic exposure to plastic-derived contaminants.