Critical target identification and human health risk ranking of metal ions based on mechanism-driven modeling

Huge amounts of metals have been released into environment due to various anthropogenic activities, such as smelting and processing of metals and subsequent application in construction, automobiles, batteries, optoelectronic devices, and so on, resulting in widespread detection in environmental media. However, some metal ions are considered as "Environmental health hazards", leading to serious human health concerns through affecting critical targets. Hence, it is necessary to quickly and effectively recognize the key target of metal ions in living organisms. Fortunately, the development of high-throughput analysis and in silico approaches offer a promising tool for target identification. In this study, the key oncogenic target (tumor suppressor protein, p53) was screened by network analysis based on the comparative toxicogenomics database (CTD). Some metal ions could bind to p53 core domain, impair its function and induce the development of cancer risk, but its mechanisms were still unclear. Therefore, a quantitative structure-activity relationship (QSAR) model was constructed to characterize the binding constants (K_a) between DNA binding domain of p53 (p53 DBD) and nine metal ions (Mg²⁺, Ca²⁺, Cu²⁺, Zn²⁺, Co²⁺, Ni²⁺, Mn²⁺, Fe³⁺ and Ba²⁺). It had good robustness and predictive ability, which could be used to predict the K_a values of other six metal ions (Li⁺, Ag⁺, Cs⁺, Cd²⁺, Hg²⁺ and Pb²⁺) within application domain. The results showed strong binding affinity between Cd²⁺/Hg²⁺/Pb²⁺ and p53 DBD. Subsequent mechanism analyses revealed that first hydrolysis constant (|logK_OH|) and polarization force (Z²/r) were key metal ion-characteristic parameters. The metal ions with weak hydrolysis constants and strong polarization forces could readily interact with N-containing histidine and S-containing cysteine of p53 DBD, which resulted in high K_a values. This study identified p53 as potential target for metal ions, revealed the key characteristics affecting the actions and provide a basic understanding of metal ions-p53 DBD interaction.