By: Sheila Evans
The lab of Professor Greg Voth may look different than what you would expect of a lab studying viruses. Computers fill the room along with students and postdocs at their desks working.
Using complex “multiscale” computer simulations modeling viruses, Voth and his team have discovered aspects of two of the deadliest viruses facing humanity today, HIV and SARS-CoV-2. With the same methods, they hope to learn even more about these other viruses to help society be better prepared for the next threat to human health.
In Nature Communications, a new insight into SARS-CoV-2 brings light to how the virus binds and enters cells. There are spike glycoproteins that coat the outside of the virus which allows it to bind and invade cells. The glycoproteins consist of S1 and S2 domains which bind to receptors in the target healthy cells called ACE2. Once this binding happens, viral fusion machinery is exposed and the virus can now infect the cell. Through complex innovative computer simulations, the mechanism behind this process was modeled. The team was also able to speculate on how new variants of the SARS-CoV-2 virus modify the binding of the spike to ACE2. The Delta variant enhances this process to be more infectious. Computer modeling is essential to understanding virus fusion to target healthy cells since no current experiment can look at this process directly.
Advanced computer simulations can be used to study other viruses. Another paper by the Voth group and collaborators published in PNAS explores the strain and rupture of HIV virus capsids just before and during uncoating expose their genetic material in the infected cell. HIV viruses are surrounded by rigid capsids made up of approximately 1200 proteins that help transport viral RNA into the infected cell. HIV packages the genome into the capsids and travels inside the cell nucleus to infect it. Once inside the nucleus, the capsid breaks apart and the genetic material of the virus hijacks the cell replication machinery to propagate itself. These capsids have markedly striated strain patterns. By studying these capsids with simulation, the properties in the disassembly process that causes the capsid to rupture become clearer. The word rupture gives the impression that this process is uncontrolled, however, it is much more predictable. The capsid begins to strain and correlated patterns are created along which the cracks can propagate. The HIV capsid has to break at just the right time and in the right way to infect new cells. This fundamental insight into viral capsid uncoating can also possibly be used to create therapeutics that cause the capsid to rupture too soon or not rupture at all.
These viruses are studied through computers rather than experimental techniques. The “supercomputers” run molecular dynamics simulations, that can examine complex systems at the molecular level. These molecular trajectories are recorded for a set period of time, and the dynamic evolution of the system can be seen up to microseconds and beyond. Cryo-electron tomography can also analyze virus capsids and their protein assemblies at near molecular resolution. These two technologies are used by the Voth lab and their collaborators to explore unknown aspects of HIV and other viruses.
Much of this work would be impossible experimentally, so the computational methodology Voth has developed could prove essential to understanding new dangerous viruses. This knowledge also facilitates possible new tools for developing therapeutics for existing and future viruses.
Citation: “Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core.” Voth et al, Nature Communications, Feb 22.
Citation: “Strain and rupture of HIV-1 capsids during uncoating.” Voth et al, PNAS, March 1.
Funding: National Science Foundation Division of Chemistry, National Institute of Allergy and Infectious Diseases of the National Institutes of Health