Simulating the inner life of an HIV virus

It took two years and two Supercomputers to simulate 1.2 microseconds in the life of an HIV capsid from the atoms up.

https://cosmosmagazine.com/biology/simulating-the-inner-life-of-an-hiv-virus

This Animal’s Immune System Holds the Clue for an HIV Vaccine, According to Science
http://www.rd.com/health/healthcare/possible-cure-for-hiv-cows/

NIH HIV/AIDS Network Refinement Update: Focusing the Science-Driven HIV Research Enterprise

Every seven years, NIH competitively renews its funding of the HIV/AIDS research networks operating in the United States and internationally. NIAID Division of AIDS Director Dr. Carl Dieffenbach describes how NIH can most effectively refine the HIV research enterprise to hasten an end to the pandemic.

The NIH HIV research agenda is grounded in three key areas, non-vaccine prevention, vaccines, and therapeutics. Dr. Dieffenbach lays out initial plans to create three clinical trials networks, one to address each of these disciplines, with strong cross-network collaboration and partnership for innovation.

https://www.niaid.nih.gov/research/focusing-s...n-hiv-research-enterprise

Researchers have solved the last unknown protein structure of HIV-1, the retrovirus that can cause AIDS. Knowledge of this structure, called the cytoplasmic tail of gp41 protein, will help researchers further understand how the virus infects human cells and how progeny viruses are assembled and released from infected cells. The cytoplasmic tail appears to play a key role in virus assembly to help incorporate the envelope spike structures into the surface of viral particles. "If we are able to inhibit incorporation of the envelope protein, we inhibit viral replication," Saad said. "This would disarm the virus and prevent disease. The cytoplasmic tail is a critical component of infectivity."

Instead of intact product, a bacterial enzyme was cutting the protein during protein expression. "We have never seen this for any other protein," Saad said. The researchers found that they had to limit protein expression to just two hours. Even then, 70 percent of the cytoplasmic tail was cut and only 30 percent was left intact. They found that the N-terminal end of the cytoplasmic tail of gp41, measuring 45 amino acid residues, lacked a regular secondary structure and was not associated with the membrane, which wraps around an HIV-1 viral particle like the leather cover of a baseball. The C-terminal end of the cytoplasmic tail of gp41, measuring 105 amino acid residues, was tightly associated to the membrane and had three alpha-helixes with portions that were hydrophobic and portions that were hydrophilic. The UAB group also showed the preferred topology of the cytoplasmic tail when bound to the membrane.

Saad says the structure opens up whole new areas of research: How the cytoplasmic tail stabilizes the envelope protein structure, how it affects membrane mobility of the envelope protein structure, and how it helps coordinate membrane-binding and the association of 2,000 HIV-1 Gag polyproteins underneath the membrane surface. The Gag polyproteins are later cut inside the maturing virus to form multiple smaller matrix, capsid and nucleocapsid proteins that produce the condensed viral core.

Saad says knowledge of the gp41 cytoplasmic tail structure will also open comparative studies of 10 different retroviruses that have similar tails to learn why some tails are shorter and some tails are longer. "The cytoplasmic tail of gp41 has been of interest for a long time, and nobody understands how it functions in infection or how it helps incorporate the envelope protein into the membrane," Saad said.

https://www.sciencedaily.com/releases/2017/10/171019123742.htm

New algorithm speeds up protein folding simulations

Conventional simulations, using molecular dynamics and Monte Carlo methods, have been successful overall at modeling biological molecules like proteins. To determine how proteins fold, the simulation searches for configurations that correspond to lower and lower energy states. Eventually, it finds the lowest energy state, which gives a stable fold. But as the simulation searches, it may encounter a configuration with a slightly higher energy, which forms a barrier that impedes the algorithm. As a result of these slowdowns, conventional methods can only simulate molecular behaviors occurring over short time scales of a few hundred microseconds. Many phenomena, such as certain protein folds or a drug binding to a potential target, happen over the course of a few seconds, minutes or even days. Simulating such long timescales would take too much computation time with just conventional approaches.

To speed up the simulations, researchers can inject energy into the system, which pushes the model over any energy barriers. But one of the biggest challenges to these methods is in defining the coordinates that describe the system -- which, for example, can be the length between atoms in the molecule, and the angles between bonds. Traditionally, researchers define the coordinates before they start the simulation. Every time step along each coordinate depends on the previous step. But this dependency can bias the simulation. Peter's new algorithm avoids this bias. He found a generalized coordinate system in which each time step doesn't rely on the previous step. "Only few parameters are needed, and no human intuition is required, which can potentially bias the simulation result," he said.

https://www.sciencedaily.com/releases/2017/12/171205120032.htm