Statistical Bioinformatics Webinar: Marzinek -- Multiscale Simulations of Dengue Virus Morphological Changes and Antibody Interactions

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.