“Free-energy” calculations are key to the model. These take all kinds
of molecular dynamics into consideration, including potential of mean
force (PMF), which is something like buoyancy or magnetism, sometimes
drawing particles in, sometimes pushing them away. These dynamics are
critical to the value of any model.
Some calculations were developed by Tanya Nesterova, an undergraduate
student who had a double major in chemistry and applied mathematics.
She has since graduated from UD and is now in a doctoral program at
Johns Hopkins University. Also key to this work was Chaoyi Xu, a
doctoral student in Perilla’s lab who has successfully defended his
dissertation and now works as a computational chemist in the
pharmaceutical industry.
“The combination of theory and experiments gives us an opportunity to
train these very talented students,” Perilla said. “And this requires a
very special kind of student — someone who studies physics, computing
and math and wants to do something as far-fetched as biology. It’s hard
to cross that barrier. I’ve been extremely privileged to work with these
people.”
The model shows important targets that drug developers could explore, Perilla said.
“This is essential,” he said. “Millions of years of evolution have driven the virus in this direction.”
And this model could provide an important path forward for addressing other viruses, Zhang said.
“In collaboration with Prof. Juan Perilla’s group at the University
of Delaware, using information derived from electron tomography, we also
built an atomistic model of the whole HIV capsid which could serve as a
blueprint for the development of capsid-targeting antivirals,” she
said. “The perforation on the enveloped virus membrane also provides a
novel approach to study host-virus interactions for other viral
systems.”
Perilla and his lab have extensive experience in virus studies, including HIV, COVID-19, hepatitis B, and Ebola.
“I’m looking forward to seeing how my students develop,” Perilla
said. “They’re the future. They’ve been through a pandemic and been
trained through HIV. They are the ones who are going to tackle the
problems when I’m old and I have no doubt they’ll succeed.”
Many questions remain about what these molecules and metabolites are doing, but this work adds to the narrative.
“Even though HIV is one of the most studied viruses, there are so
many questions that remain unclear or under debate about how HIV infects
and replicates in the cell,” said Xu. “By investigating HIV in detail,
it not only gives us new knowledge about fighting the ongoing HIV/AIDS
epidemic, but also insights about the replication cycles of other
viruses.”
The collaboration was an amazing experience, Xu said.
“We are very happy to see that our collaboration made some impacts
that we would not achieve individually,” he said. “I personally also
learned a lot by working with the researchers and students from other
labs and different backgrounds.”
Perilla hopes many more students will be drawn to this work.
“The U.S. has extremely strong, well-trained people who can produce
pharmaceuticals,” Perilla said. “But a very thin part of the population
devotes their lives to this work. We need more opportunities to bring
people to science and have them be successful in science. The talent is
out there. We just need more people.”
In addition to Zhang, this collaborative work included scientists
from the Electron Bio-Imaging Centre (eBIC), which she directs, and
partners at the University of Pittsburgh School of Medicine, the School
of Medical Sciences in Sydney, Australia, the University of Melbourne
and St. Vincent’s Institute of Medical Research in Victoria, Australia.
The lead authors of the Science Advances article were Tao Ni and Yanan
Zhu of the University of Oxford.
Support for the work came from multiple sources, including the
National Institutes of Health, the Wellcome Trust, the United Kingdom’s
Biotechnology and Biological Sciences Research Council and the
Australian Research Council.