Structural and dynamic characterization of human Wnt2-Fzd7 complex using computational approaches.

Wnt and Frizzled (Fzd) family members play crucial roles in the self-renewal of tumor-initiating cells. Until now, only a few studies have addressed the distinct mechanism of Wnt-Fzd interactions. In this study, we suggest a possible interaction mode of Wnt2 with the Fzd7 cysteine-rich domain (CRD)-both of which are up-regulated in some types of cancer. A combination of homology modeling, molecular docking and molecular dynamics (MD) simulations was carried out to study this ligand-receptor complex in great detail. The results demonstrated the unique dynamic behavior of Wnt2 upon binding to Fzd7. Interestingly, the β-strand content of the C-terminal binding site of Wnt2 was obviously reduced when bound to Fzd7 CRD. Moreover, the N-terminal and C-terminal binding sites of Wnt2 appeared to interact with the C-terminal and N-terminal binding sites of Fzd7, respectively. Calculation of the binding energies uncovered the pivotal role of electrostatic and hydrophobic interactions in the binding of Wnt2 to Fzd7 CRD. In conclusion, this study provides valuable insights into the mechanism of the Wnt2-Fzd7 CRD interaction for application in colorectal cancer prevention programs. Graphical abstract Flowchart representation of different steps used in this study.