The strong, polar covalent nature of C-F bonds contributes to the permanent nature of per- and polyfluoroalkyl substances (PFAS). PFAS are toxic to humans. Here, we have examined the ability of the small, globular milk protein β-lactoglobulin to bind PFAS. This protein transports hydrophobic and amphiphilic compounds, including retinol and fatty acids, for vision and brain development; therefore, understanding its interactions with PFAS is significant. The crystal structures of β-lactoglobulin complexed with PFOA (perfluorooctanoic acid) at 2.0 Å, PFOS (perfluorooctanesulfonic acid) at 2.5 Å, and PFDA (perfluorodecanoic acid) at 2.0 Å reveal the high affinity of the compounds for the central calyx of β-lactoglobulin, which is the canonical retinol and fatty acid binding site. Analyses of the data indicate significant hydrophobic interactions stabilizing the binding of the PFAS hydrophobic "tails" within the calyx and interactions between Lys60 and Lys69 and the PFAS polar head groups. Comparative structural analysis revealed the presence of an open conformation of the EF loop containing the Glu89 latch residue in the complexed structures compared to the apo-form. Molecular dynamics (MD) simulations revealed the high stability of PFAS binding and the attainment of energy minima in all complexes. The average binding energy of PFDA in the β-lactoglobulin calyx was -25 kcal/mol, which was higher than that of PFOS (-21 kcal/mol) and PFOA (-23 kcal/mol) due to the increased van der Waals interactions between the longer hydrophobic chain of PFDA and β-lactoglobulin. This work advances a mechanism by which β-lactoglobulin can recruit PFAS and act as a transporter for the "forever" chemical, potentially mediating its neurotoxicity.
Verma et al. (Tue,) studied this question.