The Computational Biochemistry and Biophysics Laboratory at GRIB (UPF-IMIM), led by  Gianni De Fabritiis have used molecular simulation techniques to explain a specific step in the maturation of the HIV virion, i.e. the inert form of the virus, which is essential in understanding how the virus replicates. These results, which have been published in the latest edition of PNAS, could be crucial to the design of future antiretrovirals.

HIV virions mature and become infectious as a result of the action of a protein called HIV protease. This protein acts like a pair of scissors, cutting the long chain of proteins that form HIV into individual proteins that will form the structure of new virions.

According to researchers from the Computational Biochemistry and Biophysics Laboratory (UPF-IMIM)led by Gianni De Fabritiis, " One of the most intriguing aspects of the whole HIV maturation process is how HIV protease, i.e. the "scissors protein" appears for the first time, since it is also part of the long poly-protein chains that make up the HIV virion" .

Using molecular simulations and a technology known as GPUGRID.net, Gianni De Fabritiis' group has demonstrated that the first "scissors proteins" can split from the chain on their own. They do this by binding one of their ends (the N-terminus) to its active site, which will split from the chain. This is the initial step of the whole HIV maturation process.

If we can stop the protease HIV during the maturation process, we will prevent viral particles, or virions, from reaching maturity and, therefore, from becoming infectious.

One of the unusual aspects of this work is that it has been done using GPUGRID.net, a voluntary distributed computing platform that uses Nvidia GPUs of house hold computers made available by the public for research purposes, which is akin to having access to a virtual supercomputer. One of its benefits is that it provides access to computing power that is around 10 times that generated by ordinary computers. It also reduces research costs accordingly.

Researchers use this computing power to process large numbers of data and generate highly complex molecular simulations. In this specific case, thousands of computer simulations have been carried out, each for hundreds of nanoseconds (billionths of a second) for a total of almost a millisecond.

According to researchers, this discovery in the HIV maturation process provides an alternative approach in the design of future pharmaceutical products based on the use of these new molecular mechanisms. For now, this work provides a greater understanding of a crucial step in the life cycle of HIV, a virus that directly attacks the defences of our organism, weakening the immune system and making it vulnerable to a wide range of infections, and which affects millions of people around the world.

Reference:

"Kinetic characterization of the critical step in HIV-1 protease maturation". S Kashif Sadiq, Frank Noe and Gianni De Fabritiis. PNAS. DOI:10.1073/pnas.1210983109.