Elucidating the molecular mechanisms of perfluorooctanoic acid-serum protein interactions by structural mass...

Perfluorooctanoic acid (PFOA) is a persistent environmental pollutant and will continually accumulate in blood due to its chemical inertness and strong interaction with serum proteins, especially serum albumin (SA), inducing highly adverse health risks. However, the molecular mechanisms of dynamic interactions between PFOA with serum proteins remain unclear, limiting the development of potential therapeutic strategies. Herein, we developed an integrated structural strategy to systematically profile the molecular details of dynamic interactions among PFOA, SA, and β-cyclodextrin (β-CD) by combing native mass spectrometry (nMS), lysine reactivity profiling (LRP), and molecular docking (MD) simulation. The SA site 1, site 2 pockets, and cleft nearby are observed as the primary interaction regions of PFOA. Further, β-CD can disrupt the PFOA combinations with bovine SA regions around sites Lys20, Lys280, Lys350, and Lys431-Lys439, with an overall reversing efficiency of about 26% at an identical concentration to PFOA. The interactome of PFOA with complex human serum proteins is globally profiled with molecular interaction details, including human serum albumin, apolipoprotein A-I, alpha-2-macroglobulin, and complement C3. Our results reveal molecular insights into the detail of the interaction between PFOA and serum proteins, beneficial to understanding PFOA toxicology.