Multilevel in silico structural analysis of WNT proteins

WNTs are a family of signaling proteins involved in numerous biological processes, including morphogenesis, oncogenesis, cell migration and proliferation, cellular specialization, and tissue regeneration. WNT proteins are characterized by a distinctive structure comprising two domains resembling a "thumb" and an "index finger," which enables their interaction with cellular receptors. Despite the identification of 19 WNT proteins in humans, three-dimensional structural data are available for only a subset, highlighting the importance of studying WNT proteins using in silico approaches. This study presents the in silico structural analysis of three human WNT family members - WNT1, WNT3A, and WNT5A - across multiple levels of protein organization. The primary structure of these proteins was analyzed for amino acid composition, and secondary structure predictions for α-helices, β-strands, and loops were correlated with domain structures characteristic of WNT proteins. Tertiary structures were modeled using homology modeling and deep-learning algorithms, and structural properties were investigated through molecular dynamics simulations. The ability of WNT proteins to adopt several closed and open conformational states was demonstrated, as well as the role of the flexibility of the β-hairpin forming the "index finger" in mediating conformational transitions. Thus, by applying a comprehensive bioinformatic approach to WNT proteins, the study highlights the advanced capabilities of in silico methods for analyzing protein structures at multiple levels of organization.