Viral capsids, the protein shells that encapsulate and transport the
viral genome, are one of nature's strongest nanocontainers. The shells
are made when copies of capsid proteins spontaneously come together and
assemble into a round, geometric shell.
Researchers led by Carnegie Mellon University physicist Markus Deserno
and University of Konstanz (Germany) chemist Christine Peter have
developed a computer simulation that crushes viral capsids.
‘Understanding how these proteins come together to form viral capsids may help researchers to make similar nanocontainers for a variety of uses, including targeted drug delivery.’
Understanding how these proteins
come together to form capsids may help researchers to make similar
nanocontainers for a variety of uses, including targeted drug delivery.
Additionally, the simulation could fill a void for virologists, allowing
them to study the stages of viral assembly that they aren't able to see
The study is published in the October issue of The European Physical Journal Special Topics
"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," said Deserno, a professor in the department of physics
and member of the department's Biological Physics Initiative. "With a
simulation we can build the virus, crush it and see what happens at a
very high level of resolution."
Studying the self-assembly of viral capsids is difficult. Most
viruses are too small - about 30 to 50 nanometers - and the capsid
proteins come together too rapidly for their assembly to be seen using
traditional microscopy. As an alternative, Deserno and colleagues
thought that a better way to learn about capsid assembly might be to see
what happens when an already formed capsid breaks apart.
To do this, Deserno and colleagues created a coarse-grained model of
the Cowpea Chlorotic Mottle Virus (CCMV) capsid. In the simulation,
they applied forces to the capsid and viewed how it responded to those
forces. Their model is based on the MARTINI force field, a commonly used
coarse-grained model, with an added stabilizing network within the
individual proteins that compensated for the model's shortcomings in
stabilizing a protein's folding geometry.
The CCMV capsid is made up of 180 identical proteins. In assembly,
the proteins first form pairs, called dimers, and those dimers then join
together at interfaces. While the proteins are the same, the interfaces
can be different. At some locations on the capsid, five proteins meet;
at others, six. In the simulation, the researchers found that when force
was applied to the capsid, the capsid would start to fracture at the
hexametric interfaces first, indicating that those protein-protein
contacts were weaker than those at the pentametric interfaces. In
contrast, the pentametric contacts never broke. Since stronger
connections assemble first and weaker ones assemble later, the
researchers can use this information to begin to recreate how the capsid
In the simulation, the researchers also found a likely explanation
for a strange structural feature found in the CCMV capsid. At the center
of the hexametric association site, the tail-ends of the six proteins
come together and form a beta barrel. Beta barrels are coiled secondary
protein structures. The researchers believe that they act to provide
further late-stage stabilization to the weaker hexametric interfaces.