Speaker
Description
The Ebola virus matrix protein VP40 oligomerizes at the plasma membrane inner leaflet to drive virus-like particle (VLP) formation in mammalian cells, a process dependent on the membrane lipid phosphatidylserine (PS). We previously developed an ODE model of VP40 oligomerization that provided evidence for a nucleation-elongation mechanism and explicitly incorporated the VP40–PS relationship that influences budding. However, the ODE framework cannot resolve experimentally-observed spatial effects of PS membrane heterogeneity. To address this, we developed an agent-based model (ABM) of VP40 dynamics in a VP40 transfected cell and calibrated the ABM to experimental data from HEK293 cells. Comparing calibrated ODE and agent based models revealed notable differences: the ODE required a monomer production rate of ~16 nM/s, while the ABM reproduced equivalent VLP and VP40 dynamics at <1 nM/s. Experimentally these values are hard to measure, but with this analysis we can start to see that these parameter estimates appear to be model-type specific. We use the ABM to investigate how PS spatial organization influences VLP production — specifically, how the fraction of membrane surface area enriched in PS and the spatial arrangement of high-PS domains (small versus large clusters) modulate budding efficiency. From this work, we will be able to test if membrane targeted therapies that affect PS heterogeneity are viable options for reducing VLP production.
