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  • richardmitnick 1:19 pm on July 7, 2017 Permalink | Reply
    Tags: , FAAH@home Phase II, , The Olson Laboratory,   

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

    FAAH
    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.

    1
    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.

    2
    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.

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    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.

     
  • richardmitnick 8:00 am on October 1, 2016 Permalink | Reply
    Tags: , , FAAH@home Phase II, ,   

    From FightAIDS@ WCG: “FightAIDS@Home Team Expands Techniques, Refines Phase 1 Results, and Collaborates on a New Study” 

    New WCG Logo

    WCGLarge

    World Community Grid (WCG)

    30 Sep 2016
    By: The FightAIDS@Home research team

    Summary
    The FightAIDS@Home team is working with the World Community Grid technical team to create a new sampling protocol, which will more closely predict the binding strengths of potential drugs to their HIV protein targets as determined in real-life experiments. Read about this work, and other news, in this extensive update.

    1
    (Left to right) World Community Grid program manager Juan Hindo with some of the members of the Ron Levy group at Temple University: Ron Levy, Bill Flynn, Junchao Xia, Peng He, Nanjie Deng

    Creating a New Sampling Protocol

    Background

    The simulations running under FightAIDS@Home – Phase 2 have been using two new simulation methods (independent sampling and lambda scheduling) that we tailored for the unique computing environment of World Community Grid.

    faah-phase-ii

    While volunteers have been crunching away, we have been diligently analyzing the results returned to us to determine whether these new protocols are sufficient to both meet our scientific goals and provide the volunteers with efficient, worthwhile computing tasks. The results for the first 106 batches show qualitative agreement with prior benchmarks run on high-performance computing clusters, but some results demonstrate the new simulation protocols are not satisfactory for all types of analysis.

    With the support of our collaborators at the HIV Interaction and Viral Evolution Center (HIVE) and the World Community Grid team, we have been working closely with the World Community Grid software developers to implement a more rigorous simulation scheme that closely mimics the more algorithmically efficient simulations run on non-grid computing resources.

    faah-hive
    Scripps/HIVE

    This new sampling protocol is called asynchronous replica exchange.

    How Asynchronous Replica Exchange Works

    Our Current Process: Currently, multiple copies of a protein-ligand complex (the structure consisting of a drug candidate compound docked with a protein receptor) are sent out to many volunteers and are simulated with no interaction with one another. The collective information from all those simulations are combined during analysis at the very end.

    The New Process: Asynchronous replica exchange allows information from the different copies to be shared and exchanged among all copies dynamically after short periods of simulations, and this process yields the correct equilibrium statistical physics needed for our analysis.

    Benefits of the New Process: Replica exchange drastically increases the efficiency of the computations. This means that, in addition to being more valuable in terms of analysis, (a) future work units will have shorter runtimes, making Phase 2 computations accessible to more volunteers; (b) the number of batches running simultaneously can be increased; and (c) each batch will have shorter total simulation times.

    This new technique was first prototyped and then put to use on our local BOINC-powered grid at Temple University. Now, the World Community Grid software developers are working hard to implement the same technique on the World Community Grid platform. This effort would allow the largest replica exchange simulations (by two orders of magnitude) ever performed, and we anticipate testing to begin in the next few weeks. In the meantime, we will continue to run and extract valuable information from simulations using our current algorithms.

    For more information about this work, see these two articles:

    http://onlinelibrary.wiley.com/doi/10.1002/jcc.23996/abstract

    http://www.sciencedirect.com/science/article/pii/S0010465515002556

    Refining Results from FightAIDS@Home – Phase 1

    We are moving away from benchmarking simulations, and we are working closely with our collaborators and long-time FightAIDS@Home – Phase 1 research scientists at The Scripps Research Institute to collect the best hits from the many virtual screens performed over the last decade. We are in the process of preparing the input files for the top candidates from over 35 million compounds screened in Phase 1 from the ZINC library, a free database of commercially available compounds for virtual screening. Over the next set of batches, volunteers can expect to see research tasks that are geared toward refining the Phase 1 results.

    FAAH

    New Study on Computational Modeling of HIV

    3
    Figure: (Left) ALLINI KF116 (green) bound at the interface of two Catalytic Core Domain (CCD) subunits of HIV-integrase. (Right) ALLINI-2 (green) facilitating interactions between the CCD dimer and the C-Terminal Domain (CTD) of another HIV integrase molecule. Due to the presence of the ALLINI, the interaction between the CTD of one Integrase dimer and the CCD-CCD interface of another Integrase dimer is stabilized; chains of these inter-subunit interactions lead to aggregates.

    An exciting study regarding computational modeling of HIV has come out of a collaboration with our lab and experimentalists at the HIVE Center.

    HIV Integrase is a viral protein which plays a critical role in the replication of the HIV virus. A class of compounds, called allosteric Integrase inhibitors, or ALLINIs, has a unique inhibition mechanism targeting HIV Integrase. ALLINIs act like a glue that causes many Integrase molecules to become tangled together and make it difficult for them to complete their normal job, which is to incorporate HIV viral DNA into the cell’s own DNA.

    Research scientist Nanjie Deng, an associate research professor with the Ron Levy Group at Temple University, has demonstrated with molecular dynamics simulations of HIV Integrase dimers how this process, which is called multimerization, is promoted by the ALLINIs. Deng’s predictions appear to be confirmed by a high resolution crystal structure which will be available later this year. An accelerated publication of his work can be found here.

    We appreciate the support this project has received from World Community Grid volunteers around the globe.

    See the full article here.

    Please help promote STEM in your local schools.
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    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.”
    WCG projects run on BOINC software from UC Berkeley.
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    BOINC is a leader in the field(s) of Distributed Computing, Grid Computing and Citizen Cyberscience.BOINC is more properly the Berkeley Open Infrastructure for Network Computing.

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    CAN ONE PERSON MAKE A DIFFERENCE? YOU BET!!

    MyBOINC

    “Download and install secure, free software that captures your computer’s spare power when it is on, but idle. You will then be a World Community Grid volunteer. It’s that simple!” You can download the software at either WCG or BOINC.

    Please visit the project pages-

    FightAIDS@home Phase II

    FAAH Phase II
    OpenZika

    Rutgers Open Zika

    Help Stop TB
    WCG Help Stop TB
    Outsmart Ebola together

    Outsmart Ebola Together

    Mapping Cancer Markers
    mappingcancermarkers2

    Uncovering Genome Mysteries
    Uncovering Genome Mysteries

    Say No to Schistosoma

    GO Fight Against Malaria

    Drug Search for Leishmaniasis

    Computing for Clean Water

    The Clean Energy Project

    Discovering Dengue Drugs – Together

    Help Cure Muscular Dystrophy

    Help Fight Childhood Cancer

    Help Conquer Cancer

    Human Proteome Folding

    FightAIDS@Home

    World Community Grid is a social initiative of IBM Corporation
    IBM Corporation
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    IBM – Smarter Planet
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  • richardmitnick 1:26 pm on September 13, 2016 Permalink | Reply
    Tags: , FAAH@home Phase II, , ,   

    From Scripps: “TSRI Scientists Discover Antibodies that Target Holes in HIV’s Defenses” 

    Scripps
    Scripps Research Institute

    September 12, 2016

    New Findings Could Lead to New AIDS Vaccine Candidates

    A new study from scientists at The Scripps Research Institute (TSRI) shows that “holes” in HIV’s defensive sugar shield could be important in designing an HIV vaccine.

    It appears that antibodies can target these holes, which are scattered in HIV’s protective sugar or “glycan” shield, and the question is now whether these holes can be exploited to induce protective antibodies.

    “It’s important now to evaluate future vaccine candidates to more rapidly understand the immune response they induce to particular glycan holes and learn from it,” said TSRI Professor Dennis R. Burton, who is also scientific director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center and of the National Institutes of Health’s Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) at TSRI.

    The study, published recently in the journal Cell Reports, was co-led by Burton, TSRI Associate Professor Andrew Ward, also of CHAVI-ID, and Rogier W. Sanders of the University of Amsterdam and Cornell University.

    A Clue to Stopping HIV

    Every virus has a signature structure, like the architecture of a building. By solving these structures, scientists can put together a blueprint showing where HIV is vulnerable to infection-blocking antibodies.

    In the 1990s, scientists discovered that HIV can have random holes in its protective outer shell of glycan molecules. Until now, however, scientists weren’t sure if antibodies could recognize and target these holes.

    Researchers at Cornell and TSRI had previously designed a stabilized version of an important HIV protein, called the envelope glycoprotein (Env) trimer, to prompt rabbit models to produce antibodies against the virus. In the new study, the plan was to reveal HIV’s vulnerabilities by examining where the antibodies bound the virus.

    “From work on HIV-positive individuals, we knew that the best way to understand an antibody response is to isolate the individual antibodies and study them in detail,” said Laura McCoy, a TSRI, IAVI and CHAVI-ID researcher now at University College London, who served as co-first author of the study with TSRI Senior Research Associate Gabriel Ozorowski, also of TSRI and CHAVI-ID, and Marit J. van Gils of the University of Amsterdam.

    To their surprise, when the researchers examined the rabbits’ antibodies, they found three rabbits had produced antibodies that targeted the same hole in Env. It appeared that antibodies could indeed target holes in the glycan shield.

    “This opened up a whole new concept,” said Ozorowski.

    If the immune system was targeting this hole—preferring it to other vulnerable spots on Env—maybe holes would be especially important in designing vaccine candidates.

    Toward Better Antibodies

    By analyzing the genetic sequences of thousands of strains of HIV, the researchers found that 89 percent of strains appear to have a targetable hole in the Env. The virus has a defense mechanism though—it quickly mutates to fill in these gaps.

    The researchers speculate that future vaccines might prompt the immune system to create antibodies to target holes. “Targeting a hole could help the immune system get its foot in the door,” Ozorowski said. Alternatively, the holes may prove a distraction and should be filled in so the immune system can focus on targeting better sites for neutralizing the virus.

    Burton said researchers must investigate the different possibilities, but he emphasized that this new understanding of glycan holes could help researchers narrow down the field of molecules needed in potential HIV vaccines.

    Ward added that this same method of “rational” vaccine design—where researchers use a virus’s precise molecular details to prompt the immune system to produce specific antibodies—can also be applied to efforts to fight other viruses, such as influenza and Ebola viruses.

    In addition to Burton, Ward, Sanders, McCoy, Ozorowski and van Gils, authors of the study, “Holes in the glycan shield of the native HIV envelope are a target of trimer-elicited neutralizing antibodies,” were Terrence Messmer, Bryan Briney, James E. Voss, Daniel W. Kulp, Devin Sok, Matthias Pauthner, Sergey Menis and Jessica Hsueh of TSRI, IAVI and CHAVI-ID; Christopher A. Cottrell, Jonathan L. Torres and Ian A. Wilson of TSRI and CHAVI-ID; Matthew S. Macauley of TSRI; and William R. Schief of TSRI, IAVI, CHAVI-ID and the Ragon Institute.

    This study was supported by CHAVI-ID (grant UM1AI100663), the National Institutes of Health’s HIV Vaccine Research and Design (HIVRAD) Program (grant P01 AI110657), the IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD, grants OPP1084519 and OPP1115782), a Marie-Curie Fellowship (FP7-PEOPLE-2013-IOF), the Aids Fonds Netherlands (grant 2012041), EMBO (grant ASTF260-2013), the Netherlands Organization for Scientific Research (grant 917.11.314) and the European Research Council (grant ERC-StG- 2011-280829-SHEV).

    See the full article here .

    YOU CAN HELP IN THE FIGHT AGAINST HIV/AIDS FROM THE COMFORT OF YOUR EASY CHAIR.

    The Fight AIDS at home (FAAH@home) Phase II project is now running at World Community Grid (WCG) From Scripps Research Institute.

    Scripps

    FAAH Phase II

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the FAAH@home Phase II project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

    WCGLarge

    BOINCLarge

    MyBOINC

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 12:39 pm on September 9, 2016 Permalink | Reply
    Tags: , FAAH@home Phase II, , ,   

    From Scripps: “Team Harnesses Antibody Evolution on the Path to an AIDS Vaccine” 

    Scripps
    Scripps Research Institute

    September 12, 2016
    Madeline McCurry-Schmidt

    1
    The new work shows the immune system can be prompted to mimic and accelerate a rare natural process during which antibodies slowly evolve to become better and better at targeting the constantly mutating HIV virus. Shown here is the molecule eOD-GT8 60mer, used in the team’s reductionist strategy.

    A series of new studies led by scientists at The Scripps Research Institute (TSRI) and the International AIDS Vaccine Initiative (IAVI) describe a potential vaccination strategy to jump-start the selection and evolution of broadly effective antibodies to prevent HIV infection. The researchers plan to test this strategy in an upcoming human clinical trial.

    The new studies, published September 8, 2016, in the journals Cell and Science, showed the immune system can be prompted to mimic and accelerate a rare natural process during which antibodies slowly evolve to become better and better at targeting the constantly mutating HIV virus.

    “Although we still have a long way to go, we’re making really good progress toward a human vaccine,” said William Schief, professor at TSRI and director of vaccine design for IAVI’s Neutralizing Antibody Center (NAC) at TSRI, whose lab developed many of the vaccine proteins tested in these studies.

    Schief co-led several of the new studies with TSRI Professor David Nemazee; Dennis Burton, James & Jessie Minor chair of the TSRI Department of Immunology and Microbial Science and scientific director of the IAVI NAC and the National Institutes of Health (NIH) Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID); and Ian Wilson, Hansen Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI.

    Developing a Blueprint

    A vaccine needs to elicit those rare antibodies, called “broadly neutralizing antibodies” (bnAbs), which fight a wide variety of strains of HIV—and it needs to elicit them quickly.

    One strategy to accomplish this, which scientists at TSRI have dubbed the “reductionist” strategy, is to find which antibody mutations are most important for making them effective against HIV, then to “prime” the immune system to start making antibody precursors. From there, scientists hope to prompt one important mutation after another with a series of different “booster” shots, deliberately building up a bnAb one step at a time.

    In a recent study in the journal PLOS Pathogens, the scientists created 3D maps of a structure on HIV known as the CD4 binding site. If antibodies successfully attack this site, scientists believe, most strains of HIV could be crippled. The researchers also created high-resolution maps of bnAbs that could bind to the CD4 binding site.

    “This is one of the most complete blueprints we’ve had for this target,” said Jean-Philippe Julien, a research associate in Wilson’s lab at the time of the study, who served as co-first author of the study with TSRI Research Associate Joseph Jardine, IAVI Research Scientist Devin Sok and Bryan Briney, assistant professor of immunology at TSRI.

    The scientists then studied stripped-down versions of the bnAbs to see exactly which components were important in targeting the CD4 binding site.

    With the results from the PLOS Pathogens study, the researchers finally had a guide to which mutations were the most important. They also had a better idea of which antibody-eliciting molecules, called immunogens, could be given in booster shots to trigger the right mutations at the right time.

    “We’re figuring how to boost antibodies to the next step—how to keep walking them along the path to increased breadth and potency after we get them started with a priming shot,” said Jardine.

    Training Promising Antibodies

    This finding set the stage for the three new studies. For the first one, published in Cell, researchers tested a priming immunogen, followed by a series of booster immunogens from the Schief lab. The immunogens were tested in a mouse model, developed by the Nemazee lab, which was engineered to have the genes (the raw materials) to make antibodies with the right mutations to target the CD4 binding site.

    The team found that the elicited antibodies more closely resembled mature antibodies. The sequence of immunogens had done their job.

    “The study showed that the immunogens are working,” said Nemazee. “They mutate the antibody-producing B cells in the right direction.”

    “The elicited antibodies share many genetic features with mature bnAbs and have the ability to neutralize one native HIV isolate as well as multiple other HIV isolates that we modified slightly to make them easier to neutralize,” added Briney, who served as first author of the study with Sok, Jardine, IAVI and TSRI Staff Scientist Daniel Kulp and TSRI Research Assistant Patrick Skog. “We will probably need additional booster immunogens to elicit antibodies that can broadly neutralize native HIV isolates, but our results suggest we are on the right track.”

    In the second Cell study, led by John R. Mascola at the NIH’s National Institute of Allergy and Infectious Disease (NIAID) Vaccine Research Center and Frederick W. Alt, a Howard Hughes Medical Institute (HHMI) researcher at Boston Children’s Hospital and Harvard Medical School, along with TSRI co-authors, took the reductionist approach a step further, showing that it could induce antibodies in mouse models with immune systems that can create an even wider range of antibodies—more similar to the human immune system.

    Results from the Science study further supported the reductionist vaccine approach. For the study, the researchers took on an even bigger challenge—to “prime” antibodies in a mouse model with a human-like immune system developed by Kymab Ltd, a UK-based company.

    The Kymab mouse model’s more complicated immune system made it more difficult for a vaccine protein to find and activate the “precursor” cells that have potential to produce bnAbs against the CD4 binding site. In fact, the researchers estimated that each Kymab mouse contained only one such precursor cell on average—with some mice containing none—among approximately 75 million antibody-producing cells.

    Despite this “needle-in-a-haystack” challenge, scientists found that their vaccine priming protein activated the appropriate antibody precursors in one-third to one-half of mice tested, suggesting this feat would also be possible in humans, where the targeted precursor cells are more plentiful. “This seems to be a much higher bar than we will face in humans,” Schief said.

    “The reductionist vaccine approach we’re undertaking will hopefully not only lead to an HIV vaccine, but also could potentially be applied to other challenging vaccine targets,” said Sok, who served as co-first author of the Science study with Briney, Jardine and Kulp.

    The researchers also gave credit to their strong international collaboration. “Our phenomenal results with the team at The Scripps Research Institute came from work at the interfaces—and boundaries—of vaccine technology, immunology, protein engineering and structural biology,” said Professor Allan Bradley, chief technical officer at Kymab and director emeritus of the Wellcome Trust Sanger Institute.

    IAVI and partners are planning for a clinical trial for next year to further develop and test whether the reductionist vaccine strategy—starting with activating the right precursors—will work in humans. If successful, the next step will be to test their booster immunogens.

    The first Cell study, Tailored Immunogens Direct Affinity Maturation Toward HIV Neutralizing Antibodies, included additional authors from the Ragon Institute. The study was supported by the IAVI through the NAC (grant SFP1849); NIAID grants; CHAVI-ID (grants UM1AI100663, P01AI081625 and R01AI073148); the Ragon Institute; and the Helen Hay Whitney Foundation.

    The second Cell study, Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires, included additional authors from HHMI; Boston Children’s Hospital; Harvard Medical School; the NIH’s NIAID Vaccine Research Center; Vanderbilt University; Columbia University; the Ragon Institute; Fred Hutchinson Cancer Center and the Duke University School of Medicine. This work was supported by the NIH (grants R01AI077595, AI020047, P01 AI094419, U19AI109632, P01-AI104722; CHAVI-ID (grants 5UM1 AI100645 and 1UM1 AI100663); the intramural research program of the NIAID Vaccine Research Center; the IAVI NAC Center; Collaboration for AIDS Vaccine Discovery funding for the IAVI NAC Center; the Ragon Institute and an HHMI Medical Student Fellowship.

    The Science study, Priming HIV-1 Broadly Neutralizing Antibody Precursors in Human Ig Loci Transgenic Mice, included additional authors from Kymab Ltd, the Wellcome Trust Sanger Institute and the Ragon Institute. The study was supported by IAVI, with the generous support of the United States Agency for International Development (USAID); Ministry of Foreign Affairs of the Netherlands; the Bill & Melinda Gates Foundation; the Ragon Institute; the Helen Hay Whitney Foundation; and NIAID (grants P01 AI094419 and CHAVI-ID 1UM1AI100663).

    See also additional Cell and Immunity studies on HIV/AIDS vaccine work led by TSRI scientists and published on September 8.

    See the full article here .

    YOU CAN HELP IN THE FIGHT AGAINST HIV/AIDS FROM THE COMFORT OF YOUR EASY CHAIR.

    The Fight AIDS at home (FAAH@home) Phase II project is now running at World Community Grid (WCG)

    FAAH Phase II

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the FAAH@home Phase II project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

    WCGLarge
    WCG Logo New

    BOINCLarge
    BOINC WallPaper

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 4:35 pm on July 25, 2016 Permalink | Reply
    Tags: , FAAH@home Phase II, , ,   

    From Rockefeller: ” New antibody drug continues to show promise for treatment of HIV” 

    Rockefeller U bloc

    Rockefeller University

    July 25, 2016
    Katherine Fenz
    kfenz@rockefeller.edu
    212-327-7913

    1
    Halting HIV: Antibody treatment delayed the virus (above) from rebounding in patients taken off their anti-retroviral medications.

    Great strides have been made in recent years to develop treatment options for HIV, and the disease can now be controlled with anti-retroviral drugs. But a cure remains elusive and current medications have limitations: they must be taken daily, for life, and can cause long-term complications.

    Now, Rockefeller scientists report that they are one step closer to an alternative treatment that utilizes antibodies. This therapy has the potential for long-acting effects and would allow for less frequent dosing.

    Recently published in Nature, the findings suggest that an antibody called 3BNC117 can effectively delay the virus from rebounding in patients who temporarily suspended their anti-retroviral medications, currently the standard treatment for HIV.

    “These are very positive results,” says Marina Caskey, Assistant Professor of Clinical Investigation in the Laboratory of Molecular Immunology, headed by Michel Nussenzweig. “This is the longest any antibody has been able to delay virus rebound.”

    Keeping HIV at bay

    The 3BNC117 antibody was isolated in the Nussenzweig lab several years ago by guest investigator Johannes Scheid, co-first author of this most recent publication. It was cloned from cells of an HIV-infected patient whose immune system was able to fight HIV particularly well. The virus primarily infects CD4 T cells, part of the immune system that helps protect the body from infection. 3BNC117 stops multiple strains of HIV from hijacking these cells.

    Anti-retroviral drugs suppress HIV by preventing its replication, but the virus remains dormant in the body, mostly in reservoirs within CD4 cells. If a patient stops taking anti-retroviral drugs, the virus is released from these reservoirs, and quickly rebounds.

    This small study, called a Phase IIa clinical trial, builds on a previous study from the Nussenzweig lab, in which HIV-infected patients were given the antibody without receiving other treatment. This time, the researchers tested 13 HIV-infected patients who had been treated successfully with antiviral therapy. The goal of the study was to determine whether the antibody alone would be able to maintain virus suppression in patients that were taken off anti-retroviral drugs.

    Caskey and colleagues found that the antibody was able to delay when the virus came back to about 10 weeks, compared to about 3 weeks in controls.

    Virus under pressure

    One of the many challenges in treating HIV is that the virus quickly mutates. As a result, patients carry many different strains that cannot be eliminated with a single medication, and each person’s virus repertoire is different. An advantage of 3BNC117 is that is has the ability to fight a wide range of HIV strains, but not all; some studies suggest it can neutralize about 80 percent of viral isolates taken from patients.

    In this study, the researchers tried to select participants whose viral strains were likely to be a good target for 3BNC117. However, current testing methods are not very precise in predicting exactly which strains are present, and patients had varied responses.

    “In one-third of participants, rebound happened very late, when the antibody levels were low,” says co-first author and former graduate student in the Nussenzweig lab, Josh Horwitz. “This means that the antibody was effective at suppressing the viruses that are sensitive to it, but it’s also clear that for the remaining patients with different strains of HIV, this antibody is not sufficient.”

    The researchers also found that the antibody was able to reduce the assortment of viral strains that rebounded, which tends to be very diverse in patients taken off antiretroviral medications. “We were excited to see a significant delay in rebound,” says Sheid, “but the reduced diversity of viruses that we saw is also promising because it will take fewer additional antibodies to target them.”

    The next step will be to test 3BNC117 in combination with another HIV-specific antibody, such as 10-1074, which targets the virus from a different angle, and has also been shown to decrease virus levels when given to HIV patients not on treatment.

    “There are a lot of factors at play here, part of which is that we are working with a diverse reservoir of viruses with different sensitivities to different antibodies,” says Caskey. “However, we are hopeful that testing the antibodies in combination will be successful in bringing us closer to better strategies to prevent and treat HIV.”

    This study was supported by the Collaboration for AIDS Vaccine Discovery, the National Center for Advancing Translational Sciences, NIH Clinical and Translational Science Award program, NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, Bill and Melinda Gates Foundation, the Robertson Foundation, the Ruth L. Kirschstein National Research Service Award, and other sources.

    See the full article here .

    YOU CAN HELP IN THE FIGHT AGAINST HIV/AIDS FROM THE COMFORT OF YOUR EASY CHAIR.

    The Fight AIDS at home (FAAH@home) Phase II project is now running at World Community Grid (WCG)

    FAAH Phase II

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the FAAH@home Phase II project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

    WCGLarge
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    BOINCLarge
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    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Rockefeller U Campus

    The Rockefeller University is a world-renowned center for research and graduate education in the biomedical sciences, chemistry, bioinformatics and physics. The university’s 76 laboratories conduct both clinical and basic research and study a diverse range of biological and biomedical problems with the mission of improving the understanding of life for the benefit of humanity.

    Founded in 1901 by John D. Rockefeller, the Rockefeller Institute for Medical Research was the country’s first institution devoted exclusively to biomedical research. The Rockefeller University Hospital was founded in 1910 as the first hospital devoted exclusively to clinical research. In the 1950s, the institute expanded its mission to include graduate education and began training new generations of scientists to become research leaders around the world. In 1965, it was renamed The Rockefeller University.

     
  • richardmitnick 10:20 am on July 18, 2016 Permalink | Reply
    Tags: , FAAH@home Phase II,   

    From CNN: “HIV cure study provides insight into 2008 case” 

    1
    CNN

    July 18, 2016
    Meera Senthilingam

    In 2008, one man, Timothy Ray Brown, was cured of HIV.

    Also known as the “Berlin patient,” Brown was considered cured of his infection after receiving two bone-marrow transplants to treat a separate disease he had been diagnosed with a few years earlier: acute myeloid leukemia.

    The bone marrow he received came from a donor whose genes carried a rare mutation that made them resistant to HIV, known as CCR5-delta 32, which was transferred on to Brown.

    Traces of the virus were seen in his blood a few years later, but remained undetectable despite him not being on antiretroviral treatment, meaning he was still clinically cured of his infection, according to his clinicians.

    Despite various attempts on patients after him by scientists using this same approach, including a similar transplant in two Boston patients, Brown remains the only person known about who has been cured of HIV.

    But a new study presented Sunday at the 2016 Towards an HIV Cure Symposium — ahead of the 21st International AIDS conference in Durban, South Africa, this week — revealed data on a new set of HIV positive patients whose reservoirs of HIV have fallen to very low levels after receiving a range of stem cell transplants similar to Brown’s.

    The study is part of the EPISTEM project, a European project to investigate the potential for an HIV cure using stem cell transplantation, and provides further insight into the science underlying Brown’s success.
    Everyone included in the project is in need of stem cell transplantation to cure severe blood disorders, in addition to being infected with HIV.

    Can stem cells bear a cure?

    The 15 patients monitored in the study to date are still on antiretroviral treatment, unlike Brown, but have received stem cell transplants. Three of them had their operations three years ago and have been studied in detail since.
    “In two of the three patients we were unable to detect infectious virus in the blood of the patients,” said Annemarie Wensing, a virologist at the University Medical Center Utrecht who led the study. Tissue samples were also studied and one patient also had just traces of the virus hiding there.

    “All HIV-infected patients that received a stem cell transplantation had a significant reduction of the viral reservoir in their body. This has not been demonstrated with other cure strategies,” Wensing said.
    The minute levels of the virus that have been seen to date were not considered competent enough to replicate, according to the team.
    “[This] will help us shape future HIV eradication strategies that could be applied at a larger scale than stem cell transplantation,” said Wensing.

    But there’s a long road ahead.

    “What’s interesting is that these patients have survived more than a year,” said Sharon Lewin, director of the Peter Doherty Institute for Infection and Immunity and co-chairwoman of the symposium. “There was concern that maybe when you take a CCR5-delta32 bone marrow it doesn’t engraft as well, but these patients have survived to 12 months.”
    The next step will have to explore how they fare without treatment, Lewin added.

    How the transplant works

    The process of transferring resistance to HIV is extremely complicated — and rare.
    Firstly, only 1% of Caucasians are estimated to carry the CCR5-delta 32 mutation that confers resistance to HIV, with other races having even fewer numbers. The genetic change means people lack a protein needed by HIV to enter blood cells.

    The team also cannot be 100% sure whether the mutation is the only cause of the resistance to HIV or whether the many other stages of the transplant process play a role.

    These include the body being totally cleared of its immune system using chemotherapy and irradiation ahead of it being rebuilt by the donor stem cells, and the potential for the newly formed immune cells to attack any remaining old ones that may be harboring HIV. Patients can also have one or two transplants.

    “All those factors may be really important and we’re trying to tease it out,” said Monique Nijhuis, also from the Utrecht Medical Center who works on the project.

    The unique and rare nature of the blood disorders affecting the patients also means they receive different treatments rather than everyone receiving the same treatment for comparison.

    “Each person is like a micro-clinical trial in himself or herself,” said Asier Saez-Cirion from the Institut Pasteur, also involved in the project.

    What the team does know, however, is that monitoring these patients and the new participants being recruited globally will help them understand where the virus hides within the body — known as reservoirs — and the biology involved in clearing these reservoirs to leave levels of the virus undetectable.

    “We want to know the mechanisms behind HIV cure … to understand [what] is important for the decline in HIV and why there was a cure in the Berlin patient,” said Nijhuis. “This will give us a sense of biomarkers … for the HIV reservoirs and to predict what will happen after we stop treatment.”

    The main drawback, however, is the impracticality of applying this process to more than a handful of people and the resulting unlikelihood of it becoming a generic cure.

    In 2015, almost 37 million people were living with HIV, of which only 46% were receiving antiretroviral therapy, and 2,1 million were newly infected.

    Not feasible

    “It’s impractical to think we’re going to do that for millions of people,” said Anthony Fauci, director of the National Institute of Allergy and Infectious Disease. “It’s the practicality of saying what is better: a single or two pills a day, or getting chemotherapy, getting a stem cell transplant and then having chemotherapy for a period of time after you get the transplant versus just taking a drug,” he said.

    What Fauci instead feels may be more feasible, and scalable, is using this insight to inform future therapies that involve gene editing, where people may have the CCR5 gene edited out of their cells so HIV can no longer invade them.

    “It’s interesting science and what it might do is serve as the proof of concept that you can do gene editing of someone, as opposed to stem cell transplantation,” said Fauci. He highlighted the fact that the HIV community currently does not have enough budget to provide pills to everyone who needs them, let alone transplants.

    Saez-Cirion agreed. “Bone marrow transplant won’t be applied widely … it’s extremely complex,” he said.

    But with so few cases to date showing either a cure or remission, the EPISTEM team hopes its group of patients will at least provide data to build on the existing — and limited — body of evidence.

    Targeting remission instead

    Fauci does believe the possibility of HIV remission, where levels of HIV are brought down to undetectable levels when people are not taking antiretroviral drugs, is realistic, but by other means. He presented updates on the use of broadly neutralizing antibodies, which as their name suggests could neutralize HIV reservoirs hiding in cells, at the symposium.

    The consensus among HIV cure experts attending the conference was for remission to be the end goal — at least for now.

    “We should not give up on eradication … but I would put my major emphasis on sustained virological remission … to keep people suppressed as low as they can possible be.” Fauci said.

    Remission has been shown in other groups of patients, including one known as the VISCONTI cohort where 14 adults treated for HIV soon after infection stopped taking their drugs three years later and showed no resurgence in the amount of virus found in their blood. The group is considered to be post-treatment controllers of the virus.

    Last year a French teenager was also reported to have similar control, 12 years after stopping treatment. Both groups are monitored by Saez-Cirion’s team at the Institut Pasteur.

    “Remission will be the first step in any case,” said Saez-Cirion. “Then when we get more data on survival in this remission period and more sensitive techniques we can being to talk about a cure.

    See the full article here .

    YOU CAN HELP IN THE FIGHT AGAINST HIV/AIDS FROM THE COMFORT OF YOUR EASY CHAIR.

    The Fight AIDS at home (FAAH@home) Phase II project is now running at World Community Grid (WCG)

    FAAH Phase II

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the FAAH@home Phase II project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

    WCGLarge
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    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

     
  • richardmitnick 9:45 am on July 17, 2016 Permalink | Reply
    Tags: , FAAH@home Phase II, ,   

    From Science Alert: “Scientists just discovered where HIV began” 

    ScienceAlert

    Science Alert

    19 JUN 2016 [JUst now in social media]
    NEIL C. BHAVSAR, FUTURISM

    1
    R. Dourmashkin/Cell Image Library

    Birthplace of the disease that won’t die.

    Diseases, while disastrous, often come and go in the public eye. We hear about ebola, but then another one quickly grabs national monitors and TV screens for its fifteen minutes.

    However, one condition that seems to not fit into his norm is the Human Immunodeficiency Virus (HIV). The spread of HIV is a story that would have most television dramas pale in comparison – combining elements of intrigue, suspense, and mystery into one cohesive nightmare that has blanketed the globe since the 1920s.

    It all began in Kinshasha, the capital of the Democratic Republic of Congo. However, in the 1920s, it was better known as the Belgian colony of Leopoldville.

    A high profile location for young men to sojourn to in hopes of making a fortune, as it was the capital of Belgian Congo. Therefore, with them came railroads and sex workers. Two forms of transportation that respectively spread people and infection. With a flourishing location, HIV found many opportunities to grow into the pandemic it is today.

    The irony of it all is that HIV-1 group M, the type of HIV that originated in the colony, is responsible for about 90 percent of all infections, while HIV-1 group O, another type of HIV originating nearby is still quietly confined to West Africa. Thereby suggesting it may have been the opportunities, and not the function, of that disease that enabled it to roar globally.

    “Ecological rather than evolutionary factors drove its rapid spread,” says Nuno Faria at the University of Oxford in the UK, in an interview with the BBC.

    Faria and his colleagues were able to make this determination after they built a family tree of HIV by looking at a host of HIV genomes collected from about 800 infected people from central Africa.

    Notably, by comparing two genome sequences and counting the differences in them, the team was able to figure out when the two last shared a common ancestor.

    Ultimately, Faria determined that the HIV genomes all shared a common ancestor… one that existed no more than 100 years ago. To that end, they assert that it all likely began around 1920.

    And with this information, they were able to place the virus to a specific city of origin – Kinshasa, which is now the capital of the Democratic Republic of Congo.

    All in all, the genetic assays that helped us localise the origin of the disease are still underway to help us identify points of public health intervention that may help us reduce the spread of the infection. Because, although we may know where it came from, we have yet to figure out where it will end.

    See the full article here .

    YOU CAN HELP IN THE FIGHT AGAINST HIV/AIDS FROM THE COMFORT OF YOUR EASY CHAIR.

    The Fight AIDS at home (FAAH@home) Phase II project is now running at World Community Grid (WCG)

    FAAH Phase II

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the FAAH@home Phase II project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

    WCGLarge
    WCG Logo New

    BOINCLarge
    BOINC WallPaper

    Please help promote STEM in your local schools.

    STEM Icon

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  • richardmitnick 4:29 pm on June 24, 2016 Permalink | Reply
    Tags: , FAAH@home Phase II, Levy Lab at Temple, Olson Lab at Scripps,   

    FAAH from WCG: “FightAIDS@Home – Phase II” 

    New WCG Logo

    WCGLarge

    6.24.16
    No writer credit found

    Introduction

    FightAIDS@Home Phase II is a milestone in the collaboration between Dr. Arthur Olson and the Molecular Graphics Laboratory at the Scripps Research Institute and Dr. Ronald M. Levy’s group at Temple University.

    6

    FightAidsOlsonLab@home
    Olson Lab

    3
    Levy Group at Temple

    Dr. Olson initiated the largest HIV virtual screening effort ever using his computational molecular docking software, AutoDock, over a decade ago using IBM’s distributed volunteer computing grid, the World Community Grid (WCG), called FightAIDS@Home.

    4
    AutoDock

    As director of the HIV Interaction and Viral Evolution (HIVE) Center, an NIH funded HIV collaborative research center, the virtual screening results play a significant role informing a portion of the Center’s research.

    5
    HIVE

    The HIVE Center comprises a multidisciplinary team of scientists whom together aim to elucidate the structural and dynamic relationships between interacting HIV macromolecules in an effort to design future therapeutics to combat HIV and its evolution of drug resistance. Dr. Ronald Levy brings to the HIVE Center over 30 years of leadership and experience in the development and application of molecular dynamics simulations to study the structure and dynamics of proteins and their complexes.

    During FightAIDS@Home Phase I, millions of compounds have been screened against HIV related protein targets, and thousands of potential drug candidate compounds have been identified. In Phase II, we plan to refine the selection of these thousands of possible compounds by performing more detailed computational experiments using our molecular dynamics engine IMPACT, and the Binding Energy Distribution Analysis Method (BEDAM).

    7
    BEDAM

    The introduction of BEDAM simulations into FightAIDS@Home Phase II presents an enormous opportunity to refine and enrich the results from Phase I, but also presents a technical challenge as the constraints on the simulations running on the WCG are much different than the constraints on the simulations when running on more conventional computational resources.

    The first experiments of FightAIDS@Home Phase 2 seek to achieve two goals: first, to confirm that the new simulation schema is working as intended and gives sufficiently reliable results compared to traditionally run simulations; second, to demonstrate that using BEDAM in conjunction with AutoDock results in better predictions than using AutoDock or BEDAM alone. There exists a symbiotic relationship between docking and more computationally demanding free-energy methods like BEDAM—without docking, the computing time required to score thousands of ligands with free energy methods is intractable, and without free energy methods, the relationship between docking scores and experimental binding affinities remains much more empirical and less accurate.

    Overview of Molecular Dynamics and BEDAM
    Physical free energy models of binding

    One key aspect of drug discovery is to identify compounds which bind strongly and specifically to the target receptor, and therefore there exists considerable interest in the development of computational models to predict the strength of protein-ligand interactions. Thermodynamically, this interaction strength between ligand molecule and receptor is measured by the binding free energy, and many computer models aim to predict the protein-ligand binding free energy by simulating the interactions between protein and ligand in a bound complex. Docking methods use empirical scoring functions to estimate binding free energies in order to distinguish between between ligands that bind strongly from ligands that bind weakly or not at all.

    On the other hand, physical free energy models, which use physics based effective potentials, seek to compute accurate protein-ligand binding free energies based on the principles of statistical mechanics. Unlike docking methodologies, many of these methods are exceptionally computationally intensive and are highly dependent on both accurate modeling of interaction force fields (ligand-ligand, ligand-solvent, protein-protein, protein-solvent, and protein-ligand) and efficient sampling of all rotational and translational, internal and external, degrees of freedom of the ligand and protein.

    The statistical mechanics theory of binding provides a prescription to compute the binding free energy from first principles, which can be implemented in various ways. One method developed in the Levy lab is called the binding energy distribution analysis method (BEDAM), which runs using the Levy group’s molecular dynamics engine IMPACT. This methodology uses Hamiltonian replica exchange molecular dynamics simulations of the ligand-receptor complex in an implicit solvent model to construct a free energy path that connects the unbound and bound states of the ligand with the receptor.

    Running BEDAM on IBM’s WCG
    Differences between Phase I and Phase II

    For FAH2, the concept of a batch has changed from 1,000-10,000 ligand-receptor complexes per batch to 1 complex per batch, and each workunit in that batch is running thousands of simulations of that complex which we call replicas. These replicas differ from each other in important ways, such as different energy function parameters and different starting conformations of the ligand and receptor.

    Another key difference between Phase I and Phase II is that the simulation corresponding to one replica is broken up into several workunits that must be completed serially, i.e., the output of one workunit serves as input for the next workunit. Each batch generates tens of thousands of workunits that together form the simulations of hundreds or thousands of replica trajectories.
    First computational experiments

    Additionally, the distributed and heterogeneous nature of the volunteer grid imposes some constraints on how the simulations can be run. We’re in the process of learning how best to utilize this enormous resource by running each batch with two different simulation schema and several different analysis protocols. Doing so will allow us to refine our future simulation schema in order to maximize the impact of donated computing cycles. As volunteers ourselves, we do not want to see wasted computing cycles and are working with the constraints imposed by our dynamics engine, our forcefield model, and the nature of the WCG to find the optimal computing methodology for us and the volunteers.

    The two simulation protocols currently being tested employ sampling techniques that differ from the way these simulations are run on clusters and supercomputers. The first is what we call “lambda scheduling” or “lambda cycling”, which is where throughout a replica’s simulation, key parameters associated with the coupling between ligand and receptor are cycled through a known set of values. This greatly helps to accelerate the sampling of the conformational space. Simulating multiple replicas with the same parameter changing schedule helps accelerate this sampling further.

    The second simulation scheme is independent sampling in which no two replicas will ever have the same combination of energy function parameters, initial structures, etc., and these parameters are constant throughout all workunits pertaining to each replica’s trajectory. With both simulation schema, long simulation times are needed. We have developed analysis techniques which can combine the results from all of these different replica trajectories to produce estimates of the protein-ligand complex’s binding free energy.

    2
    HIV Integration (left) and HIV maturation/cleavage (right) as illustrated by David S. Goodsell © 2015, All Rights Reserved. Read more at the HIV Interaction and Viral Evolution Center.

    See the full article here.

    Please help promote STEM in your local schools.
    STEM Icon

    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.”

    WCG projects run on BOINC software from UC Berkeley.
    BOINCLarge

    BOINC is a leader in the field(s) of Distributed Computing, Grid Computing and Citizen Cyberscience.BOINC is more properly the Berkeley Open Infrastructure for Network Computing.

    BOINC WallPaper

    CAN ONE PERSON MAKE A DIFFERENCE? YOU BET!!

    “Download and install secure, free software that captures your computer’s spare power when it is on, but idle. You will then be a World Community Grid volunteer. It’s that simple!” You can download the software at either WCG or BOINC.

    Please visit the project pages-
    OpenZika

    Rutgers Open Zika

    WCG Help Stop TB
    Help Stop TB
    WCG Help Stop TB
    Outsmart Ebola together

    Outsmart Ebola Together

    Mapping Cancer Markers
    mappingcancermarkers2

    Uncovering Genome Mysteries
    Uncovering Genome Mysteries

    Say No to Schistosoma

    GO Fight Against Malaria

    Drug Search for Leishmaniasis

    Computing for Clean Water

    The Clean Energy Project

    Discovering Dengue Drugs – Together

    Help Cure Muscular Dystrophy

    Help Fight Childhood Cancer

    Help Conquer Cancer

    Human Proteome Folding

    FightAIDS@Home

    World Community Grid is a social initiative of IBM Corporation
    IBM Corporation
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