Genotype-Resolved Interaction Landscape of the Dengue Envelope Glycoprotein with Host Cellular Proteins: Structural Dynamics, Thermodynamic Cooperativity, and Binding Specificity
1Dengue virus (DENV) entry has historically been viewed as a receptor-centric process in which viral envelope proteins engage isolated host factors to initiate infection. However, mounting evidence reveals that viral attachment, internalization, and intracellular trafficking occur within complex molecular environments where multiple interacting host proteins shape the infection landscape. Here we introduce vectorial host interaction fields--a framework that represents intermolecular contacts as directional vectors embedded within host protein interaction networks, providing structural and systems-level insight into viral entry. Docking analyses were performed across sixteen dengue envelope genotype variants, whereas molecular dynamics and MM/GBSA analyses were conducted on representative complexes selected from this genotype-informed screening. We characterized dengue envelope interactions with thirteen host proteins involved in membrane attachment, receptor signaling, cytoskeletal transport, vesicular trafficking, proteostasis, and immune regulation. Our multiscale approach integrated protein-protein docking, 200 ns molecular dynamics simulations of representative complexes, MM/GBSA binding free energy analysis, and vectorial hydrogen-bond formalism encoding orientation, persistence, and angular entropy. We identified four recurrent viral interface architectures: multivalent anchoring (BiP/GRP78, Betaglycan), electrostatic sliding (Glypican-1), focal regulation (Claudin-1, SUMO), and conserved cytoskeletal modules (Actin, Rab5). Ternary docking analyses revealed that viral stability is strongly conditioned by local network context, with conditional {Delta}{Delta}G values ranging from approximately -3.4 to +6.9 kcal mol-1 depending on neighboring proteins and assembly sequence. These findings support a systems-level model of dengue entry driven by layered host interaction fields rather than a single dominant receptor, but they should be interpreted as computational structural hypotheses requiring biochemical, biophysical, and cellular validation. Detailed structural datasets, molecular dynamics trajectories, vectorial analyses, and per-residue MM/GBSA decomposition are provided in the companion Supplementary Material, which includes extended Results and Discussion, comprehensive Limitations assessment, and VectorPROT pipeline documentation supporting these findings.