Zhang_2026_Int.J.Biol.Macromol__151966

Bisphenol TMC (BPTMC) is a substitute for bisphenol A (BPA) and serves predominantly in plastic manufacturing. It has been identified in various environmental matrices and in the human body. In this study, a comprehensive strategy involving spectroscopic techniques, atomic force microscopy (AFM), and computational simulations were employed to elucidate the impact of BPTMC on human serum albumin (HSA) at the structural and functional levels. The results indicate that BPTMC can spontaneously bind to the binding site I of HSA with an association constant (K(a)) of 7.417 x 10(5) M(-1) at 298 K, primarily through hydrophobic interactions. The larger negatively charged surface and smaller HOMO-LUMO energy gap (deltaE(gap) = 5.352 eV) of BPTMC enable it to exhibit stronger binding affinity for HSA than BPA (5.422 eV). AFM and spectroscopic analyses revealed that BPTMC alters the morphology, the environment of aromatic residues, and secondary structure of HSA. This interaction reduces the alpha-helix content 19.1%, consequently leading to a less stable and less compact conformation. Activity assays indicated that BPTMC enhances the esterase-like activity of HSA. Computational simulations confirmed these findings and the above findings and highlight that the Lys199-BPTMC interaction as critical for enzymatic activation induced by BPTMC. In summary, this work clarifies the underlying molecular interaction mechanism of BPTMC with HSA, thus raising concerns about the assumed safety of BPA structural analogues.