Chemists from the University of Chicago have successfully assembled a massive model of the nuclear pore complex and the HIV-1 virus capsid.
Because viruses have to hijack someone else’s cell to replicate, they’ve gotten very good at it—inventing all sorts of tricks.
A new study from two simulations to unravel the complex biological processes that occur as viruses attack a cell.
In this case, Voth and Hudait focused on what’s known as the HIV capsid—the capsule containing HIV’s genetic material, which enters a host cell’s nucleus and forces the cell to make copies of the key HIV components.
The capsid is a complex piece of machinery, made of more than a thousand proteins assembled into a cone-like shape, with a smaller and larger end. To get into the host cell’s nucleus, it must sneak in. But scientists didn’t know exactly how this happens. “This part has been a mystery for years,” said Voth, the senior author on the paper. “For a long time, no one was sure whether the capsid broke apart before entering the pore or afterward, for example.”
Recent imaging studies have suggested the capsid stays intact wriggling through the nuclear pore complex. This is essentially the mail slot where the nucleus sends and receives deliveries.
“The pore complex is an incredible piece of machinery; it can’t let just anything into the nucleus of your cell, or you’d be in real trouble, but it’s got to let quite a bit of stuff in. And somehow, the HIV capsid has figured out how to sneak in,” Voth said. “The problem is, we can’t watch it live. You have to go to heroic experimental efforts to even get a single, moment-in-time snapshot.”
To fill in the gaps, Hudait built a painstaking computer simulation of both the HIV capsid and the nuclear pore complex—accounting for thousands of proteins working together.
Running the simulations, the scientists saw that it was much easier for the capsid to get into the pore by wedging its smallest end in first, and then gradually ratcheting itself in. “It doesn’t need active work to do it, it’s just physics—what we call an electrostatic ratchet,” said Voth. “It’s kind of like if you’ve ever had a seatbelt tighten up on you, where it just keeps getting tighter and tighter.”
They also found both the pore and the capsid deform as it goes. Interestingly, the lattice of molecules that make up the capsid structure develops little regions of less order to accommodate the stress of the pressure. “It’s not like a solid compressing or expanding, as one might have expected,” said Hudait.
The finding may help explain why capsids are cone-shaped, rather than a shape like a cylinder, which might seem at first easier to slip through a pore.
The scientists said that each detail in HIV’s journey through the body is an opportunity to find vulnerabilities where drugs could be developed to target. It’s also a look in the broader sense at a fundamental aspect of biology.
“I think this modeling also gives us a new way to understand how many things get into the nucleus, not just HIV,” said Voth.
Reference: “HIV-1 capsid shape, orientation, and entropic elasticity regulate translocation into the nuclear pore complex” by Arpa Hudait and Gregory A. Voth, 19 January 2024, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2313737121
The simulations were performed at the Texas Advanced Computing Center at the University of Texas at Austin and the Research Computing Center at UChicago.