Computational insights into dengue virus envelope protein triggered membrane fusion process

The membrane fusion process initiated by the Envelope (E) protein of the Dengue virus (DENV) is a critical step in viral entry into host cells, yet its molecular mechanism remains only partially understood. Here, we employ a combination of all-atom and coarse-grained molecular dynamics (MD) simulations to model the insertion and progression of the dengue virus Envelope protein into a lipid bilayer, capturing key stages of the membrane fusion event. All-atom simulations provide atomistic insight into initial protein-lipid interactions, time evolution of protein-lipid contacts and conformational rearrangements of the E protein fusion loop, while coarse-grained models enable observation of long-timescale membrane remodeling events, such as curvature generation. Structural and dynamic analyses reveal how the E protein perturbs the membrane architecture, promoting negative curvature in the target membrane at the site of entry and positive curvature in adjoining regions that resemble early hemifusion intermediates. These results support the hypothesis that the fusion loop acts as a membrane anchor, and that coordinated protein insertion and tilting are essential for catalyzing membrane merger. This study offers a detailed molecular view of dengue virus fusion initiation and demonstrates the value of multiscale simulation approaches in studying complex membrane-protein interactions.