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  • richardmitnick 2:55 pm on January 7, 2017 Permalink | Reply
    Tags: , , Protein Studies, ,   

    From Uncovering Genome Mysteries at WCG: “Big Data and Big Plans: Next Steps for Uncovering Genome Mysteries” 

    New WCG Logo


    World Community Grid (WCG)

    15 Dec 2016 [Under what rock have you been hiding?]
    Wim Degrave, Ph.D.
    Laboratório de Genômica Funcional e Bioinformática Instituto Oswaldo Cruz – Fiocruz

    World Community Grid’s role in the Uncovering Genome Mysteries project has ended, but the research team’s work continues as they analyze the results of the calculations and prepare to apply the data to medical, agricultural, and other real-world applications.

    A diver collects samples from seawood off the coast of Australia. Uncovering Genome Mysteries analyzed protein sequences from a wide variety of life forms in many environments such as the ocean.


    The Uncovering Genome Mysteries project began on World Community Grid in November 2014, with the aim of analyzing protein sequences to help understand how organisms function and interact with each other and the environment. The project began with 120 million predicted protein sequences from close to 150,000 organisms. These protein sequences and organisms represent a wide variety of known or uncharacterised life forms in our biosphere. They came from organisms in samples taken from a range of environments, including water and soil, as well as on and inside plants and animals. Additionally, 70 million sequences, derived from prospective analysis of genetic information from microbial marine ecosystems from Australia were added, with the objective to add to the identification of possible functionalities of these sequences. In July 2015, we added yet another 20 million newly predicted sequences of proteins.

    Thanks to the enthusiastic contributions of more than 76,000 World Community Grid volunteers, all of these protein sequences were analyzed in approximately 24 months.

    Uncovering Genome Mysteries has been a challenging and ambitious project. Analyzing all the predicted enzymes and other proteins encoded in the genetic information known thus far from of all the organisms and life forms from our biosphere is a large task. Due to the development of new sequencing technologies for fast and cheap determination of genetic code, additional basic information will become available at an accelerating rate, making it increasingly difficult [?]to perform such a complete comparative analysis in the future.

    Our daunting task of performing close to 100 quadrillion comparisons has now been completed. The resulting data is more than 30 terabytes of compressed information (more than 150 terabytes uncompressed), even though each comparison only resulted in a single line of numbers for only the very highest probability similarities between protein sequences.

    Results to Date and Plans for the Future

    So, what is next? The research team at Fiocruz has spent the last year designing and testing new algorithms to transform the output of the comparisons with distance calculations between the genomes of the organisms included. Scientific literature cites many different ways to do this, depending on the purpose of the analysis and the views on evolutionary biology.

    The results of the Uncovering Genome Mysteries can be summarized as follows:

    More complete and precise information is now available on the structure and function of proteins encoded by living organisms in our biosphere. More proteins are being studied and experimented with each day in the thousands of laboratories around the world, and by using results from the comparison performed through the project, functional parallels can be drawn for proteins that show structural similarity between organisms. This is particularly valuable when predicted protein fragments are compared from uncharacterised organisms, for example in environmental and ecology studies, such as those originated from the laboratory of co-investigator Dr. Torsten Thomas, and his team from the Centre for Marine Bio-Innovation & the School of Biological, Earth and Environmental Sciences at the University of New South Wales, Sydney, Australia. The resulting database with these functional annotations will be made publicly available as the next version of our protein comparison database, ProteinWorldDB, in the coming months.

    Through comparison, new protein functions are discovered that can have medical, agricultural, technological or industrial applications. These can be as new biopharmaceuticals, bioinsecticides, biodegradation of waste, or enzymes for production of chemicals, but especially when part of new biochemical pathways in cells, that help laboratories to develop new green chemistry or energy production, or biosynthesis and transformation of new drugs. This also adds to the growing knowledge of biotechnology and synthetic biology.

    The group at Fiocruz has developed new ways to compare genomes from different organisms. Traditionally, such analyses consider what is conserved between genomes, resulting in distance calculations that are used for phylogenetic studies and the estimation of evolutionary relationships between organisms. However, we feel that this is only part of the picture, and the Fiocruz team designed a new algorithm that also takes differences into account. This was coupled to a new visualization method for such comparisons, resulting in a markedly faster way to add new data to the picture. We hope that this method will enable us to keep track of data from new organisms that becomes available, adding results to the growing ProteinWorld DB database.

    Thank you to all World Community Grid volunteers who supported this project, and we plan to keep in touch as we have further news about our ongoing research.

    See the full article here.

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    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.

    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



    “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.

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  • richardmitnick 11:20 am on December 4, 2016 Permalink | Reply
    Tags: , , , Protein Studies,   

    From Weizmann: “When Cells Are Fit” 

    Weizmann Institute of Science logo

    Weizmann Institute of Science

    07.11.2016 [I guess this has just ben in hiding.]
    No writer credit found

    How do the expression levels of numerous proteins affect a cell’s fitness?

    Tracking protein activity levels in a cell is essential to the study of such diseases as cancer which, alongside changes in the genes, involves changes in the activity levels of numerous proteins. However, deducing function, fitness and cellular well-being from the growing number of protein level measurements is still a major challenge. For example, is a two-fold – or 100-fold – range in activity for a particular protein tolerable over the population, or does it herald differences in the way that the cells carry out their tasks? Charting this connection could transform the way we diagnose, monitor and treat patients.

    (l-r) Maya Lotan-Pompan, Leeat Yankielowicz Keren and Prof. Eran Segal can now look at multiple protein expression levels at once

    “Most experiments examining ranging protein activity levels have, until now, focused on single proteins. What we did was to develop a way to systematically vary activity levels for hundreds of different proteins – all in a single experiment – and accurately measure how this affects the function of the cells,” says Leeat Yankielowicz Keren, a research student in the group of Prof. Eran Segal of the Computer Science and Applied Mathematics, and Molecular Cell Biology Departments at the Weizmann Institute of Science.

    The basic idea of the experiment in Segal’s lab was to create a competition in which common bakers’ yeast cells are pitted against one another. Each cell was nearly identical to its neighbors, except for a tweak to the activity level of one of its proteins. Thousands of these genetically engineered yeast cells were grown together in lab dishes; the “winners” were those in which expression levels boosted their fitness, basically enabling the yeast to eat more, grow and divide faster.

    Segal and his group developed a high-throughput genetic engineering technique that enabled them to manipulate the activity levels of different protein levels within thousands of cells simultaneously, precisely controlling, for each, the amounts of one particular protein. With 130 different activity levels – the highest 500 times the lowest – attached to 81 different protein-encoding sequences, the researchers created something like 10,000 different variations on the basic yeast cell, assigning each a “barcode” for convenient identification. With a combination of DNA sequencing techniques and an algorithm they created to reconstruct the growth rates of the various yeast cells, the team was then able to accurately map the connections between protein levels and the fitness of the cell.

    The competition took place in two different “arenas.” In one, the yeast were fed the glucose sugar they prefer; in the second, they were fed a different kind of sugar, galactose. The team found that when the competition took place on the kind of sugar it prefers, the original, untouched version of the yeast cell was the overall winner – testimony to the efficiency of evolution. But on the second kind of sugar, others came out on top. These results showed that around 20% of the yeast’s natural protein activity levels are too low or too high for growing on this sugar. This could be relevant to biotechnology: The second sugar is cheaply and abundantly found in seaweed, and the yeast break it down into ethanol, which can be burned in place of fossil fuels. The study suggests that genetically engineering yeast to alter some of these protein levels could significantly increase the efficiency of this process.

    Mapping all the activity patterns together enabled the group to begin to see patterns in the chaos. Similar activity patterns, for example, pointed to proteins that work together. Further analysis even revealed the “math” that cells use to produce these proteins in the right ratios, for example, for the construction of complexes that require exact proportions of their various proteins.

    Some of the proteins appeared to operate in a very narrow range – levels even a bit below or above this range drastically affected the fitness of the yeast. Others seemed to be much more flexible – a little or a lot did not affect the cell’s fitness, at least for the particular growing conditions. Those showing the larger ranges in the fitness competition turned out to be proteins that ordinarily vary widely from cell to cell in the natural yeast population. These findings suggest that understanding this flexibility can shed light on how activity levels are selected in evolution.

    Gene fitness profiles are different when yeast are grown on a sugar they normally prefer less

    For Segal and his team, the future goal is to create similar maps for protein activity levels in human cells. Such maps could form the basis of future diagnostic techniques that would be much more refined and precise than those of today, based on blood tests that already exist or can easily be developed. They might reveal the effects of diet or medications; and they could provide early diagnosis of cancer. Keren: “We want to eventually create a ‘chart’ that doctors can use to know which protein levels to check, and what levels should, ideally, be appearing in order to prevent disease.”

    Also participating in this study were Maya Lotan-Pompan and Dr. Adina Weinberger of Prof. Segal’s group, Dr. Jean Hausser and Prof. Uri Alon of the department of Molecular Cell Biology and Prof. Ron Milo of the department of Plant and Environmental Sciences.

    Science paper:
    Massively Parallel Interrogation of the Effects of Gene Expression Levels on Fitness, Cell

    See the full article here .

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    Weizmann Institute Campus

    The Weizmann Institute of Science is one of the world’s leading multidisciplinary research institutions. Hundreds of scientists, laboratory technicians and research students working on its lushly landscaped campus embark daily on fascinating journeys into the unknown, seeking to improve our understanding of nature and our place within it.

    Guiding these scientists is the spirit of inquiry so characteristic of the human race. It is this spirit that propelled humans upward along the evolutionary ladder, helping them reach their utmost heights. It prompted humankind to pursue agriculture, learn to build lodgings, invent writing, harness electricity to power emerging technologies, observe distant galaxies, design drugs to combat various diseases, develop new materials and decipher the genetic code embedded in all the plants and animals on Earth.

    The quest to maintain this increasing momentum compels Weizmann Institute scientists to seek out places that have not yet been reached by the human mind. What awaits us in these places? No one has the answer to this question. But one thing is certain – the journey fired by curiosity will lead onward to a better future.

  • richardmitnick 7:36 am on September 24, 2016 Permalink | Reply
    Tags: , , Protein Studies, Research at Princeton   

    From Research at Princeton: “New method identifies protein-protein interactions on basis of sequence alone (PNAS)” 

    Princeton University
    Princeton University

    September 23, 2016
    Catherine Zandonella, Office of the Dean for Research

    Researchers can now identify which proteins will interact just by looking at their sequences. Pictured are surface representations of a histidine kinase dimer (HK, top) and a response regulator (RR, bottom), two proteins that interact with each other to carry out cellular signaling functions. (Image based on work by Casino, et. al. credit: Bitbol et. al 2016/PNAS.)

    Genomic sequencing has provided an enormous amount of new information, but researchers haven’t always been able to use that data to understand living systems.

    Now a group of researchers has used mathematical analysis to figure out whether two proteins interact with each other, just by looking at their sequences and without having to train their computer model using any known examples. The research, which was published online today in the journal Proceedings of the National Academy of Sciences, is a significant step forward because protein-protein interactions underlie a multitude of biological processes, from how bacteria sense their surroundings to how enzymes turn our food into cellular energy.

    “We hadn’t dreamed we’d be able to address this,” said Ned Wingreen, Princeton University‘s Howard A. Prior Professor in the Life Sciences, and a professor of molecular biology and the Lewis-Sigler Institute for Integrative Genomics, and a senior co-author of the study with Lucy Colwell of the University of Cambridge. “We can now figure out which protein families interact with which other protein families, just by looking at their sequences,” he said.

    Although researchers have been able to use genomic analysis to obtain the sequences of amino acids that make up proteins, until now there has been no way to use those sequences to accurately predict protein-protein interactions. The main roadblock was that each cell can contain many similar copies of the same protein, called paralogs, and it wasn’t possible to predict which paralog from one protein family would interact with which paralog from another protein family. Instead, scientists have had to conduct extensive laboratory experiments involving sorting through protein paralogs one by one to see which ones stick.

    In the current paper, the researchers use a mathematical procedure, or algorithm, to examine the possible interactions among paralogs and identify pairs of proteins that interact. The method was able to correctly predict 93% of the protein-protein paralog pairs that were present in a dataset of more than 20,000 known paired protein sequences, without being first provided any examples of correct pairs.

    Interactions between proteins happen when two proteins come into physical contact and stick together via weak bonds. They may do this to form part of a larger piece of machinery used in cellular metabolism. Or two proteins might interact to pass a signal from the exterior of the cell to the DNA, to enable a bacterial organism to react to its environment.

    When two proteins come together, some amino acids on one chain stick to the amino acids on the other chain. Each site on the chain contains one of 20 possible amino acids, yielding a very large number of possible amino-acid pairings. But not all such pairings are equally probable, because proteins that interact tend to evolve together over time, causing their sequences to be correlated.

    The algorithm takes advantage of this correlation. It starts with two protein families, each with multiple paralogs in any given organism. The algorithm then pairs protein paralogs randomly within each organism and asks, do particular pairs of amino acids, one on each of the proteins, occur much more or less frequently than chance? Then using this information it asks, given an amino acid in a particular location on the first protein, which amino acids are especially favored at a particular location on the second protein, a technique known as direct coupling analysis. The algorithm in turn uses this information to calculate the strengths of interactions, or “interaction energies,” for all possible protein paralog pairs, and ranks them. It eliminates the unlikely pairings and then runs again using only the top most likely protein pairs.

    The most challenging part of identifying protein-protein pairs arises from the fact that proteins fold and kink into complicated shapes that bring amino acids in proximity to others that are not close by in sequence, and that amino-acids may be correlated with each other via chains of interactions, not just when they are neighbors in 3D. The direct coupling analysis works surprisingly well at finding the true underlying couplings that occur between neighbors.

    The work on the algorithm was initiated by Wingreen and Robert Dwyer, who earned his Ph.D. in the Department of Molecular Biology at Princeton in 2014, and was continued by first author Anne-Florence Bitbol, who was a postdoctoral researcher in the Lewis-Sigler Institute for Integrative Genomics and the Department of Physics at Princeton and is now a CNRS researcher at Universite Pierre et Marie Curie – Paris 6. Bitbol was advised by Wingreen and Colwell, an expert in this kind of analysis who joined the collaboration while a member at the Institute for Advanced Study in Princeton, NJ, and is now a lecturer in chemistry at the University of Cambridge.

    The researchers thought that the algorithm would only work accurately if it first “learned” what makes a good protein-protein pair by studying ones discovered in experiments. This required that the researchers give the algorithm some known protein pairs, or “gold standards,” against which to compare new sequences. The team used two well-studied families of proteins, histidine kinases and response regulators, which interact as part of a signaling system in bacteria.

    But known examples are often scarce, and there are tens of millions of undiscovered protein-protein interactions in cells. So the team decided to see if they could reduce the amount of training they gave the algorithm. They gradually lowered the number of known histidine kinase-response regulator pairs that they fed into the algorithm, and were surprised to find that the algorithm continued to work. Finally, they ran the algorithm without giving it any such training pairs, and it still predicted new pairs with 93 percent accuracy.

    “The fact that we didn’t need a gold standard was a big surprise,” Wingreen said.

    Upon further exploration, Wingreen and colleagues figured out that their algorithm’s good performance was due to the fact that true protein-protein interactions are relatively rare. There are many pairings that simply don’t work, and the algorithm quickly learned not to include them in future attempts. In other words, there is only a small number of distinctive ways that protein-protein interactions can happen, and a vast number of ways that they cannot happen. Moreover, the few successful pairings were found to repeat with little variation across many organisms. This it turns out, makes it relatively easy for the algorithm to reliably sort interactions from non-interactions.

    Wingreen compared this observation – that correct pairs are more similar to one another than incorrect pairs are to each other – to the opening line of Leo Tolstoy’s Anna Karenina, which states, “All happy families are alike; each unhappy family is unhappy in its own way.”

    The work was done using protein sequences from bacteria, and the researchers are now extending the technique to other organisms.

    The approach has the potential to enhance the systematic study of biology, Wingreen said. “We know that living organisms are based on networks of interacting proteins,” he said. “Finally we can begin to use sequence data to explore these networks.”

    The research was supported in part by the National Institutes of Health (Grant R01-GM082938) and the National Science Foundation (Grant PHY–1305525).

    See the full article here .

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    About Princeton: Overview

    Princeton University is a vibrant community of scholarship and learning that stands in the nation’s service and in the service of all nations. Chartered in 1746, Princeton is the fourth-oldest college in the United States. Princeton is an independent, coeducational, nondenominational institution that provides undergraduate and graduate instruction in the humanities, social sciences, natural sciences and engineering.

    As a world-renowned research university, Princeton seeks to achieve the highest levels of distinction in the discovery and transmission of knowledge and understanding. At the same time, Princeton is distinctive among research universities in its commitment to undergraduate teaching.

    Today, more than 1,100 faculty members instruct approximately 5,200 undergraduate students and 2,600 graduate students. The University’s generous financial aid program ensures that talented students from all economic backgrounds can afford a Princeton education.

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  • richardmitnick 9:11 am on September 19, 2016 Permalink | Reply
    Tags: #weekendusers Express experiments for better health, , , Protein Studies   

    From ESRF: “#weekendusers Express experiments for better health” 

    ESRF bloc
    The European Synchrotron


    Synchrotron sources are crucial for structural biology and research performed at the ESRF produces 40% of the protein structures submitted in Europe. This weekend, scientists from Barcelona spent 24 hours trying to unveil the structures of medically-relevant proteins.

    They drove more than 1000km for 24h of experiments and 130 samples. The aim: to get insight into the structures of proteins that play a role in health, such as mycoplasma, viral and membrane transport proteins. “It is very intense”, explains David Aparicio, from the Institut de Biologia Molecular de Barcelona (Spain), “but we are now coming once a month for 24h each time, so we are used to this rythm”, he adds. He is one of the four scientists on ID23-1 this weekend. Two of them, Victor Ruiz and Diego Ferrero, also come from the IBMB, but from different research groups, whilst the last one, Ekaitz Errasti works in the Institute for Research in Biomedicine (IRB) in the same city.

    Checking that the experiment is going smoothly in the small hours of Sunday. No image credit.

    The researchers came to the ESRF in the framework of the so-called Block Allocation Group from Barcelona. Crystallographers from large, well-established groups requiring a significant amount of beamtime often present their proposals in groups. BAG Barcelona includes groups that belong to the Institute for Molecular Biology of Barcelona (IBMB) from the Spanish Reseach Council (CSIC), the Institute of Biomedical Research (IRB) and the Institut de Recerca – Hospital de la Santa Creu i Sant Pau (HSCSP).

    Maria Solà, coordinator of the BAG Barcelona, explains that “the success of our projects is absolutely dependent on obtaining data using synchrotron radiation”, due to the size and characteristics of the samples. “The tunable and microfocus beamline of ID23 fulfills excellently all our requirements”, she adds, “so we are hoping for good data”.

    See the full article here .

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    The ESRF – the European Synchrotron Radiation Facility – is the most intense source of synchrotron-generated light, producing X-rays 100 billion times brighter than the X-rays used in hospitals. These X-rays, endowed with exceptional properties, are produced at the ESRF by the high energy electrons that race around the storage ring, a circular tunnel measuring 844 metres in circumference. Each year, the demand to use these X-ray beams increases and thousands of scientists from around the world come to Grenoble, to access the 43 highly specialised experimental stations, called “beamlines”, each equipped with state-of-the-art instrumentation, operating 24 hours a day, seven days a week.

    Thanks to the brilliance and quality of its X-rays, the ESRF functions like a “super-microscope” which “films” the position and motion of atoms in condensed and living matter, and reveals the structure of matter in all its beauty and complexity. It provides unrivalled opportunities for scientists in the exploration of materials and living matter in a very wide variety of fields: chemistry, material physics, archaeology and cultural heritage, structural biology and medical applications, environmental sciences, information science and nanotechnologies.

    Following on from 20 years of success and excellence, the ESRF has embarked upon an ambitious and innovative modernisation project, the Upgrade Programme, implemented in two phases: Phase I (2009-2015) and the ESRF-EBS (Extremely Brilliant Source) (2015-2022) programmes. With an investment of 330 million euros, the Upgrade Programme is paving the way to a new generation of synchrotron storage rings, that will produce more intense, coherent and stable X-ray beams. By constructing a new synchrotron, deeply rooted in the existing infrastructure, the ESRF will lead the way in pushing back the boundaries of scientific exploration of matter, and contribute to answering the great technological, economic, societal and environmental challenges confronting our society.

  • richardmitnick 9:54 am on September 12, 2016 Permalink | Reply
    Tags: , , Protein crystallography, Protein Studies   

    From ANL: “Two protein studies discover molecular secrets to recycling carbon and healing cells” 

    ANL Lab

    News from Argonne National Laboratory

    September 9, 2016
    Kate Thackrey

    Researchers at Argonne modeled the HcaR protein complex, above, a sort of molecular policeman that controls when to activate genes that code for enzymes used by Acinetobacter bacteria to break down compounds for food. Understanding these processes can help scientists develop ideas for converting more carbon in soil. (Image courtesy Kim et al./Journal of Biological Chemistry.)

    Researchers at the U.S. Department of Energy’s (DOE’s) Argonne National Laboratory have mapped out two very different types of protein. One helps soil bacteria digest carbon compounds; the other protects cells from the effects of harmful molecules.

    In order to uncover the structure of these proteins, researchers used a technique called protein crystallography. Like a mosquito trapped in amber, compounds that are crystallized are placed in array in identical positions and ordered so that scientists can target them with X-ray beams and work backwards from the scattering patterns produced to recreate their three-dimensional structures atom by atom.

    Bacterial breakdown

    In the first study, a group of researchers from the Structural Biology Center, which is funded by DOE’s Office of Science, mapped out a protein responsible for breaking down organic compounds in soil bacteria, an important process for recycling carbon in the ecosystem.

    The bacteria used, called Acinetobacter, is located mostly in soil and water habitats, where it helps to change aromatic compounds (named for their ring shape) into forms that can be used as food.

    One of the sources of aromatic compounds found in soil is lignin, a tough polymer that is an essential part of all plants and that’s hard for many organisms to digest.

    “But Acinetobacter can utilize these aromatic compounds as their sole source of carbon,” said Andrzej Joachimiak, who co-authored both studies and is the director of the Structural Biology Center and the Midwest Center for Structural Genomics at Argonne.

    In order for Acinetobacter to break down the aromatic compounds, it needs to produce catabolic enzymes, molecular machines built from an organism’s DNA that break down molecules into smaller parts that can be digested.

    Whether or not membrane transporters and catabolic enzymes are produced falls to the HcaR regulator, a sort of molecular policeman that controls when the genes that code for these enzymes can be activated.

    Joachimiak and his colleagues found that the regulator works in a cycle, activating genes when aromatic compounds are present and shutting genes down when the compounds are used up.

    “By nature it is very efficient,” Joachimiak said. “If you don’t have aromatic compounds inside a cell, the operon is shut down.”

    The research team didn’t stop at mapping out the regulator itself; to discover how the cycle worked, they crystalized the HcaR regulator during interactions with its two major inputs: the aromatic compounds and DNA.

    The group found that when aromatic compounds are not present in the cell, two wings found on either side of the HcaR regulator wrap around the DNA. This action is mirrored on both sides of the regulator, covering the DNA regulatory site and preventing genes from being activated.

    “This is something that has never been seen before,” Joachimiak said.

    When the aromatic compounds are present, however, they attach themselves to the HcaR regulator, making it so stiff that it can no longer grapple with the DNA.

    Joachimiak said that this knowledge could help outside of the lab, with applications such as a sensor for harmful pesticides and as a template for converting more carbon in soil.

    “If we can train bacteria to better degrade lignin and other polymers produced by plants during photosynthesis, more natural carbon sources can be utilized for example for production of biofuels and bioproducts,” Joachimiak said.

    The paper was published earlier this year by the Journal of Biological Chemistry under the title How Aromatic Compounds Block DNA Binding of HcaR Catabolite Regulator. It was supported by the National Institutes of Health and the U.S. Department of Energy (Office of Biological and Environmental Research).

    Protective proteins

    A second paper focuses on a family of proteins identified as DUF89, which stands for “domain unknown function.” This family is conserved across all three branches of the phylogenetic tree, which means that it is likely essential to many life forms.

    DUF89 has been identified as a type of enzyme called a phosphatase, which strips molecules of their phosphate groups. The paper’s authors hypothesized that DUF89 proteins use this ability to save useful proteins in a cell from rogue molecules which could alter their structure, making them useless or destructive.

    The study found that DUF89 proteins use a metal ion, probably manganese, to lure in potentially harmful molecules and a water molecule to break off their phosphate group.

    DUF89 proteins could have an important role in breaking down a specific type of disruptive molecule: sugar. When the concentration of sugar in blood reaches high levels, simple sugars can have unwanted side reactions with proteins and DNA through a process called glycation.

    “We always have to deal with these side reactions that happen in our cells, and when we get older, we have an accumulation of these errors in our cells,” Joachimiak said.

    Joachimiak said that this research could help scientists develop DUF89 treatments from non-human sources as a way to combat glycation in the bloodstream.

    The paper was published on the Nature Chemical Biology website on June 20 under the title A family of metal-dependent phosphatases implicated in metabolite damage-control. Other authors on the paper were from the University of Florida, the University of Toronto, the University of California-Davis and Brookhaven National Laboratory. It was supported by the National Science Foundation, Genome Canada, the Ontario Genomics Institution, the Ontario Research Fund, the Natural Sciences and Engineering Research Council of Canada, the National Institutes of Health, the C.V. Griffin Sr. Foundation and the U.S. Department of Energy (Office of Basic Energy Sciences and Office of Biological and Environmental Research).

    Both studies used X-rays from the Advanced Photon Source, a DOE Office of Science User Facility, using beamlines 19-ID and 19-BM.

    Both also stem from the goal of the Midwest Center for Structural Genomics, which is to discover the structure and function of proteins potentially important to biomedicine.

    Joachimiak said that despite the new findings from these studies, when it comes to understanding what proteins do, we still have a long way to go.

    “When we sequence genomes, we can predict proteins, but when we predict those sequences we can only say something about function for about half of them,” Joachimiak said.

    See the full article here .

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    Argonne National Laboratory seeks solutions to pressing national problems in science and technology. The nation’s first national laboratory, Argonne conducts leading-edge basic and applied scientific research in virtually every scientific discipline. Argonne researchers work closely with researchers from hundreds of companies, universities, and federal, state and municipal agencies to help them solve their specific problems, advance America’s scientific leadership and prepare the nation for a better future. With employees from more than 60 nations, Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science. For more visit http://www.anl.gov.

    The Advanced Photon Source at Argonne National Laboratory is one of five national synchrotron radiation light sources supported by the U.S. Department of Energy’s Office of Science to carry out applied and basic research to understand, predict, and ultimately control matter and energy at the electronic, atomic, and molecular levels, provide the foundations for new energy technologies, and support DOE missions in energy, environment, and national security. To learn more about the Office of Science X-ray user facilities, visit http://science.energy.gov/user-facilities/basic-energy-sciences/.

    Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science

    Argonne Lab Campus

  • richardmitnick 11:43 am on September 4, 2016 Permalink | Reply
    Tags: , , Protein Studies   

    From ICL: “A new way to create synthetic proteins could lead to more flexible designs” 

    Imperial College London
    Imperial College London

    Structure of a designed protein

    Building up proteins from scratch, rather than piecing together fragments of existing proteins, could make designing new nanomaterials easier.

    Proteins perform a myriad of functions essential for life. They also make up important and useful biological materials, for example spider silk, which is exceptionally strong but still flexible.

    The ability to design completely new proteins would help scientists create nanomaterials that, like spider silk, have a specific microstructure that confers useful properties.

    Until now, new proteins have usually been designed by piecing together fragments of existing proteins in order to simplify the design process.

    Now, a team led by researchers from Imperial College London has used a synthetic repeating protein scaffold as a base and shown that it is possible to add individual computationally designed modules, which can be chosen for their ability to perform a specific function. This gives biological engineers the possibility of designing new molecules from scratch.

    The base scaffold is a new artificial repeating helix to which functional modules can be added. The team designed the structure on a computer, created it using synthetic genes, and then used a technique called X-ray crystallography to confirm they had built what they set out to.

    Building complexity

    Study leader Dr James Murray from the Department of Life Sciences at Imperial said: “Our system would allow designers to create proteins with atoms in specific places and build up complexity module by module, rather than designing the protein all at once.”

    Dr James MacDonald from Imperial’s Centre for Synthetic Biology and Innovation added: “We have developed a new method for computationally designing brand new proteins that is potentially more flexible than taking sections from known proteins.”

    The team’s first experimental results, published today in Proceedings of the National Academy of Sciences, added just one module to a helical scaffold as a proof that the system could work. Next, they want to add more loops to build up new functionality, and then test whether the synthetic proteins perform as expected.

    Professor Paul Freemont, co-founder and co-director of the Centre for Synthetic Biology and Innovation at Imperial, said: “Being able to construct proteins at the atomic level has a lot of potential and exciting applications, including synthetic enzymes and new nanomaterials.

    These could include improved nanowire batteries, where viruses are programmed to produce thin wires that increase the surface area and performance of batteries.”

    See the full article here .

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    Imperial College London

    Imperial College London is a science-based university with an international reputation for excellence in teaching and research. Consistently rated amongst the world’s best universities, Imperial is committed to developing the next generation of researchers, scientists and academics through collaboration across disciplines. Located in the heart of London, Imperial is a multidisciplinary space for education, research, translation and commercialisation, harnessing science and innovation to tackle global challenges.

  • richardmitnick 7:21 am on September 2, 2016 Permalink | Reply
    Tags: , , , , Protein Studies   

    From Caltech: Women in STEM – “Multitasking Protein Keeps Immune System Healthy” Beth Stadtmueller 

    Caltech Logo


    Lori Dajose

    Simplified diagram of pIgR binding to an antibody. A) pIgR and an antibody. B) Recognition binding. pIgR chemically recognizes an antibody. C) Conformational change. The pIgR protein opens up. D) The bound state of pIgR and an antibody. Credit: B. Stadtmueller

    Schematic summary highlighting the differences in pIgR structure among fish, birds and humans.
    Credit: B. Stadtmueller

    The polymeric immunoglobulin receptor, or pIgR, is a multitasking protein produced in the lining of mucosal surfaces, such as the intestines. It plays a pivotal role in the body’s immune functions by sequestering bacteria and by assisting antibodies—large proteins that can identify and neutralize specific bacteria and viruses. Now, scientists at Caltech have determined the three-dimensional structure of pIgR, providing important insights into how the protein keeps the immune system running smoothly.

    Beth Stadtmueller, a postdoctoral scholar in the laboratory of Centennial Professor of Biology Pamela Björkman, is the first author on two recent papers describing the findings.

    Beth Stadtmueller

    “Proteins such as pIgR are folded into complicated shapes,” says Stadtmueller. “Having a complete model of a protein is analogous to an architectural model of a building showing scaled dimensions of walls, the locations of windows and doors, angles of the roof, and so on. Understanding the structure of this protein provides information on how it carries out normal functions while also providing a basis to rationally engineer modified proteins with enhanced functions, which could be used as therapeutics.”

    The pIgR protein is best known for attaching to antibodies and ferrying them from the bloodstream to the interior of the intestines, where the antibodies can neutralize pathogens. In mammals such as humans, the group discovered that pIgR looks like five round beads—biologists call these regions “domains”—that are connected to form a tightly closed, triangle-shaped loop. The group also showed that upon encountering an antibody, the pIgR molecule opens up—like changing from a fist to an open hand—to enclose around the antibody and to transport it into the intestines.

    While pIgR is crucial for helping antibodies to function, the protein also has disease-fighting abilities of its own. For example, some molecules of pIgR are released into the intestines where they alone engage bacteria, such as pneumonia-causing Streptococcus pneumoniae.

    The group also studied the structures of pIgR from fish and birds, to see how the protein has changed as vertebrates evolved. In fish, pIgR has only two domains and forms a straight line. In birds, an evolutionary intermediary between fish and humans, the protein has four domains. The group was surprised to find that the shape of the bird pIgR is not fixed in a closed loop or a straight line—it can change freely between closed and open configurations, and can grasp antibodies much like the human protein.

    “The human pIgR is like a door that has to be unlocked to open, whereas the bird pIgR is constantly opening and closing like a revolving door,” Stadtmueller says. “These are very different structures, which are likely to support functions unique to each protein.”

    “The immune system has changed considerably as vertebrates have evolved,” she adds. “Studying pIgR in a spectrum of vertebrates illustrates how the protein architecture has changed to support species-specific defense systems. It helps us to understand why certain immune system functions have evolved and provides a foundation to test their contributions to specific states of health and disease.”

    The three-dimensional structure of human pIgR is described in a March 2016 paper published in the journal eLife, titled The structure and dynamics of secretory component and its interactions with polymeric immunoglobulins. A follow-up study, titled Biophysical and biochemical characterization of avian secretory component provides structural insights into the evolution of the polymeric Ig receptor, describing the structure of avian pIgR, was published in the Journal of Immunology on August 15, 2016. The work was done in collaboration with the Hubbell laboratory at UCLA and supported by grants from the National Institute of Allergy and Infectious Diseases, the Cancer Research Irving Postdoctoral Fellowship, the Jules Stein Professorship Endowment, and the National Institutes of Health.

    See the full article here .

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    The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”
    Caltech buildings

  • richardmitnick 5:55 am on August 30, 2016 Permalink | Reply
    Tags: , , Protein Studies   

    From UCLA: “UCLA researchers develop method to speed up detection of infectious diseases, cancer” 

    UCLA bloc


    August 26, 2016
    Matthew Chin

    UCLA researchers were able to use a molecular chain reaction to detect the presence of proteins in blood and plasma in a way that is faster and simpler.

    A team of UCLA researchers has found a way to speed and simplify the detection of proteins in blood and plasma opening up the potential for diagnosing the early presence of infectious diseases or cancer during a doctor’s office visit. The new test takes about 10 minutes as opposed to two to four hours for current state-of-the-art tests.

    The new approach overcame several key challenges in detecting proteins that are biomarkers of disease. First, these proteins are often at low abundance in body fluids and accurately identifying them requires amplification processes. The current approach uses enzymes to amplify the signal from proteins. However, enzymes can break down if they are not stored at proper temperatures. Also, to avoid a false positive, excess enzymes need to be washed away. This increases the complexity and cost of the test.

    The study, which included researchers from the Henry Samueli School of Engineering and Applied Science, the California NanoSystems Institute, and the David Geffen School of Medicine, was published online in the journal ACS Nano.

    The researchers included lead author Donghyuk Kim, a UCLA post-doctoral researcher in bioengineering and Dino Di Carlo, professor of bioengineering. They collaborated with Aydogan Ozcan, Chancellor’s Professor of Electrical Engineering and Bioengineering and Omai Garner, assistant professor of pathology and medicine at the David Geffen School of Medicine at UCLA.

    The UCLA team devised an approach to amplify a protein signal without any enzymes, thus eliminating the need for a complex system to wash away excess enzymes, and that would work only in the presence of the target protein. This new approach made use of a molecular chain reaction that was strongly triggered only in the presence of a target protein.

    The molecular chain reaction is driven by a cycle of DNA binding events. The process begins with a DNA key divided into two parts. If the target protein is present, the two parts bind together to form a DNA complex. The formation of the DNA complex generates DNA signaling molecules, which in turn generates the same DNA complex, leading to more signaling molecules, thus propagating repeated cycles.

    “By cutting the DNA ‘key’ into two parts, we found that each part could not catalyze or ‘open’ the reaction separately, but only when a protein acted as glue — essentially bridging the parts together, does the DNA key became functional again,” said Kim, a member of Di Carlo’s laboratory.

    The UCLA team’s findings build on previous work that employed this enzyme-free mechanism of nucleic acid amplification to detect DNA.

    “Unlike previous approaches to achieve an amplified readout of proteins, such as the proximity ligation assay, this approach does not require multiple enzymes, longer polymerization-based enzymatic reactions, or temperature control to amplify signal,” Di Carlo said. “In fact the new assay operates at room temperature and achieves results in about 10 minutes.”

    The team demonstrated the approach with two target proteins — streptavidin, widely used as a test protein for new diagnostic assays, and influenza nucleoprotein, which is a protein associated with the influenza virus.

    In the long term the team aims to combine the technique with portable readers that could be particularly beneficial in clinics in resource-poor areas.

    “Because the technique requires fewer steps than other assays, it can have a significant impact on distributed diagnostics and public health reporting, especially in combination with cost-effective portable and networked reader technology that our lab is developing,” Ozcan said.

    The team demonstrated a synergistic handheld microplate reader suitable for protein diagnostic assays based on a cellphone’s optical and computational systems earlier this year.

    Garner, who is also the associate director of the clinical microbiology lab at UCLA Health, emphasized the broad application of the technique. “Although demonstrated initially in detecting protein associated with flu, we envision the approach can be generalized to a range of protein biomarkers associated with infectious diseases and cancer,” said Garner. He noted it could be configured to detect diseases such as Zika or Ebola.

    The researchers emphasized that additional work is required to adapt the assay to complex clinical samples that may have other interfering compounds, and further optimization of the reagents for the assay can enhance performance.

    This interdisciplinary work was supported through a team science grant from the National Science Foundation Emerging Frontiers in Research and Innovation program.

    See the full article here .

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    UC LA Campus

    For nearly 100 years, UCLA has been a pioneer, persevering through impossibility, turning the futile into the attainable.

    We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

    This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

  • richardmitnick 9:58 am on August 29, 2016 Permalink | Reply
    Tags: , Protein Studies,   

    From TUM: “A look at the molecular quality assurance within cells” 

    Techniche Universitat Munchen

    Techniche Universitat Munchen

    Technical University of Munich
    Prof. Dr. Matthias J. Feige

    A look at the molecular quality assurance within cells. (Illustration: Joshua Stokes, St. Jude Children’s Research Hospital)

    Proteins fulfill vital functions in our body. They transport substances, combat pathogens, and function as catalysts. In order for these processes to function reliably, proteins must adopt a defined three-dimensional structure. Molecular “folding assistants”, called chaperones, aid and scrutinize these structuring processes. With participation from the Technical University of Munich (TUM), a team of researchers has now revealed how chaperones identify particularly harmful errors in this structuring process. The findings were published in the scientific journal “Molecular Cell”.

    Chaperones are a kind of Technical Inspection Authority for cells. They are proteins that inspect other proteins for quality defects before they are allowed to leave the cell.

    If a car does not pass its technical inspection, it implies that it has severe defects that could lead to serious accidents. If a protein folds into a faulty structure, this may lead to serious diseases. Examples of these are neurodegenerative disorders such as Alzheimer’s, but also metabolic diseases such as cystic fibrosis and diabetes.

    Matthias Feige, professor for cellular protein biochemistry at the TUM, worked within a team headed by Linda Hendershot at St. Jude Children’s Research Hospital in Memphis/TN, USA, to investigate how chaperones identify structurally flawed proteins. In the study, the scientists focused on proteins which are produced in a part of the cell called the endoplasmic reticulum. “We are mainly interested in cellular protein folding”, explains Feige. “How the self-organization of proteins occurs at the molecular level – and how cells identify errors in this process – is a truly fascinating question.”

    Defective proteins need to be eliminated by the cell

    The endoplasmic reticulum consists of a network of hollow spaces and tubules. It is specialized in protein folding and the quality control for this process, and a third of all human proteins are produced here. Just like in any production process, errors may occur: Proteins form a folding core mostly made up of hydrophobic (water-repellent) amino acids, around which the rest of the protein is able to structure itself. However, if errors occur in the folding process, these hydrophobic areas may not be buried in the core, but instead be exposed on the surface of a protein where they may result in proteins clumping together. This can become hazardous to the cell or the entire organism.

    Into the cell via a shuttle

    Thus far, scientists knew that chaperones were able to identify general hydrophobic amino acid sequences if they remained exposed on protein surfaces. However, not all proteins which present such sequences should necessarily be degraded. That is because not all proteins with hydrophobic amino acid sequences on the surface are defective. How exactly the cell decides if a protein is so dangerous that it needs to be eliminated remained a mystery.

    The researchers developed a new method which made it possible to observe the behavior of chaperones in the living biological system of the cell. To do this, they inserted precisely defined sequences of amino acids, which are the building blocks of proteins, into a shuttle system that transported them into the endoplasmic reticulum within the cell. Via this ingenious trick, they were able to observe, under biologically relevant conditions, which sequences the various chaperones recognized.

    Two classes of chaperones

    What they discovered was that there existed not only one, but two classes of chaperones in the endoplasmic reticulum, each of which identifies different types of hydrophobic amino acid sequences. Furthermore, the sequences identified by the chaperones of the second class, which are described in this journal article for the first time, form particularly dangerous clumps in the cell. Once they are identified, the proteins possessing them can be eliminated rapidly.

    “This is an important piece in the puzzle of how molecular quality control functions”, says Feige. “Follow-up studies will now be required to see how the chaperones recognize their target sequences on a structural level.”

    This research is also important for the biotechnological production of proteins, such as antibodies. In order to prevent these pharmaceutical products from being broken down by the body too quickly, biotechnologists can now ensure that the corresponding sequences do not appear on the surface of the proteins.

    Publication: Julia Behnke, Melissa J. Mann, Fei-Lin Scruggs, Matthias J. Feige, Linda M. Hendershot, “Members of the Hsp70 Family Recognize Distinct Types of Sequences to Execute ER Quality Control“, Molecular Cell, published online August 18, 2016

    See the full article here .

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    Techniche Universitat Munchin Campus

    Technische Universität München (TUM) is one of Europe’s top universities. It is committed to excellence in research and teaching, interdisciplinary education and the active promotion of promising young scientists. The university also forges strong links with companies and scientific institutions across the world. TUM was one of the first universities in Germany to be named a University of Excellence. Moreover, TUM regularly ranks among the best European universities in international rankings.

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

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



    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.


    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.

    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.

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    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



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