Investigating haloacetic acids - human serum albumin interactions: A comprehensive approach using multi-spectroscopy, DFT calculations, and molecular docking

Haloacetic acid (HAAs) has been shown in studies to be teratogenic and mutagenic. The toxicity of HAAs to macromolecules and their mechanism of action are still unclear. To further explore the potential impact of HAAs on organisms, this study used multi-spectroscopy, density functional theory (DFT), and molecular docking to analyze the characteristics and mechanisms of five typical HAAs interactions with HSA. Multispectral analysis indicates that the binding energies of the interactions between the five HAAs and HSA are weaker than other HSA-ligand complex systems. The order of binding constants at 298 K was as follows: DBAA (458.14 L·mol−1) > TCAA (374.71 L·mol−1) > DCAA (242.89 L·mol−1) > MBAA (140.73 L·mol−1) > MCAA (102.05 L·mol−1). The quenching processes of the interactions between the five HAAs and HSA belong to static quenching, an exothermic reaction process. Hydrogen bonds and van der Waals forces are the main driving forces in the formation process of the HSA-HAAs complex. Molecular docking results indicate that TCAA, DBAA, and DCAA are more likely to bind with HSA. Correlation analysis based on DFT calculations reveals the intrinsic relationship between the chemical structural features of HAAs and the binding performance of HSA-HAAs. For the first time, the research discovered that among the quantum chemical descriptors, the highest ALIE maximum, the highest ESP maximum, and the maximum local electrophilic index f −(r) all correlate well with the HSA-HAAs binding constants. Their correlation coefficients are 0.83, 0.94, and -0.56, respectively, which can effectively predict the binding performance of HAAs with HSA. In-vitro toxicity experiments on LO2 cells show that within the concentration range of 0.002-10 mmol·L−1, MBAA, MCAA, and DBAA exhibit higher toxicity to normal human liver cells. In contrast, DCAA and TCAA show low or no toxicity. Through comprehensive research combining experimental and theoretical analysis, the mechanism of HSA-HAAs has been deeply revealed. This holds significant scientific value for assessing the environmental risks of HAAs and understanding their impact on biological activities.