The researchers used a supercom-
puter to determine the complete HIV capsid structure, accounting for the interactions of 64 million atoms;
© University of Illinois/K. Schulten, J. Perilla
Researchers report that they have determined the precise chemical structure of the HIV capsid, a protein shell that protects the virus's genetic material and is a key to its virulence.
Scientists have long sought to understand how the HIV capsid is constructed, and many studies have chipped away at its mystery. Until the arrival of petascale supercomputers, however, no one could piece together the entire HIV capsid – an assemblage of more than 1,300 identical proteins forming a cone-shaped structure – in atomic-level detail. The simulations that added the missing pieces to the puzzle were conducted during testing of Blue Waters, a new supercomputer at the National Center for Supercomputing Applications at the University of Illinois.
"This is a big structure, one of the biggest structures ever solved," said Professor Klaus Schulten, who conducted the molecular simulations that integrated data from laboratory experiments performed by colleagues at the University of Pittsburgh and Vanderbilt University. "It was very clear that it would require a huge amount of simulation – the largest simulation ever published – involving 64 million atoms."
Previous research had established that the HIV capsid contained a number of identical proteins. Scientists knew that the proteins were arranged into pentagons and hexagons, and guessed that the pentagons formed the most tightly rounded corners of the capsid shape seen under an electron microscope. But they did not know how many of these protein building blocks were needed, or how the pentagons and hexagons fit together to form the capsid.
"The work of matching the overall capsid, made of 64 million atoms, to the diverse experimental data can only be done through computer simulation using a methodology we have developed called molecular dynamic flexible fitting," Schulten said. "You basically simulate the physical characteristics and behavior of large biological molecules but you also incorporate the data into the simulation so that the model actually drives itself toward agreement with the data." The simulations revealed that the HIV capsid contained 216 protein hexagons and 12 protein pentagons arranged just as the experimental data had indicated. The proteins that composed these pentagons and hexagons were all identical, and yet the angles of attachment between them varied from one region of the capsid to another. "That is really the mystery of it," Schulten said. "How can a single type of protein form something as varied as this thing? The protein has to be inherently flexible."
Possessing a chemically detailed structure of the HIV capsid will allow researchers to further investigate how it functions, with implications for pharmacological interventions to disrupt that function, Schulten said. "The HIV capsid has actually two completely opposite properties," he said. "It has to protect the genetic material but once it gets into the cell it has to release the genetic material. That has to happen with really good timing – too quick is not good, too slow is not good. And this is a moment when you can throw a wrench into the system." Some of the most potent antiviral drugs target the viral capsid, Schulten said. "The timing of the opening of the capsid is essential for the degree of virulence of the virus," he said. "This is where we could perhaps best interfere with HIV infection."
MEDICA.de; Source: University of Illinois at Urbana-Champaign