Uslupehlivan, MuhammetDeveci, Remziye2025-11-252025-11-2520251746-07941746-0808https://doi.org/10.1080/17460794.2025.2581464https://hdl.handle.net/20.500.14365/6612Zika (ZIKV) and Dengue virus (DENV) are transmitted to humans via Aedes mosquitoes, collectively infecting approximately 400 million individuals annually. Both viruses replicate on the endoplasmic reticulum membrane, where the NS4A protein serves as a key component of the viral replication complex and mediates interactions with the host Sec61G protein. Although host glycosylation enzymes have been reported to interact with NS4A, the three-dimensional structure of NS4A, potential glycosylation sites, precise interaction interfaces with Sec61G, and the functional role of glycosylation in these interactions remain largely unknown. This study aims to characterize the molecular determinants of NS4A - Sec61G interactions to provide insights into virus-host interactions. Structures of NS4A proteins were predicted via molecular modeling. Glycosylation sites were identified using glycoinformatics analyses, and NS4A - Sec61G interactions were assessed using three distinct molecular docking programs to ensure reliability and cross-validation of predicted binding modes. Glycosylation analysis revealed that only NS4A from ZIKV contains O-glycosylation sites. Docking simulations highlighted Arg127 in NS4A ZIKV, and Arg76 and Glu124 in NS4A DENV as critical residues potentially mediating stable interactions with Sec61G. These residues likely play essential roles in NS4A - Sec61G interactions, and their identification may contribute to the development of effective therapeutic strategies targeting both viral and host factors.eninfo:eu-repo/semantics/closedAccessZikaDengueNS4ASec61GMolecular Docking3D Molecular ModelingGlycosylationArticle10.1080/17460794.2025.25814642-s2.0-105020600298