Identification and computational analysis of conserved YXXΦ motifs in the pan-serotypes of dengue virus NS5 protein and their implications in host-virus interactions

Dengue is a major global health challenge, caused by the dengue virus (DENV) and transmitted through the Aedes aegypti mosquito. The four DENV serotypes (DENV1-4) infect about 400 million people annually. The non-structural protein 5 (NS5) is the most conserved DENV protein, crucial for viral replication. This study aims to elucidate the replication and pathogenesis mechanisms of DENV by targeting tyrosine-based motifs and YXX Phi-like tetrapeptides in the NS5 protein across all serotypes. We employed computational tools to identify and analyze tyrosine-based motifs (TM) and YXX Phi-like tetrapeptides within the NS5 protein. The structural characteristics of these motifs were determined using the AlphaFold2 web server. Additionally, we investigated post-translational modifications (PTMs) within these motifs to assess their potential roles in pathogenesis and immune response. Our analysis revealed various TM and YXX Phi-like tetrapeptides structurally conserved across the DENV serotypes. Several PTM sites were identified within these motifs, suggesting their involvement in virulence, enhanced propagation, and modulating the host immune system. The identified TM and tetrapeptides hold significant promise as targets for vaccine development against DENV. They potentially regulate key viral functions and immune evasion mechanisms. Molecular dynamics (MD) simulation analysis of conserved TM and YXX Phi-like tetrapeptides revealed distinct stability patterns. However, further in vivo and in vitro studies are needed to validate these findings and fully explore their therapeutic potential.