Abstract
The interactions between the DIX domains of three proteins (Axin1/2, Dishevelled1/2/3, and Coiled-coil-DIX1) are essential to the mechanism of action downstream of the Wnt/β-catenin signaling pathway. Structural and biophysical studies have shown that DIX domains polymerize via head-to-tail interface interactions. In our recently published study entitled 'Exploring DIX-DIX Homo- and Hetero-Oligomers in Wnt Signaling with AlphaFold2", we examined the monomer structures of DIX domains, and DIX-mediated homodimers and heterodimers with AlphaFold2 (AF2) ColabFold. First, we evaluated the AF2-based prediction by comparing the reported monomer and complex structures of the DIX domains. The results showed that AF2 is an excellent tool for predicting the 3D structures of monomers of DIX domains and of homodimers and heterodimers of DIX-mediated proteins. Second, we evaluated the calculated binding affinities (KD) of DIX domains using the PRODIGY method. The results showed that the calculated KD values are compatible with experimentally obtained values. In this commentary, we present new computational results using AlphaFold3 (AF3), the latest version of AlphaFold, and VD-MM/GBSA calculations with HawkDock2. Overall, AF2/3 and other bioinformatics tools provide valuable insights into the DIX-mediated signaling pathway at the molecular level.
Keywords
AlphaFold2/3, HawkDock2, VD-MM/GBSA, DIX domain, Protein-Protein Interactions, Wnt signaling