Computer simulation used to study viral capsid breakage

Credit: Aisha Han/Assistant Visual Editor Credit: Aisha Han/Assistant Visual Editor

Markus Deserno, from Carnegie Mellon’s Department of Physics, and Christine Peter, from the University of Konstanz in Germany, led a research team that developed a method to study the structure of viral capsids, the protein shell that houses the virus. The team used multi-scale modeling to understand the molecular assembly of the viruses and proteins by breaking the capsid apart. This research was published in The European Physical Journal Special Topics.

Viruses are essentially just genetic material (RNA or DNA) enclosed in nano-containers made of protein, called viral capsids. Given the limitations of genetic material carried by a virus, viruses encode for a small number of proteins to form round, stable, crystal-like structures on repeated combination.

This process of self-assembly of the capsid is extremely rapid and takes place on a microscopic scale of 30 to 50 nanometers, which makes it hard to study using current microscopic methods.

Thus, Deserno and Peter’s team used computer simulation to first construct the model of a viral capsid and then break it apart to understand capsid assembly.
In a university press release, Deserno said, “The concept of breaking something to see how it’s made isn’t new. It’s what’s being done at particle accelerators and in materials science labs worldwide — not to mention by toddlers who break their toys to see what’s inside.” He explains, “with a simulation we can build the virus, crush it and see what happens at a very high level of resolution.”

In the study, the research team studied the stability of the capsid of a particular virus called Cowpea Chlorotic Mottle Virus (CCMV) using a coarse-grained simulation model of the virus. They mechanically compressed the virus in the simulation, then studied the location and sequence of breakage events and the change of interactions between the forces that hold the proteins together.

In the paper, they say that this method, though very similar to the Atomic Force Microscope (AFM), provides a better resolution of the location of the capsid breakage than what is possible with the AFM model.

The study also creates a hierarchical model of assembly order based on “binding strength and mechanical stability.” This order suggests a likely model for the components of viral capsids that assemble before others, thus giving a fair idea of what the intermediates look like.

This research could be used to identify the factors that are responsible for structuring the viral unit, and therefore, can help to provide a greater understanding of the effect of drugs on the mutation of this unit. For instance, researchers are looking into combating the Hepatitis B viral infection by creating a drug that interferes with the virus’ capsid assembly process.

Another application of this information, as mentioned in their paper, is to engineer capsid proteins to build “containers” to encapsulate chemicals for targeted drug delivery.

The research concludes that the bonds that break first are the ones that form last during capsid assembly. During the assembly process, the proteins form pairs called dimers, where five proteins meet or hexamers of dimers, where six proteins meet. They found that hexamers of dimers broke before pentamers of dimers, which implies that hexametric contacts are weaker.

This, in turn implies that hexamers of dimers are not formed in the preliminary stages of assembly and sheds some light on the order in which intermediates of viral capsid structures are formed.