The binding mechanism of benzophenone-type UV filters and human serum albumin: The role of site, number, and type of functional group substitutions.

Benzophenone-type UV filters (BPs) are common in natural aquatic environments. They can cause endocrine disruption or other adverse effects once they enter the human body via the food chain or drinking water. The primary cause of BPs accumulation and toxicity is the transport of BPs into the human body. Functional group substitutions can have a significant impact on the interactions of BPs and transporters, resulting in a variety of impact effects. Therefore, we explored the interaction between human serum albumin (HSA, a typical transporter) and ten typical BPs [benzophenone (BP1), 2-hydroxybenzophenone (BP2), 4-hydroxybenzophenone (BP3), 2,2'-dihydroxybenzophenone (BP4), 2,4-dihydroxybenzophenone (BP5), 4,4'-dihydroxybenzophenone (BP6), 2,4,4'-trihydroxybenzophenone (BP7), 2,2',4,4'-tetrahydroxybenzophenone (BP8), 2-hydroxy-4-methoxybenzophenone (BP9), and 2,2'-dihydroxy-4-methoxybenzophenone (BP10)] to study the role of functional group substitutions in binding. The results showed that BPs could bind to HSA at site 2, with binding constants ranging from 2.01 × 10 to 4.57 × 10 L/mol. Compared to BP1, hydroxyl and methoxy substitutions enhanced the BPs-HSA binding. The combined effect of the number and site of hydroxyl substitution at BPs determined the binding strength between BPs and HSA. It was more accessible to bind HSA when BPs were substituted with para-hydroxyl (4-hydroxyl) groups than with ortho-hydroxyl (2-hydroxyl) groups. Moreover, the additional para-methoxy (4-methoxy) group increased the BP-HSA binding strength by approximately 47 times under the same hydroxyl substitution conditions. Theoretical calculations revealed that functional group substitutions increased the intermolecular binding force by increasing the negative electrostatic potential surface area of BPs, which significantly increased the electrostatic and dispersion forces between the BPs and HSA. This BPs-HSA binding decreased the α-helix of HSA and influenced the ratio of other secondary structures, including β-sheet, β-turn, and random coil of HSA. This study provides a theoretical and experimental foundation for understanding the human health risks associated with BPs.