Computational prediction and functional analysis of arsenic‐binding proteins in human cells

Background Arsenic has a broad anti‐cancer ability against hematologic malignancies and solid tumors. To systematically understand the biological functions of arsenic, we need to identify arsenic‐binding proteins in human cells. However, due to lack of effective theoretical tools and experimental methods, only a few arsenic‐binding proteins have been identified. Methods Based on the crystal structure of ArsM, we generated a single mutation free energy profile for arsenic binding using free energy perturbation methods. Multiple validations provide an indication that our computational model has the ability to predict arsenic‐binding proteins with desirable accuracy. We subsequently apply this computational model to scan the entire human genome to identify all the potential arsenic‐binding proteins. Results The computationally predicted arsenic‐binding proteins show a wide range of biological functions, especially in the signaling transduction pathways. In the signaling transduction pathways, arsenic directly binds to the key factors ( e.g ., Notch receptors, Notch ligands, Wnt family proteins, TGF‐beta, and their interacting proteins) and results in significant inhibitions on their enzymatic activities, further having a crucial impact on the related signaling pathways. Conclusions Arsenic has a significant impact on signaling transduction in cells. Arsenic binding to proteins can lead to dysfunctions of the target proteins, having crucial impacts on both signaling pathway and gene transcription. We hope that the computationally predicted arsenic‐binding proteins and the functional analysis can provide a novel insight into the biological functions of arsenic, revealing a mechanism for the broad anti‐cancer of arsenic.