Human proteome-wide molecular interaction analysis based on AlphaFold3 to evaluate toxicity between PFOS and its...

F-53B, primarily composed of 6:2 chlorinated polyfluoroalkyl ether sulfonate (Cl-PFESA) and 8:2 Cl-PFESA, has been widely used as an alternative to perfluorooctane sulfonic acid (PFOS), but emerging evidence indicates that F-53B also exhibits toxicity and may not be a safe substitute. We conducted systematic molecular interaction analysis between three compounds - PFOS, 6:2 Cl-PFESA, and 8:2 Cl-PFESA - and 19,508 human proteins using AlphaFold3-predicted three-dimensional structures combined with AutoDock Vina molecular docking. Binding affinity distributions, compound-specific binding patterns, and functional enrichment analyses were performed to identify differential toxicity mechanisms. This study completed a total of 58,496 molecular docking calculations between the three compounds and human proteins. 8:2 Cl-PFESA demonstrated the strongest overall binding capacity, with top-ranked binding targets including emopamil-binding protein-like protein (EBPL) and lanosterol synthase (LSS). In comparison, PFOS showed highest-ranked binding to olfactory receptor 5D14 (OR5D14), while 6:2 Cl-PFESA preferentially bound to sulfotransferase 6B1 (SULT6B1). For ultra-strong binding targets with binding affinity ≤ -10.0 kcal/mol, 8:2 Cl-PFESA exhibited 413 targets, 6:2 Cl-PFESA showed 98 targets, and PFOS had 78 targets. Functional enrichment analysis revealed significant enrichment in olfactory transduction pathways across all compounds, suggesting potential impacts on chemosensory functions. Additionally, 8:2 Cl-PFESA showed preferential binding to cholesterol synthesis enzymes, while 6:2 Cl-PFESA demonstrated interactions with epigenetic regulatory enzymes, including histone deacetylase 11 (HDAC11) and sirtuin 6 (SIRT6). The findings suggest that F-53B, particularly its 8:2 Cl-PFESA component, may exhibit enhanced toxicity potential compared to PFOS across multiple molecular dimensions. These computational predictions require experimental validation through in vitro binding assays, cell-based toxicity tests, and in vivo studies.