Effects of 2,3-dibromopropyl substituents on the binding characteristics of TBBPS with HSA: insights from multispectroscopic and computational simulations

• TBBPS/TBBPS-BDBPE bond to HSA through hydrophobic interactions. • The binding of TBBPS-BDBPE to HSA induced greater conformational changes. • Alanine Scanning shown TRP214′s key role in TBBPS and its derivatives binding to HSA. • Substituents influenced the toxicity of TBBPS and its derivatives toward HSA. Tetrabromobisphenol S (TBBPS) and its derivative TBBPS bis (2,3-dibromopropyl ether) (TBBPS-BDBPE) are known for their potential reproductive toxicity, neurotoxicity, and immunotoxicity effects in human. Despite the detection of these compounds in human blood serum, their impact on the structural stability and functional properties of human serum albumin (HSA) remained unclear. This study employed multispectroscopic analyses, enzymatic activity assays, computational techniques, and toxicological prediction methods to investigate their interactions with HSA. Results showed that the HSA-TBBPS/TBBPS-BDBPE complexes were formed at site I through hydrophobic interaction forces with TBBPS exhibiting stronger binding affinity. The higher toxicity of TBBPS compared to TBBPS-BDBPE can be explained by its inhibition of HSA esterase-like activity and higher bioaccumulation capacity. Besides, conformational studies combined with molecular dynamics (MD) experiments revealed that both ligands led to a looser structure of HSA, with TBBPS-BDBPE exhibiting a more pronounced effect. Meanwhile, the Computational Alanine Scanning (CAS) analysis highlighted the critical role of Tryptophan 214 (TRP214) in the interactions. Additionally, the interactions of these complexes also involved other distinct types of amino acid residues. These above differences can be attributed to the larger accessible surface area of 2,3-dibromopropyl group in the side chain of TBBPS skeleton. In summary, structural modifications on the TBBPS skeleton can significantly influence the interactions between TBBPS derivatives and HSA. This study provides novel insights into the molecular mechanisms underlying the toxicity of TBBPS and its derivatives, highlighting how chemical modifications influence their protein-binding interactions and resultant toxicological effects.