From FAAH at WCG: “FightAIDS@Home Targeting a Key HIV Protein”

FightAIDS@home

By: The FightAIDS@Home research team
15 Jun 2017

Summary
FightAIDS@Home researchers restarted the first phase of the project at the end of 2016, and in just a few months, they have completed approximately 46 percent of their projected work on World Community Grid. Read about their progress on finding compounds that could stop HIV from replicating.

Background

FightAIDS@Home is searching for possible compounds to target the protein shell of HIV (called a capsid), which protects the virus. Currently, there are no approved drugs that target this protein shell.

The virtual docking techniques used in Phase 1 are an approximation of the potential effectiveness of promising compounds. Phase 2 of FightAIDS@Home uses a different simulation method to double-check and further refine the virtual screening results that are generated in Phase 1.

The research team is examining a library of approximately 1.6 million commercially available compounds to find promising treatment prospects. The team estimates that they will need to carry out roughly 621 million docking computations on World Community Grid to thoroughly test each potential compound. With the help of many volunteers who are supporting this project, they’ve already completed 46 percent of their goal.

You can keep up with the research team’s progress on their website, which includes frequent updates on their experiments and progress.

Please read below for a detailed look at the technical aspects of their recent work.

Insilico search for novel drugs targeting the HIV-1 mature capsid protein

The importance of the capsid protein

The capsid protein (CA) plays crucial roles in the HIV replication cycle1. After viral and host cell membrane fusion, the capsid core is released into the cytoplasm. This core, which corresponds to the assembly of ~1200 capsid proteins, contains and protects viral RNA and proteins from degradation. Reverse transcription occurs in the core in a process which is tightly connected to the capsid core disassembly. This leads to the import of the cDNA viral genome into the host cell’s nucleus, where it is integrated into the host DNA to finalize the infection.

To date, no drugs targeting CA are approved for clinical use. With the goal of identifying novel active molecules which destabilize the capsid core, we set up a high throughput virtual screening (VS) campaign in collaboration with World Community Grid as part of the FightAIDS@Home (FA@H) project.

Figure 1: PDB 4xfx, the hexamer structure of the native HIV-1 mature capsid protein. (Credit: Pierrick Craveur)

Targeted structures

The main target of the docking calculations was the recently solved structure of the CA hexameric assembly2. Four pockets of interest were selected at the surface of the hexamer in order to perform focused dockings, mainly at the CA-CA dimer interfaces. Structural variability surrounding these pockets was analyzed by comparing this X-ray structure from the PDB (4xfx, see Figure 1), and the two full capsid core models assembled by Schulten’s lab3 (3j3q and 3j3y, see Figure 2). Based on that, 36 different conformations were selected as targets for the VS, including the X-ray structure and structures from the models. Each target was set as full rigid and also with a specific combination of residue side chains defined as flexible.

Figure 2: The 2 models of the capsid core assembly. (Credit: Pierrick Craveur)

An extended library of ~1.6 million commercially available compounds was used for the screening. Replicate computations were performed for each docking experiment in order to assess the consistency of the results. In total ~621 million docking computations will be performed on World Community Grid. For the time being, ~46% of the computation is completed, with an ending date estimated at the end of 2017 if the computation does not increase in speed. However, in one month we will be able to propose to our collaborators from the HIVE Center a selection of compounds (focusing one of the four pockets) for experimental binding and infectivity assays.

Other information

Dedicated web pages (see http://fightaidsathome.scripps.edu/Capsid/index.html) were developed to inform the public and the World Community Grid volunteers as the project advances. The pages contain an overview of the project, details on targets and the selection process, a description of the compound library, an hourly updated status of the computations, and a “people” section where volunteers can appear in the page to be fully part of the project.

An automatic pipeline has been developed in order to constantly post-process the docking results received from World Community Grid. These post computations involve the High Performance Computing (HPC) cluster from The Scripps Research Institute, and are mainly related to the identification of the interactions between drug candidates and the CA protein. The pipeline ends in filling a MySQL database, which will be made public as soon as it will be stable. In details, 3.3TB of compressed data are estimated to be received from World Community Grid, and 1TB to be generated after post-processing.

Our team from The Scripps Research Institute of San Diego, which includes Dr. Pierrick Craveur, Dr. Stefano Forli, and Prof. Arthur Olson, really appreciates the essential support this project receives from World Community Grid volunteers around the globe.

References [Sorry, no links]

Campbell, E. M. & Hope, T. J. HIV-1 capsid: the multifaceted key player in HIV-1 infection. Nat Rev Microbiol 13, 471-483, doi:10.1038/nrmicro3503 (2015).
PDB 4xfx : Gres AT, Kirby KA, KewalRamani VN, Tanner JJ, Pornillos O, Sarafianos SG. X-Ray Structures of Native HIV-1 Capsid Protein Reveal Conformational Variability. Science (New York, NY). 2015;349(6243):99-103.
PDB 3j3q & 3j3y : Zhao G, Perilla JR, Yufenyuy EL, et al. Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics. Nature. 2013;497(7451):643-646.

See the full article here.

Please help promote STEM in your local schools.

Stem Education Coalition

FightAIDS@Home is a project run by the Olson Laboratory that uses distributed computing to contribute your computer’s idle resources to accelerate research into new drug therapies for HIV, the virus that causes AIDS. FightAIDS@Home made history in September 2000 when it became the first biomedical Internet-based grid computing project. FightAIDS@Home was started with Scott Kurowski, founder of Entropia. People all around the World continue to donate their home computer’s idle cycles to running our AutoDock software on HIV-1 protease inhibitor docking problems. With the generous assistance of IBM, we joined World Community Grid in late 2005, and launched FightAIDS@Home on World Community Grid on 21 November, 2005.

How do I join the FightAIDS@Home Project?

All you need to do is download and install the free client software. Once you have done this, your computer is then automatically put to work and you can continue using your computer as usual.

From FAAH at WCG: “Virtual Screening of the HIV-1 Mature Capsid Protein”

World Community Grid (WCG)

This webpage is dedicated to the virtual screening of the HIV-1 capsid protein in her mature form. This project is part of the HIVE Center and the FA@H initiative in collaboration with IBM and their World Community Grid (WCG).

People involved in the project come from the Olson Lab in The Scripps Research Institute, and from all over the world as volunteers of the WCG. Meet them here.

For any question about the project or this webpage, please contact
Dr. Pierrick Craveur : pcraveur@scripps.edu

Background

During the maturation of the HIV virus, the HIV-1 capsid protein (CA) assembles with thousands of copies to forms the capsid core [ref 1] with a characteristic conical shape (see Figure 1 and Figure 2C). This core encloses the RNA viral genome. Upon the entry of the HIV in host cells, the capsid core is released into the cytoplasm, and it dissociates in connection with the reverse transcription in a not completely understood process. This leads to the importation of DNA viral genome in the host cell’s nucleus, where it is integrated in the host DNA to finalize the infection.

Figure 1: The early phase of the HIV-1 replication cycle.
(credit: Nature Reviews Microbiology 13, 471–483 (2015) | doi:10.1038/nrmicro3503)

The critical role of CA protein, in early and late stages of the viral replication life cycle, has led to recent efforts on drug development, targeting the mature form of the protein. Currently, none of these molecules are used in clinic, and some face natural polymorphism and resistant mutations [ref 2]. Therefore, continued development of drugs targeting the CA protein is still needed.

The critical role of CA protein, in early and late stages of the viral replication life cycle, has led to recent efforts on drug development, targeting the mature form of the protein. Currently, none of these molecules are used in clinic, and some face natural polymorphism and resistant mutations [ref 2]. Therefore, continued development of drugs targeting the CA protein is still needed.

Figure 2: The HIV-1 mature capsid assembly.
(credit: Pierrick Craveur)

Different level of the capsid protein structure

CA protein consist of a sequence of 231 amino acids which folds into 3 different domains (Figure 2A): The N-terminal domain (N-ter), the linker, and the C-terminal domain (C-ter). This protein chain complexes with other chains to form hexamers (Figure 2B) or pentamers; which assemble together to form the fullerene-cone shape of the capsid core (Figure 2C). There are several models of the core assembly, but all are composed of ~200 hexamers, and exactly 12 pentamers.

High Throughput Virtual Screening

The FightAIDS@Home team is working with World Community Grid to find active compounds which could attach to the CA proteins and mediate the assembly of the capsid core. This computational experiment will be performed using the docking software AutoDock VINA [ref 3].
Thanks to the volunteers, around 2 million molecules will be screened across ~50 conformations of the capsid protein, and hopefully lead to a reduced selection of molecules. This will be the starting point of a drug discovery process targeting the HIV-1 capsid protein.
This computational experiment will be performed using the docking software AutoDock VINA [ref 3].
With the support of our collaborators from the HIV Interaction and Viral Evolution (HIVE), experimental biding assays and infectivity assays will be conducted to determine if the selected compounds could be optimized as a promising drug candidate.

Figure 3: The four pockets of interest.
(credit: Pierrick Craveur)

Four pockets of interest

Based on X-ray structures of CA protein, models of the core, and computational analysis of their flexibility, four pockets of interest have been selected on the surface of the hexamer assembly (see Figure 3).
These pockets involve either one monomer (as pocket 2 along the linker domain), at the interface of two monomers (pocket 1 & 4), or at the six-fold interface (pocket 3).
Mutagenesis experiments revealed that core stability is fine-tuned to allow ordered disassembly during early stage of virus replication cycle [ref 4]. This is why selection of compounds will be done either for molecules which could stabilize or destabilize the hexamer; assuming that both actions could have impacts on the equilibrium of the core.

References

Briggs, J. A. and H. G. Krausslich (2011). “The molecular architecture of HIV.” J Mol Biol 410(4): 491-500.
Thenin-Houssier, S. and S. T. Valente (2016). “HIV-1 Capsid Inhibitors as Antiretroviral Agents.” Curr HIV Res 14(3): 270-282.
Trott, O. and A. J. Olson (2010). “AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.” J Comput Chem 31(2): 455-461.
Forshey, B. M., U. von Schwedler, et al. (2002). “Formation of a human immunodeficiency virus type 1 core of optimal stability is crucial for viral replication.” J Virol 76(11): 5667-5677.

See the full article here.

Please help promote STEM in your local schools.

Stem Education Coalition

“World Community Grid (WCG) brings people together from across the globe to create the largest non-profit computing grid benefiting humanity. It does this by pooling surplus computer processing power. We believe that innovation combined with visionary scientific research and large-scale volunteerism can help make the planet smarter. Our success depends on like-minded individuals – like you.”
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