Presentation by Dr. Jan Marzinek, Senior Post-doctoral Research Fellow, from A*STAR in Singapore A primary causative agent of infectious disease is the positive single-stranded RNA family of flaviviruses, which includes dengue (DENV), tick-borne encephalitis, West Nile virus, Japanese encephalitis, yellow fever, and Zika virus. Flavivirus particles undergo many structural rearrangements throughout their life cycle, such as during maturation or endocytosis. Another example involves "breathing", in which the virus can change its shape in response to a change in temperature, a phenomenon which can be modulated through mutations in the surface envelope proteins in order to evade vaccines and therapeutics. A multiscale molecular dynamics simulation approach was employed to investigate such conformational changes associated with the envelope protein during the DENV life cycle. Based on cryo-electron microscopy maps, we constructed a near-atomic resolution model of the complete viral envelope, containing envelope and membrane proteins embedded within a\ lipid bilayer vesicle. We leveraged this model to probe the dynamics of the viral outer shell associated with different stages of the virus life cycle, triggered by changes in the host microenvironment, such as temperature, pH and salt. We also used all-atom simulations to probe molecular details of the breathing process and its dependence upon mutations. We subsequently investigated interactions with antibodies different morphological states of the virus particle and, supported by diverse biophysical data, rationalise the occurrence of antibody-dependent enhancement, which can lead to the most serious forms of DENV infection including dengue hemorrhagic fever and shock syndrome. The combination of multiscale simulation and experiment reported here provides novel insights into appropriate therapeutic strategies for different stages of DENV infection and could give rise to new approaches for vaccine development and antibody engineering.