Tungsten Oxide Nanodots Exhibit Mild Interactions with WW and SH3 Modular Protein Domains

[Image: see text] Tungsten oxide nanodot (WO(3–x)) is an active photothermal nanomaterial that has recently been discovered as a promising candidate for tumor theranostics and treatments. However, its potential cytotoxicity remains elusive and needs to be evaluated to assess its biosafety risks. Herein, we investigate the interactions between WO(3–x) and two ubiquitous protein domains involved in protein–protein interactions, namely, WW and SH3 domains, using atomistic molecular dynamics simulations. Our results show that WO(3–x) interacts only weakly with the key residues at the putative proline-rich motif (PRM) ligand-binding site of both domains. More importantly, our free energy landscape calculations reveal that the binding strength between WO(3–x) and WW/SH3 is weaker than that of the native PRM ligand with WW/SH3, implying that WO(3–x) has a limited inhibitory effect over PRM on both the WW and SH3 domains. These findings suggest that the cytotoxic effects of WO(3–x) on the key modular protein domains could be very mild, which provides new insights for the future potential biomedical applications of this nanomaterial.