Supercomputer Visualization Shows 1.2 Microseconds in the Life of a 4-Million-Atom HIV Capsid

While some researchers look for drugs to treat HIV, other scientists delve deep into the virus itself for answers on how it causes infections.

Using two supercomputers, University of Illinois research scientist Juan R. Perilla and late physics professor Klaus Schulten simulated 1.2 microseconds of the life of the HIV capsid, the structure that contains the virus's genetic material. The simulation, which took two years to complete, gives us a view of the virus on a molecular level and provides us with insight into how HIV senses its environment and becomes infective.

The huge undertaking simulated the dynamics of 64 million atoms in the entire virus particle and revealed information about the stability, forces between atoms, ion permeability, surface waves, and mechanical properties of the HIV-1 capsid. The researchers reported the project results in the July 19 issue of Nature Communications.

"We are learning the details of the HIV capsid system, not just the structure but also how it changes its environment and responds to its environment," Perilla said in a press release.

HIV Viral Components

Previous studies done over the last 25 years have used X-ray and crystal structure analyses to determine HIV's components and their arrangement. We know that the virus is composed of two strands of RNA — its genetic material — which the cell uses as templates to make 15 viral proteins. These complex proteins serve many functions, from helping the virus attach to a host cell, replicate its genetic material, and bud off as new viral particles.

The capsid, in blue, protects the virus after it enters a cell and shuttles it to the nucleus, where it completes the process of infection.

The capsid is one of the virus's structural proteins, located at the heart of the virion. It's a large structure, made of about 1300 proteins and 4 million atoms. Unlike other proteins in the virus, the capsid proteins are all identical. In the cell, they arrange into a cone-shaped structure made of hexamers — six sided proteins — and pentamers, with five sides.

HIV belongs to the lentivirus genus of viruses. These viruses infect non-dividing cells, so to get the viral RNA into the host cell's DNA, the virus must evade the body's immune system, activate an enzyme to convert viral RNA to DNA, and get into the host cell's nucleus. Where once scientists thought the capsid only served to transport viral genetic material, we now know that the capsid has a role in all those other functions as well.

Perilla and Schulten wanted to look at the how the viral capsid acts at the molecular level, but it interacts with every other viral protein. They solved the problem by simulating interactions of the entire virus, all 64 million atoms of it, while only showing the 4 million atoms of the capsid proteins.

A Closer Look

Perilla and Schulten used a process called molecular dynamics to study the HIV capsid. Molecular dynamics allows a scientist to simulate the forces between atoms of a compound — in this case, a virus — and something it's interacting with. Those simulations can be used to watch how molecules interact with their environment and each other. Recording those simulated forces generated the data they researchers were looking for, but because of the sheer number of atoms, simulating the forces between all of them over just 1.2 microseconds took two years.

Molecular dynamics is just understanding how molecules move and impact each other. The forces between those molecules are not particularly complex, but if you model a system with thousands or millions of atoms, then you need to calculate the forces between every single atom, it's just enormously computationally expensive.

The research duo used two different supercomputers to perform their elegant study. The capsid simulation was done on the Titan supercomputer at the US Department of Energy. Analysis of the massive amounts of data generated by the DOE computer was accomplished by Blue Waters at the National Center for Supercomputing Applications at the University of Illinois. Both are among the fastest computers in the world.

HIV-1 capsid fluctuations

As the supercomputers collected and analyzed data from the simulations, the results showed that different parts of the capsid oscillate — moves or swings back and forth — at different frequencies. Perilla believes the oscillations probably transmit information from one part of the capsid to another.

The study also showed that ions — charged particles — flow into and out of the pores in the capsid that allow the passage of water and ions from their environment. Negatively charged ions accumulate on the positively charged inner surface of the capsid protein layer, while positive ions stick to the negatively charged exterior.

The hexamers act as a channel for negatively charged chloride. It moves through the middle of the hexamer. Positively charged sodium, on the other hand moves between hexamers on the surface.

Translocation of ions through the HIV-1 capsid. Left: Chloride ions (cyan) translocate through the center of hexamers. Right: Sodium ions (yellow) translocate through the seams between hexamers (right).

Perilla believes this could help bring enzymes and other factors into the capsid to use in converting RNA to DNA. The nucleotides that make up DNA are negatively charged and are small enough to pass through pores in the HIV capsid, much the way chloride ions do.

Translocation of chloride ions (blue) through hexamers

Another significant finding was that it might be possible to stress the mechanical and charged forces that hold the capsid together to make it susceptible to bursting. Previous research has found several areas on the capsid that seem especially prone to stress.

Zooming out from the molecular level to the level of HIV infections, the new study has given Perilla ideas about how to use the new revelations about the HIV capsid to defeat the virus.

"If you can break this electrostatic balance that the capsid is trying to keep together, you may be able to force it to burst prematurely," Perilla said in a press release.

This painstaking and eloquent study may have given us the much closer look we needed to understand the innermost workings of HIV.

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