Investigating the structure of the DENV-2 envelope protein in complex with the EDE2 B7 antibody using metadynamics simulations

• Main Author: Lim, Eric Jit-Kai
• Other Authors: Lu Lanyuan
• Format: Final Year Project
• Language: English
• Published: 2016
• Subjects: DRNTU::Science::Biological sciences
• Online Access: http://hdl.handle.net/10356/69194
• Institution: Nanyang Technological University

Dengue is a serious disease with a particularly high transmission rate in the tropics. There is currently only one WHO-approved vaccine, but it has limitations. A key therapeutic target on the dengue virus is the envelope glycoprotein (E protein) dimer which coats the outer surface. A new type of antibody has been discovered that binds to the E-dimer dependent epitope (EDE) which involves both monomers within the same epitope. However, the exact mechanism of action is unknown. It is possible that it locks the monomers to prevent subsequent acid-induced dissociation and trimerisation that are required for viral fusion with the cell. A computer simulation study was designed to investigate the mechanism of the EDE2 B7 antibody in complex with the soluble ectodomain of the E dimer. Metadynamics was used in molecular dynamics simulations of the E protein dimer with and without the antibody in neutral and acidic conditions. Bias potentials were applied on the collective variables of inter-dimer contacts, inter-dimer distance and root-mean square deviation during the simulation to enhance conformational sampling. Acidic conditions were found to destabilise the dimer while the presence of the antibody maintained the binding between the monomers, thus highlighting the therapeutic potential of this antibody.