Membrane vesiculation induced by proteins of the dengue virus envelope studied by molecular dynamics simulations

de Oliveira dos Santos Soares, Ricardo; Bortot, Leandro Oliveira; van der Spoel, David; Caliri, Antonio

Biological membranes are continuously remodeled in the cell by specific membrane-shaping machineries to form, for example, tubes and vesicles. We examine fundamental mechanisms involved in the vesiculation processes induced by a cluster of envelope (E) and membrane (M) proteins of the dengue virus (DENV) using molecular dynamics simulations and a coarse-grained model. We show that an arrangement of three E-M heterotetramers (EM(3)) works as a bending unit and an ordered cluster of five such units generates a closed vesicle, reminiscent of the virus budding process. In silico mutagenesis of two charged residues of the anchor helices of the envelope proteins of DENV shows that Arg-471 and Arg-60 are fundamental to produce bending stress on the membrane. The fine-tuning between the size of the EM(3) unit and its specific bending action suggests this protein unit is an important factor in determining the viral particle size.