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  • richardmitnick 11:19 am on September 16, 2016 Permalink | Reply
    Tags: , , BOINC, , Hyperstable peptides, Institute for Protein Design,   

    From U Washington: “Super-stable peptides might be used to create ‘on-demand’ drugs” 

    U Washington

    University of Washington

    09.14.2016
    Michael McCarthy

    1
    An artist’s conception of a peptide created at the UW Medicine Institute for Protein Design. The backbone structure is shown in pink, and the molecular surface is blue. White indicates the crossbonds that stabilize the peptide’s shape. Vikram Mulligan

    2

    Scientists at the University of Washington’s Institute for Protein Design have shown it is possible to create small, hyperstable peptides that could provide the basis for developing powerful new drugs and diagnostic tests.

    “These super stable peptides provide an ideal molecular scaffold on which it should be possible to design ‘on demand’ a new generation of peptide-based drugs,” said UW Medicine protein engineering pioneer David Baker, who oversaw the research project. He is a UW professor of biochemistry.

    David Baker
    David Baker

    In a study, which appears in the journal Nature, the researchers demonstrate that not only is it possible to design peptides that fold into a wide variety of different conformations, but also that it is possible to incorporate functional groups of chemicals not normally found in peptides.

    3
    Illustrations of designed peptides with different configurations of two structures: tightly wound ribbons and flat, arrow-shaped ribbons.

    Both of these abilities could give designers even greater flexibility to create drugs that act on their molecular targets with high precision. Such drugs should not only be more potent but would also be less likely to have harmful side effects.

    Most drugs work by binding to a key section of a protein in a way that alters how the protein functions, typically by stimulating or inhibiting the protein’s activity. For the binding to occur, the drug must fit into the target site on the protein as a key fits into a lock. How close the lock-and-key fit is can often determine how well the medication works.

    Currently, most prescription drugs are either made of small molecules or much larger proteins. Both classes of drugs have advantages and disadvantages.

    Small molecule drugs, for example, tend to be easy to manufacture, tend to have a long shelf life, and are often easily absorbed. But they often don’t fit the targeted “lock” as selectively as could be hoped. This imperfect fit can result in off-target binding and side-effects that diminish their effectiveness. Protein drugs, on the other hand, often fit their target receptors very well but they are difficult to manufacture, are more unstable, and lose their potency if they are not kept refrigerated. Because of their size and instability, they need to be injected into patients.

    Peptide drugs fall in between these two classes. They are small, so they have many of advantages of small molecule drugs. But they are made of a chain of amino acids, the same components that make up proteins, so they have the potential to achieve the precision of larger protein drugs.

    The power of some tiny peptides can be observed in venomous creatures. A number of poisonous insects and sea creatures produce small peptide toxins. Those are some of the most potent pharmacologically active compounds known. Their potency is among the reasons why medical scientists are interested in tapping into beneficial uses of peptides.

    In the new study, Gaurav Bhardwaj, Vikram Khipple Mulligan, Christopher D. Bahl, senior fellows in the Baker lab, and their colleagues, developed computational methods that are now incorporated in the computer program called Rosetta.

    rosetta-screensaver
    rosettahome
    Rosetta@home, a project running on BOINC software from UC Berkeley
    BOINC WallPaper

    These methods are being used to design peptides ranging from 18 to 47 amino acids in length in 16 different conformations, called topologies.

    Originally developed by Baker and his earlier team, Rosetta uses advanced modelling algorithms to design new proteins by calculating the energies of the biochemical interactions within a protein, and between the protein and its surroundings. Because a protein will assume the shape in which the sum of these interaction energies is at its minimum, the program can calculate which shape a protein will most likely assume in nature.

    The peptides were made hyperstable by designing them to have interior crosslinking structures, called disulfide bonds, which staple together different sections of the peptide. Additional stabilization was secured by tying the two ends of the peptide chain together, a process called cyclization. The resulting constrained peptides were so stable that they were able to survive temperatures to 95 °C, nearly boiling. This survival feat would be impossible for antibody drugs.

    The researchers also showed that the design of these peptides could include amino acids not normally found in proteins. Amino acids have a property called handedness or chirality. Two amino acids can be made of the same atoms but have different arrangements, just as our hands have the same number of fingers but have two mirror-image configurations, right and left. This handedness keeps the right hand from fitting properly into a left-handed glove and vice versa.

    In nature, perhaps due to a chance event billions of years ago, amino acids in living cells are all left-handed. Right-handed amino acids are very rare in naturally occurring proteins. Nevetheless, the researchers were able to insert right-handed amino acids in their designed peptides.

    “Being able to include other types of amino acids allows us to create peptides with a much wider variety of conformations,” said Baker, “and being able to use right-handed amino acids essentially doubles your palette.”

    “By making it possible to create peptides that include ‘unnatural’ amino acids, this approach will allow researchers to explore peptide structures and function that have not been explored by nature through evolution,” Baker said.

    Today’s edition of Nature also has a special supplement, Insight The Protein World. Baker, Po-Ssu, and Scott E. Boyken authored the review article, The coming of age of de novo protein design.

    Also see coverage of the Nature hyperstable peptide design paper in Hutch News by the Fred Hutchinson Cancer Research Center.

    The National Institutes of Health provided partial support for this work through grants P50 AG005136, T32-H600035., GM094597, GM090205, and HHSN272201200025C. Additional funding was provided by The Three Dreamers.

    See the full article here .

    Please help promote STEM in your local schools.

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    Stem Education Coalition

    u-washington-campus
    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.

    So what defines us — the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 9:57 am on September 9, 2016 Permalink | Reply
    Tags: , BOINC, , , , ,   

    From Vanderbilt: “Investigators create ‘Trojan Horse’ to fight Ebola” 

    Vanderbilt U Bloc

    Vanderbilt University

    Sep. 8, 2016
    Bill Snyder
    william.snyder@Vanderbilt.Edu
    (615) 322-4747

    A multi-center research team including scientists from the Vanderbilt Vaccine Center has come up with a clever “Trojan Horse” strategy for thwarting the highly lethal Ebola virus.

    Using “bispecific” antibodies — two monoclonal antibodies combined into a single package — they first tricked the virus into revealing a normally hidden binding site required for infection. Then in a mouse model, they blocked the site, fully protecting the animals from Ebola infection.

    Their findings, reported in this week’s Science magazine, suggest that this two-step, “deliver-and-block” strategy can provide broad protection against Ebola and other members of its hemorrhagic filovirus family, including the Marburg virus.

    We were intrigued to find this remarkable antibody that has the capacity to inhibit both Marburg and Ebola viruses,” said James Crowe Jr., M.D., Ann Scott Carell Professor in the Vanderbilt University School of Medicine and director of the Vanderbilt Vaccine Center at Vanderbilt University Medical Center.

    “The team’s feat of delivering the antibody into cells using creative engineering tricks so that it can kill Ebola inside cells is very exciting,” Crowe said.

    This advance is only the latest in a string of fundamental discoveries made during the past decade by a far-flung group of researchers including Crowe and four other corresponding authors of the paper.

    The four are Kartik Chandran, Ph.D., and Jonathan Lai, Ph.D., of Albert Einstein College of Medicine in New York, John Dye, Ph.D., of the U.S. Army Medical Research Institute of Infectious Diseases in Fort Detrick, Maryland, and Javad Aman, Ph.D., of Integrated Biotherapeutics in Gaithersburg, Maryland.

    Like other viruses, Ebola must “hijack” factors in the cells it infects to make copies of itself. As a first step, the virus enters a vesicle called an endosome inside the cell. There it commandeers two cellular enzymes called proteases to cut a sugar-bearing glycoprotein on its surface in two.

    Cleavage of the glycoprotein reveals a previously hidden receptor-binding site that attaches to another cellular factor, a cholesterol transporter protein called Niemann–Pick C1 or NPC1. This step is essential for infection to occur.

    Mutations in the NPC1 gene result in an abnormal protein that causes the rare lipid storage disorder Niemann-Pick type C disease. While patients with this disease are often quite ill, their abnormal NPC1 protein also renders them resistant to infection by Ebola and the related Marburg virus.

    Last year, Crowe, Vanderbilt graduate student Andrew Flyak and colleagues at The Scripps Research Institute in La Jolla, California, reported that a human survivor of a severe Marburg infection had neutralizing antibodies that recognized and blocked the NPC1 binding site in Marburg virus

    These antibodies also could bind to the Ebola virus, but only to the form of the virus inside cells.

    Crowe and Flyak followed up that finding by generating a “monoclonal” antibody, called MR72, which specifically recognized and could block the NPC1 binding site. To actually prevent Ebola virus infection, however, they’d have to get the antibody into the endosome inside the cell where the action is taking place.

    To do that, the researchers fused MR72 to another antibody, called FVM09, which recognizes and attaches to the Ebola glycoprotein before it is cut in two. The result was an immunological “Trojan horse.” Once the virus brought its antibody cargo into the endosome, MR72 went to work, and blocked infection.

    “This Trojan horse bispecific antibody approach may also find utility against other viral pathogens known to use intracellular receptors,” they concluded.

    Other contributors to the current study were Erica Ollmann Saphire, Ph.D., at Scripps and Zachary Bornholdt, Ph.D., now at Mapp Pharmaceutical in San Diego. The study was supported in part by National Institutes of Health grants AI109762, AI088027 and AI122403.

    See the full article here .

    You can Help Stamp Out EBOLA.

    This WCG project runs at Scripps Institute

    Outsmart Ebola Together

    Visit World Community Grid (WCG). Download and install the BOINC software on which it runs. Attach to the Outsmart Ebola Together project. This will allow WCG to use your computer’s free CPU cycles to process computational data for the project.

    WCGLarge
    WCG Logo New

    BOINCLarge
    BOINC WallPaper

    While you are at WCG and BOINC, check out the other very worthwhile projects running on this software. All project results are “open source”, free for the use of scientists world while to advance health and other issues of mankind.

    MyBOINC

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Vanderbilt Campus

     
  • richardmitnick 6:09 am on September 1, 2016 Permalink | Reply
    Tags: , BOINC, , Fight Malaria @ home, ,   

    From COSMOS: “Mass drug hand-out curbed Liberian malaria during Ebola outbreak” 

    Cosmos Magazine bloc

    COSMOS

    01 September 2016
    Anthea Batsakis

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    Liberian capital Monrovia was hit hard by Ebola in 2014. But malaria is also endemic to the country, and the two diseases present similar symptoms. John Moore / Getty Images

    Almost 15,000 people dodged malaria while Ebola devastated West Africa in 2014, thanks to preventative drugs on an enormous scale doled out by Médecins Sans Frontières.

    The life-saving treatments targeted a 10th of Liberia’s population and saw the number of malaria cases plummet – even though most people didn’t take their medication.

    The analysis, published in PLOS One by an international team, shows large-scale drug treatments are promising ways to fight malaria.

    Malaria is curable and preventable – if suitable healthcare can be accessed. Almost half the world’s population is at risk of the disease, but according to the World Health Organisation, 90% of malaria deaths last year were in Sub-Saharan Africa.

    To complicate matters, malaria is often impossible to distinguish from Ebola without taking a blood sample to a laboratory. They share symptoms, such as high fever.

    So when the Ebola outbreak hit West Africa in 2014, malaria cases were misdiagnosed. Some people with malaria were put in the same hospitals as those with Ebola, dangerously exposing them to the virus and overcrowding hospitals.

    This is when Médecins Sans Frontières stepped in.

    From October to December 2014, they distributed vouchers entitling two rounds of the malaria medication to hundreds of thousands of people in Liberia’s capital city Monrovia. All in all, 1,259,699 courses were given out.

    The medication called ASAQ (artesunate/amodiaquine) is a standard treatment for uncomplicated malaria. It’s been widely used since 2003.

    “With malaria, we were certainly concerned about any intervention that may lead to drug resistance,” says study co-author Amanda Tiffany, an epidemiologist from Epicentre in Geneva, Switzerland.

    “In this case, however, ASAQ has been shown to be a very safe drug and was already well known by the community as it is the first-line malaria treatment in Liberia.”

    And it worked: self-reported fever dropped from 4.2% to 1.5% in only a month. In other words, the mass drug administration meant 14,821 fewer fever episodes in Monrovia.

    To top it off, mathematical modelling in early 2015 suggested that in future, if three rounds of the malaria prevention drugs were given to 70% of Liberia’s population, as many as 700,000 malaria cases could be avoided.

    The scientists write in this instance, though, the drugs weren’t always taken correctly. The majority of participants, if they felt healthy, held on to the drugs in case of any future malaria episodes rather than taking them as a preventative measure.

    And they note that for better results, mass drug administrations should be coupled with adequate healthcare and long-term interventions.

    So why haven’t malaria preventative treatments been distributed on this scale before?

    Tiffany says complicated logistics were the main problem. A massive portion of the community had to stop what they were doing to take part in education sessions which were part of the campaign.

    “For malaria, in particular, such campaigns are still novel and challenging as they involve the distribution of medication to predominately healthy people that is to be taken, unsupervised, over three days,” Tiffany says.

    And, she adds, mass drug distribution isn’t always the right intervention for every context.

    See the full article here .

    YOU CAN HELP IN THE BATTLE AGAINST MALARIA

    FightMalariaatHome

    Fight Malaria @ homeCrowd-sourcing antimalarial drug discovery

    Goal:

    To discover novel targets for antimalarial drugs.

    Context:

    Malaria kills a child every 45 seconds. The disease is most prevalent in poorer countries, where it infects 216 million people and kills 650,000 each year, mostly African children under 5 years old [WHO]. And Plasmodium falciparum continues to evolve resistance to available medication. We therefore urgently need to discover new drugs to replace existing drugs. Importantly, these new drugs need to target NEW proteins in the parasite. The FightMalaria@Home project is aimed at finding these new targets.

    Resources:

    The Plasmodium falciparum genome has been sequenced, the proteome has been mapped, and protein expression has been confirmed at various stages in this apicoplexan’s life cycle. Numerous crystal structures of target proteins are also available, and the remainder have been modelled using available structural templates. Excitingly, large research organisations (GSK, Novartis) have already tested millions of compounds and found nearly 19,000 hits that show promising activity against Plasmodium falciparum [MMV]. But they don’t know which target protein is inhibited by these compounds. Drug discovery and development will be significantly enhanced by knowing the target protein for each of these hits.

    Problem:

    We plan to dock each of the 18,924 hits into structures of each of the 5,363 proteins in the malaria parasite. The computational power needed is enormous.

    Solution:

    We aim to harness the donated computational power of the world’s personal computers. Most computers only use a fraction of their available CPU power for day-to-day computation. We have built a BOINC server that distributes the docking jobs to donated ‘client’ computers, which then do the work in the background. By connecting 1000s of computers this way, we’ll be able harness the equivalent power of large supercomputers.

    To join the project, visit BOINC, download and install the software, then attach to the project. While you are at BOINC, look over the other projects some of which you might find of interest.

    BOINCLarge

    BOINC WallPaper

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    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

     
  • richardmitnick 9:38 am on August 25, 2016 Permalink | Reply
    Tags: , BOINC, Fight Aids at Home - Phase 2,   

    From FightAIDS@Home – Phase 2 at WCG: “AIDS is constantly evolving. So are the tools to fight it.” 

    New WCG Logo

    WCGLarge

    World Community Grid (WCG)

    Since 2005, the volunteers behind FightAIDS@Home have helped scientists advance HIV research. The next phase of that effort is just beginning, and you can play a key role in helping the millions of people afflicted by this deadly virus.

    FightAIDS@Home – Phase 2

    Even with the advances in treating people infected with HIV, there are still about two million new infections and one million HIV-related deaths each year. HIV continues to be a challenge because it quickly mutates in ways that make existing drug treatments ineffective. FightAIDS@Home joined World Community Grid 10 years ago with the simple – but challenging – goal of finding new treatments for HIV. Since then, the project has made some incredible advances in understanding the virus, developing better drug search tools, and identifying chemical compounds that might be able to bind to the virus and disrupt its lifecycle.

    The computing power donated by World Community Grid volunteers has allowed the FightAIDS@Home research team to significantly expand their research beyond what they originally planned. Phase 1 of this project is considered to be the biggest docking experiment ever conducted with more than 20 billion drug-target comparisons performed. The research team was able to computationally evaluate millions of chemical compounds against many different regions of the entire viral machinery, rather than restricting the search to only certain compounds or certain binding sites.

    Although the researchers expect to run additional Phase 1 screenings in the future, they will now focus on identifying the most valuable results from Phase 1. While the team has already identified thousands of potentially promising candidates to be confirmed experimentally in the lab, it would be cost and time prohibitive to lab test all of the potential candidates. The virtual docking techniques used in Phase 1 are only an approximation of the potential effectiveness of these promising compounds. They can be evaluated in the lab, but this is expensive and slow, because each chemical must be either synthesized or purchased, and then thoroughly tested. Therefore, results from Phase 1 will be filtered to prioritize computationally-selected candidate compounds, evaluating them using more accurate methods in Phase 2.

    This is necessary for two related reasons. First, Phase 1 generated a significant number of “false positives,” compounds that looked promising in Phase 1 screening but would not actually be effective as HIV drugs. Second, the large number of results is likely to contain other candidates, “false negatives,” which scored lower but merit further investigation.

    Phase 2 of FightAIDS@Home uses a different simulation method to double-check and further refine the virtual screening results that were generated in Phase 1. The technique is called BEDAM (Binding Energy Distribution Analysis Method), which has proven effective in computational contests, but has been limited to evaluating just a few dozen molecules. It has not yet been used on such a large scale because of the much larger amount of processing time required. With World Community Grid, it will be possible to more thoroughly evaluate the top candidates from the vast number of results generated in Phase 1.

    So Phase 2 has two main goals: increase the success rate by reducing false positives and false negatives from the Phase 1 docking data, and prove the BEDAM analysis techniques on a large scale. This should save enormous amounts of time and money in the lab testing stage of drug development.

    This new phase is another chapter in a long and well-established collaboration between World Community Grid and The Scripps Research Institute, a world-renowned research organization. Our teams have already collaborated on other research efforts including the search for treatments against Ebola and malaria. The relationship has been beneficial for all involved. For the researchers, the enormous amount of computing power available through World Community Grid has enabled them to run larger experiments and explore greater numbers of chemicals than they ever thought possible. Furthermore, the virtual screening tools they have developed and refined (AutoDock and AutoDock Vina) are the world’s most widely used and cited molecular docking programs and have benefited other World Community Grid research projects searching for drug candidates for other diseases. Once BEDAM is validated on a large scale, it could prove equally useful to these other research efforts as well.

    Please continue to support the FightAIDS@Home project as it establishes a new front in the fight against the world’s deadliest virus.

    Learn more

    Follow this project:
    Project forum
    Project website

    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!!

    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
    ibm

    IBM – Smarter Planet
    sp

     
  • richardmitnick 5:18 pm on August 13, 2016 Permalink | Reply
    Tags: , , BOINC, , ,   

    From Rosetta@home: “Designed Protein Containers Push Bioengineering Boundaries” 

    Rosetta@home

    Rosetta@home

    Rosetta@home has posted in their forum a new (July 21, 2016) article, Designed Protein Containers Push Bioengineering Boundaries
    from U Washington’s Institute for Protein Design which I highly recommend for anyone interested in Protein Studies.

    3

    This forum article cites Designed Protein Containers Push Bioengineering Boundariess which goes on to cite Icosahedral protein nanocage – new paper and podcast published in Nature, and “Accurate design of megadalton-scale multi-component icosahedral protein complexes”, published in Science.

    Of this second paper, they write, “In this paper, former Baker lab graduate student Jacob Bale, Ph.D. and collaborators describe the computational design and experimental characterization of ten two-component protein complexes that self-assemble into nanocages with atomic-level accuracy. These nanocages are the largest designed proteins to date with molecular weights of 1.8-2.8 megadaltons and diameters comparable to small viral capsids. The structures have been confirmed by X-ray crystallography (see figure). The advantage of a multi-component protein complex is the ability to control assembly by mixing individually prepared subunits. The authors show that in vitro mixing of the designed subunits occurs rapidly and enables controlled packaging of negatively charged GFP by introducing positive charges on the interior surfaces of the two copmonents.

    The ability to design, with atomic-level precision, these large protein nanostructures that can encapsulate biologically relevant cargo and that can be genetically modified with various functionalities opens up exciting new opportunities for targeted drug delivery and vaccine design.”

    Also referenced in the forum is an article in Science, Jul. 21, 2016 by Robert F. Service This protein designer aims to revolutionize medicines and materials, about Dr David Baker.

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    From this Science article, David Baker shows off models of some of the unnatural proteins his team has designed and made.© Rich Frishman

    included also is this video from Science.

    See the full article here.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Rosetta@home needs your help to determine the 3-dimensional shapes of proteins in research that may ultimately lead to finding cures for some major human diseases. By running the Rosetta program on your computer while you don’t need it you will help us speed up and extend our research in ways we couldn’t possibly attempt without your help. You will also be helping our efforts at designing new proteins to fight diseases such as HIV, Malaria, Cancer, and Alzheimer’s (See our Disease Related Research for more information). Please join us in our efforts! Rosetta@home is not for profit.

    About Rosetta

    One of the major goals of Rosetta is to predict the shapes that proteins fold up into in nature. Proteins are linear polymer molecules made up of amino acid monomers and are often refered to as “chains.” Amino acids can be considered as the “links” in a protein “chain”. Here is a simple analogy. When considering a metal chain, it can have many different shapes depending on the forces exerted upon it. For example, if you pull its ends, the chain will extend to a straight line and if you drop it on the floor, it will take on a unique shape. Unlike metal chains that are made of identical links, proteins are made of 20 different amino acids that each have their own unique properties (different shapes, and attractive and repulsive forces, for example), and in combination, the amino acids exert forces on the chain to make it take on a specific shape, which we call a “fold.” The order in which the amino acids are linked determines the protein’s fold. There are many kinds of proteins that vary in the number and order of their amino acids.

    To predict the shape that a particular protein adopts in nature, what we are really trying to do is find the fold with the lowest energy. The energy is determined by a number of factors. For example, some amino acids are attracted to each other so when they are close in space, their interaction provides a favorable contribution to the energy. Rosetta’s strategy for finding low energy shapes looks like this:

    Start with a fully unfolded chain (like a metal chain with its ends pulled).
    Move a part of the chain to create a new shape.
    Calculate the energy of the new shape.
    Accept or reject the move depending on the change in energy.
    Repeat 2 through 4 until every part of the chain has been moved a lot of times.

    We call this a trajectory. The end result of a trajectory is a predicted structure. Rosetta keeps track of the lowest energy shape found in each trajectory. Each trajectory is unique, because the attempted moves are determined by a random number. They do not always find the same low energy shape because there are so many possibilities.

    A trajectory may consist of two stages. The first stage uses a simplified representation of amino acids which allows us to try many different possible shapes rapidly. This stage is regarded as a low resolution search and on the screen saver you will see the protein chain jumping around a lot. In the second stage, Rosetta uses a full representation of amino acids. This stage is refered to as “relaxation.” Instead of moving around a lot, the protein tries smaller changes in an attempt to move the amino acids to their correct arrangment. This stage is regarded as a high resolution search and on the screen saver, you will see the protein chain jiggle around a little. Rosetta can do the first stage in a few minutes on a modern computer. The second stage takes longer because of the increased complexity when considering the full representation (all atoms) of amino acids.

    Your computer typically generates 5-20 of these trajectories (per work unit) and then sends us back the lowest energy shape seen in each one. We then look at all of the low energy shapes, generated by all of your computers, to find the very lowest ones. This becomes our prediction for the fold of that protein.

    To join this project, download and install the BOINC software on which it runs. Then attach to the project. While you are at BOINC, look at some of the other projects to see what else might be of interest to you.

    Rosetta screensaver

    BOINC

    1

     
  • richardmitnick 10:34 pm on August 11, 2016 Permalink | Reply
    Tags: , , BOINC, , World Travel Market   

    From World Travel Market by and for WCG: “Why every tourism company should sign up to the World Community Grid” 

    1

    World Travel Market

    August 9, 2016
    Jeremy Smith

    2

    For many of us in the northern hemisphere, August is a month when our computers finally lie idle, emails get bounced back with out of office replies, and we spend our time either relishing finally switching off from connectivity, or driving into the local village or up the nearest hill to try to get some signal.

    Holiday time gives us a chance to recharge. More often than not, it is a period when – granted some time to switch off from day to day busy-ness – we actually get some proper thinking done. Freed of routine, we drift down unexpected avenues, potter along unknown routes, and stumble upon some of our most rewarding of discoveries as a result.

    This happened to me earlier today, when I inadvertently discovered the World Community Grid and found what I believe offers an enormous opportunity for tourism businesses around the world to help solve many of the most pressing global problems – the likes of Zika, climate change and cancer.

    WCG Logo New

    WCGLarge

    And this is a particular suitable solution for August as we can do this by doing almost nothing at all.

    Little did I know, but the World Community Grid has existed since 2004. Co-ordinated by IBM, it is a vast, global, collaborative effort to create the world’s largest public computing grid to tackle scientific research projects that benefit humanity.

    IBM

    SmarterPlanet

    And it is open to anyone – individual, organisation, multinational hotel chain, OTA, travel services company, or local five room B&B – to get involved. So long as you are connected to the internet (which if you are reading this, we can assume you are), and can spare a few minutes to sign up.

    Since it launched, more than 2.3 million devices – including smartphones and tablets – belonging to over 600,000 individuals and organizations in 80 countries, have contributed their processing power into World Community Grid projects, resulting in one of the world’s fastest virtual supercomputers, which has provided scientists with the equivalent of more than 800,000 years of computing activity at absolutely no cost to them.

    Many corporations have signed up as partners, offering the enormous computing power held within their offices to support these efforts. So far, however, according to the official list on the World Community Grid’s website, only one of these corporate partners works in tourism. Huge kudos therefore to Melia Hotels, who signed up back in 2013 and committed many of its computers to supporting both the Computing for Clean Water environmental project, and the Help Fight Childhood Cancer social project.

    Clean Water
    Computing for Clean Water

    ChildhoodCancer
    Help Fight Childhood Cancer

    There are countless opportunities like this for travel companies looking to align themselves with important causes. This could make a real difference to issues like climate change and Zika that not only affect the wellbeing of the general population of the world, but threaten the viability of the tourism industry in many regions.

    Rutgers Open Zika
    OpenZika project

    Offering our support is simple to implement, and can have a significant impact. As an article from late last month on Forbes.com reports on the current OpenZika project: “in the first two months of the study, more than 50,000 volunteers from all over the world have enrolled and donated the equivalent of over 4,000 years of computing time and performed more than 20,000 virtual experiments, saving researchers $1.5 million in equivalent computing resources.”

    I’ve just signed up. It took me about a minute. I encourage anyone with an internet connection to join me. I’ve also created a group called ‘Responsible Tourism Grid‘, so that as tourism companies and individuals we can connect and build a stronger network together as an industry.

    We are one of the biggest, most networked industries around. Our core purpose is to enable people across the world to enjoy much needed idle time. By supporting the World Community Grid we can use our many millions of computers’ idle time to help even more.

    WCG projects run on BOINC software from UC Berkeley.
    BOINCLarge

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

    BOINC WallPaper

    MyBOINC

     
  • richardmitnick 4:37 pm on August 10, 2016 Permalink | Reply
    Tags: , BOINC, , ,   

    From Help Stop TB at WCG: “Researchers Partner with World Community Grid to Help Stop a Leading Killer” 

    New WCG Logo

    WCGLarge

    [I may have posted this before; but it is a worthwhile story. If you have not signed on to WCG, maybe this will give you another nudge.]

    World Community Grid (WCG)

    24 Mar 2016
    By: Dr. Anna Croft
    University of Nottingham, UK

    Summary
    Tuberculosis is one of the world’s most prevalent and deadly infectious diseases. Researchers from the University of Nottingham, UK, have partnered with World Community Grid to take a close look at the bacterium that causes tuberculosis, so that scientists can develop more effective treatments.

    Tuberculosis (TB) is one of the biggest global killers. In 2014, there were 9.6 million newly diagnosed cases and more than 1.5 million people who died from the disease. More than 1 million of these new cases, and 140,000 deaths, were estimated for children. The World Health Organization has declared TB to be the world’s deadliest infectious disease, along with HIV. To help combat this disease, my team and I are working with World Community Grid on a [new] project called Help Stop TB.

    TB is caused by infection from a bacterium known as Mycobacterium tuberculosis (M. tb). Typical symptoms of an active TB infection include persistent cough, fever, loss of weight, and night sweats. If the infection is left untreated, the bacteria are likely to cause increased damage to the lungs and spread throughout the body, which may ultimately lead to death. Treatment for an uncomplicated TB infection lasts more than six months and requires a combination of antibiotics.

    I am an associate professor in the Department of Chemical and Environmental Engineering at the University of Nottingham, UK. My team and I seek to improve the understanding, and therefore the treatment, of TB. To do this, we are excited to partner with World Community Grid and its community of volunteers to study and understand the protective outer coating of M. tb, and learn how to penetrate its defenses.

    Background
    Mycobacterium tuberculosis is a slow killer, often remaining dormant for long periods of time before seizing an opportunity to turn into active TB disease. Poor nutrition, old age or a weakened immune system can all precipitate the onset of active TB. It is an airborne disease, most often spreading from one person to another via a droplet from a cough entering someone’s lungs. Symptoms can start with cough, weight loss, and fever, developing into difficulty breathing and coughing up blood, and can spread to other organs.

    Problem
    Although a vaccine and several drugs have been developed to help combat TB, the TB bacterium has been evolving resistance to available treatments. Drug treatment can last up to two years, but when patients interrupt or discontinue treatment, the bacteria can develop resistance. This, along with inconsistent availability of drugs, and increased risk of infection for HIV patients with weakened immune systems, have all contributed to a resurgence of the disease. Nearly half of European cases are now resistant to at least one drug, and 4% of all cases worldwide are resistant to a combination of drugs.

    Proposed Solution
    The bacterium has an unusual coat which protects it from many drugs and the patient’s immune system. Among the fats, sugars and proteins in this coat, the TB bacterium contains a type of fatty molecules called mycolic acids. Help Stop TB will use the massive amount of computing power donated by World Community Grid members to simulate the behavior of these molecules in their many configurations to better understand how they offer protection to the TB bacteria. Scientists hope to use the resulting information to finally develop better treatments for this deadly disease.

    Help Stop TB Researchers Begin First Stages of Data Analysis

    21 Jul 2016

    Summary
    In Help Stop TB’s first project update, researcher Athina Meletiou gives an overview of why this project is important and what the team is doing with the early data.

    Help Stop TB launched about four months ago, and the research team has begun the early stages of data analysis. We asked researcher Athina Meletiou to provide an overview of the project along with the first update, and to also tell us about how she came to be involved with Help Stop TB.

    In the presentation below, Athina discusses the goals and importance of Help Stop TB, and gives us a behind-the-scenes look at what it takes to get a World Community Grid project ready to launch.

    About the Project

    The Problem

    Tuberculosis (TB) is one of the biggest global killers with the World Health Organization (WHO) reporting 9 million newly diagnosed cases and more than 1.5 million people who died from the disease in 2014. More than half a million cases were reported in children less than 15 years old.

    Within the Western world, the threat of TB has decreased through diligent treatment and containment, to the point where much of the general public does not regard this disease as a risk. Nevertheless, an increase in multi-drug resistant strains and a rise in HIV infection, combined with decreasing vaccination rates in some regions, has led to a resurgence in TB. Recently awareness of this disease has been raised through the annual commemoration of World TB day on March 24th.

    What is Tuberculosis

    TB is caused by infection from Mycobacterium tuberculosis bacteria (M. tb). It is spread by droplets produced by sneezing or coughing of an infected person. After initial infection, if not cleared, the M. tb bacteria enter a dormant state, where they are able to evade detection from the body’s immune system. However, this means that the infection can reappear months or even years later.

    Typical symptoms of an active TB infection include persistent cough, fever, loss of weight, and night sweats. If the infection is left untreated, the bacteria are likely to cause increased damage to the lungs and spread throughout the body, infecting other organs. Such rampant infection may ultimately lead to death. Treatment for an uncomplicated TB infection lasts over 6 months and requires a combination of antibiotics. If treatment is not effective, or is terminated too soon, the bacteria become resistant to the drugs, followed by a spread of the infection if left unchecked.

    M. tb is a particularly old disease, with cases being identified from human burials from more than 4000 years ago, and evidence from fossilized bison that the disease is at least 17,500 years old. The disease was particularly endemic in North America and Europe from the 17th to 19th centuries and is it thought to have killed more people than any other microbial disease in history. Control of TB in these regions started to be achieved after World War II, with the mass acceptance of the BCG vaccine, combined with introduction of one of the first antibiotics effective against the bacteria, Isoniazid, in 1952, followed by another class of antibiotics, the rifamycins in 1957.

    Multidrug resistance

    Bacterial resistance against the drugs available to treat TB is on the increase throughout the world and is making TB treatment even more challenging. Currently around 500,000 diagnosed cases are of multi-drug resistant TB (in these cases M. tb is resistant to Isoniazid and Rifampicin). A more dangerous, extensively drug-resistant (XDR) form of TB, where M. tb is resistant to the other available drugs in addition to Isoniazid and Rifampicin, has been reported in 100 countries. As these drugs lose their effectiveness, the threat of TB infection worldwide rises.

    Tuberculosis and HIV

    TB infection is a particular challenge in areas where Human Immunodeficiency Virus (HIV) infection is high, such as sub-Saharan Africa, and co-infection rates are estimated to be as high as 13% of the total cases. People who have both these diseases are far more likely to die, and have been harder to diagnose because of the lack of standard immunomarkers. Treatment with standard HIV drugs for patients with a latent TB infection can lead to severe complications, known as TB-immune reconstitution inflammatory syndrome (TB-IRIS), so early diagnosis and treatment of TB is critical.

    Related diseases

    Mycobacterium tuberculosis is part of the family of mycobacteria. Other diseases in this family include bovine TB that infects cattle and badgers (M. bovis), avian TB, that can infect HIV patients (M. avium), leprosy (M. leprae), and Buruli ulcer (M. ulcerans).

    The Proposed Solution

    Mycobacteria have a highly unusual outer coat, which is important for their survival and provides protection from both incoming drugs and the host immune system. We know that changes to this outer coat can result in much less dangerous bacteria. Help Stop TB is specifically targeting molecules from this outer coat.

    What is special about the M. Tb outer coat?

    Most bacteria have an outer coat or membrane that helps to protect them from the outside environment. These membranes typically consist of a mixture of fats, sugars and proteins, all with different functions. In particular, the fats act as a barrier against water and other water-soluble molecules from entering the bacteria. M. tb and other mycobacteria have an additional layer of fats in their cell wall. These fats are 3-5 times longer than those from other bacteria and contain a highly unique chemical signature. These special fats are known as mycolic acids, and are the molecules of interest for this project.

    Immune response and the M. Tb outer coat

    Mycolic acids and their derivatives are sometimes able to break free of the M. tb cell wall, and these free mycolic acids have been shown to initiate a variety of immune responses. More importantly, in HIV infected patients, they can activate alternative immune responses to those that are normally shut down in HIV infection, to give us a potential alternative way to identify TB exposure rapidly through blood tests. How mycolic acids can act as antigens (promoters of the immune response) is closely linked to how these molecules are able to fold, what shapes these folds take, and how tight these folds are. Part of the information that we are gathering for Help Stop TB will give us insight into this phenomenon.

    Project Goals

    The specific goals of the Help Stop TB project are:


    To create a database of mycolic acid structures, covering the different variations found in the naturally occurring molecules.


    To discover how these variations impact the way that these molecules fold – both in water and in more membrane-like (cell-wall) environments.


    To obtain the simulation data needed in order to create full-scale membrane models that will directly contribute to a better understanding of the molecule’s behaviour in its natural environment


    To better understand the different effects mycolic acids and their derivatives have on the immune system.

    The specific goals listed above are ultimately a way of improving our understanding of how TB protects itself from drugs and attack from the host’s immune system, with the broader goal of developing strategies that evade these defences.

    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!!

    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
    ibm

    IBM – Smarter Planet
    sp

     
  • richardmitnick 3:05 pm on August 9, 2016 Permalink | Reply
    Tags: , BOINC, , Cosmology@home   

    From BOINC project Cosmology@home: “Planck parameter sims paper out” 

    Cosmology@home new
    Cosmology@home

    9 Aug 2016
    Marius

    In February we started running a new application. Today the paper making use of the results that thousands of you guys calculated is out! Look here in the coming weeks for more posts detailing exactly what we found. Until then, you can see the paper here. On behalf of the C@H team and of the Planck collaboration, thanks again everyone!

    See the full article here.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The goal of Cosmology@home is to search for the model that best decribes our universe and to find the range of models that agree with the available astronomical and particle physics data.

    FEATURED CONCEPT: Dark Matter
    Unlike ordinary matter, dark matter does not emit or absorb light–or any other type of electromagnetic radiation. Consequently, dark matter cannot be observed directly using a telescope or any other astronomical instrument that has been developed by humans. If dark matter has these strange properties, how do we know that it exists in the first place?
    Like ordinary matter, dark matter interacts gravitationally with ordinary matter and radiation. Astronomers study the distribution of dark matter through observing its gravitational effects on ordinary matter in its vicinity and through its gravitational lensing effects on background radiation.

    Cosmology@home supporters

    Cosmology@home runs on software from BOINC at UC Berkeley. Visit BOINC, download and install the software. Then attach to this project and review all of the projects running on BOINC.

    BOINCLarge

    BOINC WallPaper

     
  • richardmitnick 1:44 pm on August 8, 2016 Permalink | Reply
    Tags: , , BOINC, medium.com,   

    From Medium via WCG: “Writers and Journalists, Science Needs Your Help!” 

    New WCG Logo

    WCGLarge

    World Community Grid (WCG)

    1

    Medium

    8.6.16
    Johnnie Chamberlin, PhD

    Volunteer computing efforts boosting research on cancer, clean energy, and more, depend on press coverage for volunteer recruitment and coverage is falling. You can help!

    I am a big fan of volunteer computing efforts like BOINC and World Community Grid and hope I can convince you to be one too. Here’s why:

    There are billions of bored computers and Android devices out there that are just begging for something to do. Imagine what we could accomplish if all that spare computational power could be put to work doing research on diseases, clean energy, astrophysics, climate change, and more.

    Well guess what? It can and it is so easy you can get started helping cure cancer or Zika in just a couple minutes.

    “Wait!” you say, “This article’s title mentioned writers and journalists, what can we do to help”? Good question. BOINC and World Community Grid don’t have marketing or advertising budgets so new volunteers are largely recruited via word of mouth, social media, and…through coverage in print and online publications. In fact, any time a project gets written up in a big magazine, volunteer numbers jump (see images below); proving that lack of awareness is holding back volunteer computing’s immense potential.

    1
    Large Spike in SETI@Home Volunteers Due to Press Coverage. Image from BoincStats.com

    2
    Spike in Rosetta@Home Volunteers Following Media Coverage. Image from BoincStats.com

    Knowing that media coverage leads to short-term spikes in volunteer registration, it is a shame that media attention to, and public awareness of, this incredible technology seems to be dropping.

    4

    That’s where you come in. After you install BOINC and pick all the amazing projects you want to help out, why not write or tweet about your experience?

    Let your readers know that they can easily join hundreds of thousands of volunteers whose computers are helping research some of the world’s biggest problems and greatest questions. Thanks!

    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!!

    WCG credits not shown below 14,612,295
    2

    “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
    ibm

    IBM – Smarter Planet
    sp

     
    • cjslman 8:30 pm on August 8, 2016 Permalink | Reply

      Thanks for publishing this article on your blog. Hopefully it will bring in some more “crunchers” for WCG. I’ve been processing work units in WCG for over 10 years and hopefully I’ll keep “crunching” for another 10 years.

      Like

    • richardmitnick 8:44 pm on August 8, 2016 Permalink | Reply

      Thanks so much for your comment. I saw that several people from wCG had viewed the post, but you are the first to comment on any post that I have done for WCG. I had to leave crunching several years ago, OCD and three burned out CPU’s did me in. But I believe very strongly in the process and all of Citizen Science and Citizen Cyberscience. So I have kept all of my BOINC and WCG registrations and I post whenever articles such as this one give me the opportunity.

      Thanks again.

      Like

  • richardmitnick 8:45 am on July 22, 2016 Permalink | Reply
    Tags: , BOINC, Proteins, , , , This protein designer aims to revolutionize medicines and materials   

    From Science: “This protein designer aims to revolutionize medicines and materials” 

    AAAS

    Science

    1
    David Baker shows off models of some of the unnatural proteins his team has designed and made.

    Jul. 21, 2016
    Robert F. Service

    David Baker appreciates nature’s masterpieces. “This is my favorite spot,” says the Seattle native, admiring the views from a terrace at the University of Washington (UW) here. To the south rises Mount Rainier, a 4400-meter glacier-draped volcano; to the west, the white-capped Olympic Mountain range.

    But head inside to his lab and it’s quickly apparent that the computational biochemist is far from satisfied with what nature offers, at least when it comes to molecules. On a low-slung coffee table lie eight toy-sized, 3D-printed replicas of proteins. Some resemble rings and balls, others tubes and cages—and none existed before Baker and his colleagues designed and built them. Over the last several years, with a big assist from the genomics and computer revolutions, Baker’s team has all but solved one of the biggest challenges in modern science: figuring out how long strings of amino acids fold up into the 3D proteins that form the working machinery of life. Now, he and colleagues have taken this ability and turned it around to design and then synthesize unnatural proteins intended to act as everything from medicines to materials.

    2

    Already, this virtuoso proteinmaking has yielded an experimental HIV vaccine, novel proteins that aim to combat all strains of the influenza viruses simultaneously, carrier molecules that can ferry reprogrammed DNA into cells, and new enzymes that help microbes suck carbon dioxide out of the atmosphere and convert it into useful chemicals. Baker’s team and collaborators report making cages that assemble themselves from as many as 120 designer proteins, which could open the door to a new generation of molecular machines.

    f the ability to read and write DNA spawned the revolution of molecular biology, the ability to design novel proteins could transform just about everything else. “Nobody knows the implications,” because it has the potential to impact dozens of different disciplines, says John Moult, a protein-folding expert at the University of Maryland, College Park. “It’s going to be totally revolutionary.”

    Baker is by no means alone in this pursuit. Efforts to predict how proteins fold, and use that information to fashion novel versions, date back decades. But today he leads the charge. “David has really inspired the field,” says Guy Montelione, a protein structure expert at Rutgers University, New Brunswick, in New Jersey. “That’s what a great scientist does.”

    Baker, 53, didn’t start out with any such vision. Though both his parents were professors at UW—in physics and atmospheric sciences—Baker says he wasn’t drawn to science growing up. As an undergraduate at Harvard University, Baker tried studying philosophy and social studies. That was “a total waste of time,” he says now. “It was a lot of talk that didn’t necessarily add content.” Biology, where new insights can be tested and verified or discarded, drew him instead, and he pursued a Ph.D. in biochemistry. During a postdoc at the University of California, San Francisco, when he was studying how proteins move inside cells, Baker found himself captivated instead by the puzzle of how they fold. “I liked it because it’s getting at something fundamental.”

    In the early 1960s, biochemists at the U.S. National Institutes of Health (NIH) recognized that each protein folds itself into an intrinsic shape. Heat a protein in a solution and its 3D structure will generally unravel. But the NIH group noticed that the proteins they tested refold themselves as soon as they cool, implying that their structure stems from the interactions between different amino acids, rather than from some independent molecular folding machine inside cells. If researchers could determine the strength of all those interactions, they might be able to calculate how any amino acid sequence would assume its final shape. The protein-folding problem was born.

    From DNA to proteins

    The machinery for building proteins is essential for all life on earth. Click on the arrows at the bottom or swipe horizontally to learn more.

    One way around the problem is to determine protein structures experimentally, through methods such as x-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. But that’s slow and expensive. Even today, the Protein Data Bank, an international repository, holds the structures of only roughly 110,000 proteins out of the hundreds of millions or more thought to exist.

    Knowing the 3D structures of those other proteins would offer biochemists vital insights into each molecule’s function, such as whether it serves to ferry ions across a cell membrane or catalyze a chemical reaction. It would also give chemists valuable clues to designing new medicines. So, instead of waiting for the experimentalists, computer modelers such as Baker have tackled the folding problem with computer models.

    They’ve come up with two broad kinds of folding models. So-called homology models compare the amino acid sequence of a target protein with that of a template—a protein with a similar sequence and a known 3D structure. The models adjust their prediction for the target’s shape based on the differences between its amino acid sequence and that of the template. But there’s a major drawback: There simply aren’t enough proteins with known structures to provide templates—despite costly efforts to perform industrial-scale x-ray crystallography and NMR spectroscopy.

    Templates were even scarcer more than 2 decades ago, when Baker accepted his first faculty position at UW. That prompted him to pursue a second path, known as ab initio modeling, which calculates the push and pull between neighboring amino acids to predict a structure. Baker also set up a biochemistry lab to study amino acid interactions, in order to improve his models.

    Early on, Baker and Kim Simons, one of his first students, created an ab initio folding program called Rosetta, which broke new ground by scanning a target protein for short amino acid stretches that typically fold in known patterns and using that information to help pin down the molecule’s overall 3D configuration. Rosetta required such extensive computations that Baker’s team quickly found themselves outgrowing their computer resources at UW.

    Seeking more computing power, they created a crowdsourcing extension called Rosetta@home, which allows people to contribute idle computer time to crunching the calculations needed to survey all the likely protein folds. Later, they added a video game extension called Foldit, allowing remote users to apply their instinctive protein-folding insights to guide Rosetta’s search. The approach has spawned an international community of more than 1 million users and nearly two dozen related software packages that do everything from designing novel proteins to predicting the way proteins interact with DNA.

    “The most brilliant thing David has done is build a community,” says Neil King, a former Baker postdoc, now an investigator at UW’s Institute for Protein Design (IPD). Some 400 active scientists continually update and improve the Rosetta software. The program is free for academics and nonprofit users, but there’s a $35,000 fee for companies. Proceeds are plowed back into research and an annual party called RosettaCon in Leavenworth, Washington, where attendees mix mountain hikes and scientific talks.

    Despite this success, Rosetta was limited. The software was often accurate at predicting structures for small proteins, fewer than 100 amino acids in length. Yet, like other ab initio programs, it struggled with larger proteins. Several years ago, Baker began to doubt that he or anyone else would ever manage to solve most protein structures. “I wasn’t sure whether I would get there.”

    Now, he says, “I don’t feel that way anymore.”

    What changed his outlook was a technique first proposed in the 1990s by computational biologist Chris Sander, then with the European Molecular Biology Laboratory in Heidelberg, Germany, and now with Harvard. Those were the early days of whole genome sequencing, when biologists were beginning to decipher the entire DNA sequences of microbes and other organisms. Sander and others wondered whether gene sequences could help identify pairs of amino acids that, although distant from each other on the unfolded proteins, have to wind up next to each other after the protein folds into its 3D structure.

    Clues from genome sequences

    Comparing the DNA of similar proteins from different organisms shows that certain pairs of amino acids evolve in tandem—when one changes, so does the other. This suggests they are neighbors in the folded protein, a clue for predicting structure.

    Sander reasoned that the juxtaposition of those amino acids must be crucial to a protein’s function. If a mutation occurs, changing one of the amino acids so that it no longer interacts with its partner, the protein might no longer work, and the organism could suffer or die. But if both neighboring amino acids are mutated at the same time, they might continue to interact, and the protein might work as well or even better.

    The upshot, Sander proposed, was that certain pairs of amino acids necessary to a protein’s structure would likely evolve together. And researchers would be able to read out that history by comparing the DNA sequences of genes from closely related proteins in different organisms. Whenever such DNA revealed pairs of amino acids that appeared to evolve in lockstep, it would suggest that they were close neighbors in the folded protein. Put enough of those constraints on amino acid positions into an ab initio computer model, and the program might be able to work out a protein’s full 3D structure.

    Unfortunately, Sander says, his idea “was a little ahead of its time.” In the 1990s, there weren’t enough high-quality DNA sequence data from enough similar proteins to track coevolving amino acids.

    By the early part of this decade, however, DNA sequences were flooding in thanks to new gene-sequencing technology. Sander had also teamed up with Debora Marks at Harvard Medical School in Boston to devise a statistical algorithm capable of teasing out real coevolving pairs from the false positives that plagued early efforts. In a 2011 article in PLOS ONE, Sander, Marks, and colleagues reported that the coevolution technique could constrain the position of dozens of pairs of amino acids in 15 proteins—each from a different structural family—and work out their structures. Since then, Sander and Marks have shown that they can decipher the structure of a wide variety of proteins for which there are no homology templates. “It has changed the protein-folding game,” Sander says.

    It certainly did so for Baker. When he and colleagues realized that scanning genomes offered new constraints for Rosetta’s ab initio calculations, they seized the opportunity. They were already incorporating constraints from NMR and other techniques. So they rushed to write a new software program, called Gremlin, to automatically compare gene sequences and come up with all the likely coevolving amino acid pairs. “It was a natural for us to put them into Rosetta,” Baker says.

    The results have been powerful. Rosetta was already widely considered the best ab initio model. Two years ago, Baker and colleagues used their combined approach for the first time in an international protein-folding competition, the 11th Critical Assessment of protein Structure Prediction (CASP). The contest asks modelers to compute the structures of a suite of proteins for which experimental structures are just being worked out by x-ray crystallography or NMR. After modelers submit their predictions, CASP’s organizers then reveal the actual experimental structures. One submission from Baker’s team, on a large protein known as T0806, came back nearly identical to the experimental structure. Moult, who heads CASP, says the judge who reviewed the predicted structure immediately fired off an email to him saying “either someone solved the protein-folding problem, or cheated.”

    “We didn’t [cheat],” Sergey Ovchinnikov, a grad student in Baker’s lab, says with a chuckle.

    The implications are profound. Five years ago, ab initio models had determined structures for just 56 proteins of the estimated 8000 protein families for which there is no template. Since then, Baker’s team alone has added 900 and counting, and Marks believes the approach will already work for 4700 families. With genome sequence data now pouring into scientific databases, it will likely only be a couple years before protein-folding models have enough coevolution data to solve structures for nearly any protein, Baker and Sander predict. Moult agrees. “I have been waiting 10 years for a breakthrough,” he says. “This seems to me a breakthrough.”

    For Baker, it’s only the beginning. With Rosetta’s steadily improving algorithms and ever-greater computing power, his team has in essence mastered the rules for folding—and they’ve begun to use that understanding to try to one-up nature’s creations. “Almost everything in biomedicine could be impacted by an ability to build better proteins,” says Harvard synthetic biologist George Church.

    Baker notes that for decades researchers pursued a strategy he refers to as “Neandertal protein design,” tweaking the genes for existing proteins to get them to do new things. “We were limited by what existed in nature. … We can now short-cut evolution and design proteins to solve modern-day problems.”

    Take medicines, such as drugs to combat the influenza virus. Flu viruses come in many strains that mutate rapidly, which makes it difficult to find molecules that can knock them all out. But every strain contains a protein called hemagglutinin that helps it invade host cells, and a portion of the molecule, known as the stem, remains similar across many strains. Earlier this year, Baker teamed up with researchers at the Scripps Research Institute in San Diego, California, and elsewhere to develop a novel protein that would bind to the hemagglutinin stem and thereby prevent the virus from invading cells.

    The effort required 80 rounds of designing the protein, engineering microbes to make it, testing it in the lab, and reworking the structure. But in the 4 February issue of PLOS ONE, the researchers reported that when they administered their final creation to mice and then injected them with a normally lethal dose of flu virus, the rodents were protected. “It’s more effective than 10 times the dose of Tamiflu,” an antiviral drug currently on the market, says Aaron Chevalier, a former Baker Ph.D. student who now works at a Seattle biotech company called Virvio here that is working to commercialize the protein as a universal antiflu drug.

    Another potential addition to the medicine cabinet: a designer protein that chops up gluten, the infamous substance in wheat and other grains that people with Celiac disease or gluten sensitivity have trouble digesting. Ingrid Swanson Pultz began crafting the gluten-breaker even before joining Baker’s lab as a postdoc and is now testing it in animals and working with IPD to commercialize the research. And those self-assembling cages that debut this week could one day be filled with drugs or therapeutic snippets of DNA or RNA that can be delivered to disease sites throughout the body.

    The potential of these unnatural proteins isn’t limited to medicines. Baker, King, and their colleagues have also attached up to 120 copies of a molecule called green fluorescent protein to the new cages, creating nano-lanterns that could aid research by lighting up as they move through tissues.

    Church says he believes that designer proteins might soon rewrite the biology inside cells. In a paper last year in eLife, he, Baker, and colleagues designed proteins to bind to either a hormone or a heart disease drug inside cells, and then regulate the activity of a DNA-cutting enzyme, Cas9, that is part of the popular CRISPR genome-editing system. “The ability to design sensors [inside cells] is going to be big,” Church says. The strategy could allow researchers or physicians to target the powerful gene-editing system to a specific set of cells—those that are responding to a hormone or drug. Biosensors could also make it possible to switch on the expression of specific genes as needed to break down toxins or alert the immune cells to invaders or cancer.

    Protein for every purpose

    The ability to predict how an amino acid sequence will fold—and hence how the protein will function—opens the way to designing novel proteins that can catalyze specific chemical reactions or act as medicines or materials. Genes for these proteins can be synthesized and inserted into microbes, which build the proteins.
    array

    2D arrays can be used as nanomaterials in various applications.

    3

    Information can be coded into protein sequences, like DNA.

    5

    Antagonists bind to a target protein, blocking its activation.

    4

    Channels through membranes act as gateways.

    6

    Cages can contain medicinal cargo or carry it on their surfaces.

    7

    Sensors travel throughout the body to detect various signals.

    8

    Baker’s lab is abuzz with other projects. Last year, his group and collaborators reported engineering into bacteria a completely new metabolic pathway, complete with a designer protein that enabled the microbes to convert atmospheric carbon dioxide into fuels and chemicals. Two years ago, they unveiled in Science proteins that spontaneously arrange themselves in a flat layer, like interlocking tiles on a bathroom floor. Such surfaces may lead to novel types of solar cells and electronic devices.

    In perhaps the most thought-provoking project, Baker’s team has designed proteins to carry information, imitating the way DNA’s four nucleic acid letters bind and entwine in the genetic molecule’s famed double helix. For now, these protein helixes can’t convey genetic information that cells can read. But they symbolize something profound: Protein designers have shed nature’s constraints and are now only limited by their imagination. “We can now build a whole new world of functional proteins,” Baker says.

    See the full article here .

    YOU CAN JOIN IN THIS WORK FROM THE COMFORT OF YOUR EASY CHAIR.

    Rosetta@home runs on software from Berkeley Open Infrastructure for Network Computing (BOINC).
    Visit the BOINC website, download and install the BOINC software, attach to the Rosetta@home project. It is that simple. The project will use the available cpu cycles of your computer, tablet or cell phone to “crunch” data for the Baker Lab.

    While you are at the BOINC website, check out some of the other really important projects running at universities and institutions all over the world. They could all use your help and would run simultaneously with no conflicts on your devices.

    BOINCLarge

    BOINC WallPaper

    The American Association for the Advancement of Science is an international non-profit organization dedicated to advancing science for the benefit of all people.

    Please help promote STEM in your local schools.
    STEM Icon
    Stem Education Coalition

     
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