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  • richardmitnick 10:12 am on April 17, 2019 Permalink | Reply
    Tags: , , , , , , Rosetta@home, ,   

    UW Medicine Newsroom: “Protein design named as an Audacious project” 

    U Washington
    University of Washington

    UW Medicine Newsroom

    April 16, 2019

    Leila Gray
    UW Medicine
    leilag@uw.edu
    206.685.0381

    Susan Gregg
    UW Medicine
    sghanson@uw.edu
    206.390.3226

    The Institute for Protein Design at the UW School of Medicine will advance medicine and improve healthcare with an initial $45 million in funding through TED’s The Audacious Project.

    1
    At the Institute for Protein Design, David Baker (left) and Neil King display enlarged 3-D printouts of computer-engineered proteins. ian Haydon/IPD

    The Institute for Protein Design at the University of Washington School of Medicine in Seattle has received a commitment of an initial $45 million in funding through The Audacious Project, a philanthropic collaborative that surfaces and funds critical projects with the potential to create massive global change.

    “This is simply wonderful, and it comes at the best possible time,” said David Baker. He is the the institute’s director, a UW School of Medicine professor of biochemistry, and a Howard Hughes Medical Institute investigator. He also holds the Henrietta and Aubrey Davis Endowed Professorship in Biochemistry.

    “As we get better and better at designing proteins to perform specific tasks,” said Baker, “it has become possible to have bold new approaches to solving some of the most vexing problems in medicine today.”

    The institute will use The Audacious Project funds to pursue the computational design of:

    A universal flu vaccine capable of providing lifetime immunization
    New drug candidates with enhanced abilities to enter the brain
    Advanced protein containers for targeted gene delivery (including the delivery of RNA into cells)
    Smart proteins capable of identifying cancerous or otherwise unhealthy cells
    Self-assembling protein nanomaterials for use in solar energy and nanofabrication

    Please see the Institute for Protein Design fact sheet for more information on the institute and its innovation hub of projects.

    The institute will expand its team of engineers and scientists who will work together to advance their best-in-class Rosetta protein design software. It will also add three new tenure-track professors, five acting instructors, and will support additional postdoctoral fellows, graduate students, and staff scientists from around the world. The funding will also support investments in equipment, supplies, and laboratory space needed to design, build, and characterize millions of synthetic proteins.

    Support leveraged via The Audacious Project was made possible through the generosity of Laura and John Arnold, Steve and Genevieve Jurvetson, Chris Larsen and Lyna Lam, Lyda Hill Philanthropies, Miguel McKelvey, the Clara Wu and Joe Tsai Foundation, Rosamund Zander and Hansjörg Wyss for the Wyss Foundation, and several anonymous donors. The UW School of Medicine hopes these funds will spur more contributions to the Institute for Protein Design.

    Baker said the goal of the initiative is to create the Bell Labs of protein design, referring to the enormous productivity and invention of Bell Telephone Laboratories. There, scientists and engineers invented such technologies as the transistor and the laser, as well as information theory, which underpins the digital age. “We hope to attract some of the best and brightest from around the world to work on what we think is going to be a protein design revolution,” Baker said.

    “We believe that protein-based technologies will play an increasingly transformative role in this space,” said Neil King, an assistant professor of biochemistry at the UW School of Medicine, who leads the institute’s vaccine design efforts. “The Audacious Project will help us realize that vision in a way that simply wouldn’t be possible through traditional grant-based funding.”

    “We created The Audacious Project to give lift-off to some of the world’s most transformative projects — the ones with the potential to revolutionize entire fields,” said Anna Verghese, executive director of The Audacious Project. “The Institute for Protein Design has been a long-standing pioneer in computational protein design. Now, with a solid blueprint in place and support through The Audacious Project, the Institute for Protein Design will venture to accelerate the pace of discovery, disseminate new protein technology, and fundamentally change how drugs, vaccines, fuels, and new materials are made.”

    About the Audacious Project

    The Audacious Project was launched in April 2018, with a mission to foster “collaborative philanthropy for bold ideas.” Housed at TED (the nonprofit devoted to ideas worth spreading) and operated with support from The Bridgespan Group (a leading social impact advisor to nonprofits and NGOs, philanthropists and investors), The Audacious Project brings together some of the most respected organizations and individuals in philanthropy—the Skoll Foundation, Virgin Unite, Dalio Foundation and more. The Audacious Project surfaces and funds critical projects with the potential to create global change. By removing barriers associated with funding, The Audacious Project empowers social entrepreneurs to dream boldly and take on the world’s biggest and most urgent challenges.

    The 2019 projects include: Center for Policing Equity, Educate Girls, Institute for Protein Design at the UW School of Medicine, Salk Institute for Biological Studies, the END Fund, The Nature Conservancy, Thorn and Waterford UPSTART. Learn more or support an existing project at http://www.AudaciousProject.org.

    About the Institute for Protein Design at the University of Washington School of Medicine

    Proteins perform the vast array of functions in life. At the Institute for Protein Design, established in 2012 in the Department of Biochemistry at the University of Washington School of Medicine in Seattle, researchers use computers to design entirely new proteins from scratch. These custom proteins not only mimic many of the functions of naturally occurring proteins, but they also can perform entirely new functions that natural proteins cannot.

    “For many years, when protein researchers wanted to solve a problem, they looked to nature for a molecule that did something close to what they wanted, then they would try to make small changes to it,” said David Baker, director of the Institute for Protein Design at the University of Washington School of Medicine.

    U Washington Dr. David Baker

    “It’s similar to how our Stone Age ancestors developed their technology: If you wanted to dig a hole, you went looking for a bone that was roughly the right shape, and you sharpened it a bit.”

    Baker added, “What we do at the Institute for Protein Design is, first, determine what shape a protein would need to do a certain task — say, to serve as an enzyme — and then, using the Rosetta computer software developed at the institute, identify the amino acid sequence that will give us a protein that can do that task,” Baker said. The approach allows researchers to move beyond the limitations of proteins that were created by evolution over millions of years of trial and error.

    In recent years, researchers at the institute have developed a mini-protein that can neutralize the flu virus, an enzyme that degrades gluten in the stomach and which is now in clinical trials as a potential treatment for celiac disease, and a first-of-its-kind nanoparticle vaccine candidate for respiratory syncytial virus, oro RSV, which is second only to malaria as a cause of infant mortality worldwide. To date, eight spinout companies have been launched to further develop several of the institute’s engineered, novel proteins ffor clinical and commercial use.

    Institute for Protein Design
    Foldit (Institute’s online protein-folding video game)
    Rosetta@home (Institute’s citizen-science portal)

    David Baker’s Rosetta@home project, a project running on BOINC software from UC Berkeley


    Rosetta@home BOINC project

    See the full article here .

    five-ways-keep-your-child-safe-school-shootings

    Please help promote STEM in your local schools.

    Stem Education Coalition

    About UW Medicine

    UW Medicine is one of the top-rated academic medical systems in the world. With a mission to improve the health of the public, UW Medicine educates the next generation of physicians and scientists, leads one of the world’s largest and most comprehensive biomedical research programs, and provides outstanding care to patients from across the globe.

    The UW School of Medicine, part of the UW Medicine system, leads the internationally recognized, community-based WWAMI Program, serving the states of Washington, Wyoming, Alaska, Montana and Idaho. The school has been ranked No. 1 in the nation in primary-care training for more than 20 years by U.S. News & World Report. It is also second in the nation in federal research grants and contracts with $749.9 million in total revenue (fiscal year 2016) according to the Association of American Medical Colleges.

    UW Medicine has more than 27,000 employees and an annual budget of nearly $5 billion. Also part of the UW Medicine system are Airlift Northwest and the UW Physicians practice group, the largest physician practice plan in the region. UW Medicine shares in the ownership and governance of the Seattle Cancer Care Alliance with Fred Hutchinson Cancer Research Center and Seattle Children’s, and also shares in ownership of Children’s University Medical Group with Seattle Children’s.

    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 12:43 pm on September 18, 2018 Permalink | Reply
    Tags: Completely artificial fluorescent beta-barrel protein, , Rosetta@home,   

    From Rosetta@home: “Fluorescent proteins designed from scratch” 

    Rosetta@home

    From Rosetta@home

    17 Sep 2018
    University of Washington
    http://www.bakerlab.org

    1

    Dr. David Baker, Baker Lab, U Washington

    Congrats to all Rosetta@home volunteers who contributed to a recent report in Nature describing the design of a completely artificial fluorescent beta-barrel protein. As described by one of the main authors, Anastassia, in this forum post:

    The paper presents many “firsts” in computational protein design. It is the first de novo design of the beta-barrel fold (one of the most described folds in the past 35 years, yet mysterious until now). It is also the first de novo design of a protein tailored to bind a small-molecule, which requires very high accuracy in the placement of side chains on protein backbones assembled from scratch. Additionally, we could show that these new proteins could fold and function as expected in vivo! We hope that the advances described in the paper will further enable the de novo design of many biosensors and catalysts tailored for specific applications.

    Thanks to all the Rosetta@home volunteers who contributed to the validation of our designed proteins and binding sites.

    Here is the link to the IPD webpage that contains a copy of the paper. The work was also featured in the news articles below (the news in Science contains a video of one of our proteins glowing in living cells).

    https://www.bakerlab.org/index.php/2018/09/12/de-novo-fluorescent-proteins

    https://cen.acs.org/physical-chemistry/periodic-table/Designer-protein-tackles-binding/96/i37
    http://www.sciencemag.org/news/2018/09/watch-these-new-designer-proteins-light-when-they-hit-their-target

    See the full article here.

    five-ways-keep-your-child-safe-school-shootings

    Please help promote STEM in your local schools.

    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.

    U Washington Dr. David Baker

    Rosetta screensaver

    BOINC

    My BOINC

     
  • richardmitnick 10:08 am on March 29, 2018 Permalink | Reply
    Tags: , , Bloomberg View, , , , Rosetta@home   

    From Rosetta@home via Bloomberg View: “Protein Engineering May Be the Future of Science” 

    Rosetta@home

    Rosetta@home

    2

    Bloomberg View

    March 27, 2018
    Faye Flam

    Some scientists think designing new proteins could become as significant as tweaking DNA.

    3
    Let’s build a better sperm whale. Photograph: SSPL/Getty Images

    Scientists are increasingly betting their time and effort that the way to control the world is through proteins. Proteins are what makes life animated. They take information encoded in DNA and turn it into intricate three-dimensional structures, many of which act as tiny machines. Proteins work to ferry oxygen through the bloodstream, extract energy from food, fire neurons, and attack invaders. One can think of DNA as working in the service of the proteins, carrying the information on how, when and in what quantities to make them.

    Living things make thousands of different proteins, but soon there could be many more, as scientists are starting to learn to design new ones from scratch with specific purposes in mind. Some are looking to design new proteins for drugs and vaccines, while others are seeking cleaner catalysts for the chemical industry and new materials.

    David Baker, director for the Institute for Protein Design at the University of Washington, compares protein design to the advent of custom tool-making. At some point, proto-humans went beyond merely finding uses for pieces of wood, rock or bone, and started designing tools to suit specific needs — from screwdrivers to sports cars.

    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.

    U Washington Dr. David Baker

    Rosetta screensaver

    BOINC

    My BOINC

     
  • richardmitnick 6:52 pm on March 6, 2018 Permalink | Reply
    Tags: , , , , Rosetta@home, , U Wasington Medicine News Room   

    From UW Medicine Newsroom: “Scientists create complex transmembrane proteins from scratch” 

    U Washington
    University of Washington

    UW Medicine Newsroom

    March 1, 2018
    Leila Gray
    206.685.0381
    leilag@uw.edu

    The ability to build transmembrane proteins opens the way for custom-designing structures that span living cell membranes and perform new tasks.

    1
    Four computer-designed proteins combine to form a transmembrane tetramer with the top of structure facing the cytoplasm. Institute for Protein Design.

    In the living world, transmembrane proteins are found embedded in the membrane of all cells and cellular organelles. They are essential for them to function normally. For example, many naturally occurring transmembrane proteins act as gateways for the movement of specific substances across a biological membrane. Some transmembrane proteins receive or transmit cell signals. Because of such roles, many drugs are designed to target transmembrane proteins and alter their function.

    Now researcher are looking at designing the transmembrane proteins themselve to perform specific tasks.

    “Our results pave the way for the design of multispan membrane proteins that could mimic proteins found in nature or have entirely novel structure, function and uses,” said David Baker, a University of Washington School of Medicine professor biochemistry and director of the UW Institute of Protein Design who led the project.

    U Washington Dr. David Baker

    David Baker’s Rosetta@home project, a project running on BOINC software from UC Berkeley

    But understanding how transmembrane proteins are put together and how they work has proved challenging. Because they act while embedded within the cellular membrane, transmembrane proteins have proven to be more difficult to study than proteins that operate in the watery solution that make up the cells’ cytoplasm or in the extracellular fluid.

    In the new study, Lu and his coworkers used a computer program, developed in the Baker lab and called Rosetta, that can predict the structure a protein will fold into after it has been synthesized. The architecture of a protein is crucial because a protein’s structure determines its function.

    A protein’s shape forms from complex interactions between the amino acids that make up the protein chain and between the amino acids and the surrounding environment. Ultimately, the protein assumes the shape that best balances out all these factors so that the protein achieves the lowest possible energy state.

    The Rosetta program used by Lu and his colleagues can predict the structure of a protein by taking into account these interactions and calculating the lowest overall energy state. It is not unusual for the program to create tens of thousands of model structures for an amino acid sequence and then identify the ones with lowest energy state. The resulting models have been shown to accurately represent the structure the sequence will likely assume in nature.

    Determining the structure of transmembrane proteins is difficult because portions of transmembrane proteins must pass though the membrane’s interior, which is made of oily fats called lipids.

    In aqueous fluids, amino acid residues that have polar sidechains – components that can have a charge under certain physiological conditions or that participate in hydrogen bonding — tend to be located on the surface of the protein where they can interact with water, which has negatively and positively side charges to its molecule. As a result, polar residues on proteins are called hydrophilic, or “water-loving.”

    Non-polar residues, on the other hand, tend to be found packed within the protein core away from the polar aqueous fluid. Such residues are called hydrophobic or “water-fearing.” As a result, the interaction between the water-loving and water-fearing residues of the protein and the surrounding watery fluids helps drive protein folding and stabilizes the protein’s final structure.

    In membranes, however, protein folding is more complicated because the lipid interior of the membrane is non-polar, that is, it has no separation of electrical charges. This means to be stable the protein must place nonpolar, water-fearing residues on its surface, and pack its polar, water-loving residues inside. Then it must find a way to stabilize its structure by creating bonds between the hydrophilic residues within its core.

    The key to solving the problem, said Lu, was to apply a method developed by Baker lab to design the transmembrane portion so that the polar, hydrophilic residues fit in such a way that enough would form hydrongen bonds– that can tie the protein together from within

    “Putting together these ‘buried hydrogen bond networks’ was like putting together a jig-saw puzzle,” Baker said.

    With this approach, Lu and his colleagues were able to manufacture the designed transmembrane proteins inside bacteria and mammalian cells by using as many as 215 amino acids. The resulting proteins proved to be highly thermally stable and able to correctly orient themselves on the membrane. Like naturally occurring transmembrane proteins, the proteins are multipass, meaning they traverse the membrane several times, and assemble into stable multi-protein complexes, such as dimers, trimers and tetramers.

    “We have shown that it is now possible to accurately design complex, multipass transmembrane proteins that can be expressed in cells. This will make it possible for researchers to design transmembrane proteins with entirely novel structures and functions,” said Lu.

    This work was supported by the Howard Hughes Medical Institute, National Institutes of Health (R01GM063919), the Raymond and Beverly Sackler fellowship, and the National Research Foundation of Korea (NRF- 2016R1A6A3A03007871).

    The research is reported in the March 1 issue of the journal Science. Peilong Lu, a senior fellow in the Baker lab, is the paper’s lead author.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    About UW Medicine

    UW Medicine is one of the top-rated academic medical systems in the world. With a mission to improve the health of the public, UW Medicine educates the next generation of physicians and scientists, leads one of the world’s largest and most comprehensive biomedical research programs, and provides outstanding care to patients from across the globe.

    The UW School of Medicine, part of the UW Medicine system, leads the internationally recognized, community-based WWAMI Program, serving the states of Washington, Wyoming, Alaska, Montana and Idaho. The school has been ranked No. 1 in the nation in primary-care training for more than 20 years by U.S. News & World Report. It is also second in the nation in federal research grants and contracts with $749.9 million in total revenue (fiscal year 2016) according to the Association of American Medical Colleges.

    UW Medicine has more than 27,000 employees and an annual budget of nearly $5 billion. Also part of the UW Medicine system are Airlift Northwest and the UW Physicians practice group, the largest physician practice plan in the region. UW Medicine shares in the ownership and governance of the Seattle Cancer Care Alliance with Fred Hutchinson Cancer Research Center and Seattle Children’s, and also shares in ownership of Children’s University Medical Group with Seattle Children’s.

    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 5:20 pm on January 2, 2018 Permalink | Reply
    Tags: , , , , Rosetta@home, Scientists Are Designing Artisanal Proteins for Your Body,   

    From NYT: “Scientists Are Designing Artisanal Proteins for Your Body” 

    New York Times

    The New York Times

    DEC. 26, 2017
    CARL ZIMMER

    1
    John Hersey

    The human body makes tens of thousands of cellular proteins, each for a particular
    task. Now researchers have learned to create custom versions not found in nature.

    Our bodies make roughly 20,000 different kinds of proteins, from the collagen in our skin to the hemoglobin in our blood. Some take the shape of molecular sheets. Others are sculpted into fibers, boxes, tunnels, even scissors.

    A protein’s particular shape enables it to do a particular job, whether ferrying oxygen through the body or helping to digest food.

    Scientists have studied proteins for nearly two centuries, and over that time they’ve worked out how cells create them from simple building blocks. They have long dreamed of assembling those elements into new proteins not found in nature.

    But they’ve been stumped by one great mystery: how the building blocks in a protein take their final shape. David Baker, 55, the director of the Institute for Protein Design at the University of Washington, has been investigating that enigma for a quarter-century.

    Now, it looks as if he and his colleagues have cracked it. Thanks in part to crowdsourced computers and smartphones belonging to over a million volunteers, the scientists have figured out how to choose the building blocks required to create a protein that will take on the shape they want.

    In a series of papers published this year, Dr. Baker and his colleagues unveiled the results of this work. They have produced thousands of different kinds of proteins, which assume the shape the scientists had predicted. Often those proteins are profoundly different from any found in nature.

    This expertise has led to a profound scientific advance: cellular proteins designed by man, not by nature. “We can now build proteins from scratch from first principles to do what we want,” said Dr. Baker.

    2
    Dr. David Baker in his lab at the University of Washington, where scientists are learning how to create cellular proteins to perform a variety of tasks. Credit Evan McGlinn for The New York Times.

    Scientists soon will be able to construct precise molecular tools for a vast range of tasks, he predicts. Already, his team has built proteins for purposes ranging from fighting flu viruses to breaking down gluten in food to detecting trace amounts of opioid drugs.

    William DeGrado, a molecular biologist at the University of California, San Francisco, said the recent studies by Dr. Baker and his colleagues represent a milestone in this line of scientific inquiry. “In the 1980s, we dreamed about having such impressive outcomes,” he said.

    Every protein in nature is encoded by a gene. With that stretch of DNA as its guide, a cell assembles a corresponding protein from building blocks known as amino acids.

    Selecting from twenty or so different types, the cell builds a chain of amino acids. That chain may stretch dozens, hundreds or even thousands of units long. Once the cell finishes, the chain folds on itself, typically in just a few hundredths of a second.

    Proteins fold because each amino acid has an electric charge. Parts of the protein chain are attracted to one another while other parts are repelled. Some bonds between the amino acids will yield easily under these forces; rigid bonds will resist.

    The combination of all these atomic forces makes each protein a staggering molecular puzzle. When Dr. Baker attended graduate school at the University of California, Berkeley, no one knew how to look at a chain of amino acids and predict the shape into which it would fold. Protein scientists referred to the enigma simply as “the folding problem.”

    The folding problem left scientists in the Stone Age when it came to manipulating these important biological elements. They could only use proteins that they happened to find in nature, like early humans finding sharp rocks to cut meat from bones.

    We’ve used proteins for thousands of years. Early cheese makers, for example, made milk curdle by adding a piece of calf stomach to it. The protein chymosin, produced in the stomach, turned liquid milk into a semisolid form.

    Today scientists are still looking for ways to harness proteins. Some researchers are studying proteins in abalone shells in hopes of creating stronger body armor, for instance. Others are investigating spider silk for making parachute cords. Researchers also are experimenting with modest changes to natural proteins to see if tweaks let them do new things.

    To Dr. Baker and many other protein scientists, however, this sort tinkering has been deeply unsatisfying. The proteins found in nature represent only a minuscule fraction of the “protein universe” — all the proteins that could possibly be made with varying combinations of amino acids.

    “When people want a new protein, they look around in nature for things that already exist,” Dr. Baker said. “There’s no design involved.”

    Crowdsourced Discovery

    Dr. Baker has an elfin face, a cheerful demeanor, hair that can verge on chaotic, and a penchant for wearing T-shirts to scientific presentations. But his appearance belies a relentless drive.

    After graduating from Berkeley and joining the University of Washington, Dr. Baker joined the effort to solve the folding problem. He and his colleagues took advantage of the fact that natural proteins are somewhat similar to one another.

    New proteins do not just pop into existence; they all evolve from ancestral proteins. Whenever scientists figured out the shape of a particular protein, they were able to make informed guesses about the shapes of related ones.

    Scientists also relied on the fact that many proteins are made of similar parts. One common feature is a spiral stretch of amino acids called an alpha helix. Researchers learned how to recognize the series of amino acids that fold into these spirals.

    3
    John Hersey

    In the late 1990s, the team at the University of Washington turned to software for individual studies of complex proteins. The lab decided to create a common language for all this code, so that researchers could access the collective knowledge about proteins.

    In 1998, they launched a platform called Rosetta, which scientists use to build virtual chains of amino acids and then compute the most likely form they will fold into.

    A community of protein scientists, known as the Rosetta Commons, grew around the platform. For the past twenty years, they’ve been improving the software on a daily basis and using it to better understand the shape of proteins — and how those shapes enable them to work.

    In 2005, Dr. Baker launched a program called Rosetta@home, which recruited volunteers to donate processing time on their home computers and, eventually, Android phones. Over the past 12 years, 1,266,542 people have joined the Rosetta@home community.

    My BOINC

    I have 1,005,660 BOINC credits for Rosetta from my days as a BOINC cruncher.

    Rosetta@home project, a project running on BOINC software from UC Berkeley


    Step by step, Rosetta grew more powerful and more sophisticated, and the scientists were able to use the crowdsourced processing power to simulate folding proteins in greater detail. Their predictions grew startlingly more accurate.

    The researchers went beyond proteins that already exist to proteins with unnatural sequences. To see what these unnatural proteins looked like in real life, the scientists synthesized genes for them and plugged them into yeast cells, which then manufactured the lab’s creations.

    “There are subtleties going on in naturally occurring proteins that we still don’t understand,” Dr. Baker said. “But we’ve mostly solved the folding problem.”

    Proteins and Pandemics

    These advances gave Dr. Baker’s team the confidence to take on an even bigger challenge: They began to design proteins from scratch for particular jobs. The researchers would start with a task they wanted a protein to do, and then figure out the string of amino acids that would fold the right way to get the job done.

    In one of their experiments, they teamed up with Ian Wilson, a virologist at Scripps Research Institute, to devise a protein to fight the flu.

    Dr. Wilson has been searching ways to neutralize the infection, and his lab had identified one particularly promising target: a pocket on the surface of the virus. If scientists could make a protein that fit snugly in that pocket, it might prevent the virus from slipping into cells.

    Dr. Baker’s team used Rosetta to design such a protein, narrowing their search to several thousand of chains of amino acids that might do the job. They simulated the folding of each one, looking for the combinations that might fit into the viral niche.

    The researchers then used engineered yeast to turn the semifinalists into real proteins. They turned the proteins loose on the flu viruses. Some grabbed onto the viruses better than others, and the researchers refined their molecular creations until they ended up with one they named HB1.6928.2.3.

    To see how effective HB1.6928.2.3 was at stopping flu infections, they ran experiments on mice. They sprayed the protein into the noses of mice and then injected them with a heavy doses of influenza, which normally would be fatal.

    But the protein provided 100 percent protection from death. It remains to be seen if HB1.6928.2.3 can prove its worth in human trials.

    “It would be nice to have a front-line drug if a new pandemic was about to happen,” Dr. Wilson said.

    5
    In Dr. Baker’s office are models of complex proteins. The human body makes roughly 20,000, each suited to a different task. Credit Evan McGlinn for The New York Times

    HB1.6928.2.3 is just one of a number of proteins that Dr. Baker and his colleagues have designed and tested. They’ve also made a molecule that blocks the toxin that causes botulism, and one that can detect tiny amounts of the opioid fentanyl. Yet another protein may help people who can’t tolerate gluten by cutting apart gluten molecules in food.

    Last week, Dr. Baker’s team presented one of its most ambitious projects: a protein shell that can carry genes.

    The researchers designed proteins that assemble themselves like Legos, snapping together into a hollow sphere. In the process, they can also enclose genes and can carry that cargo safely for hours in the bloodstream of mice.

    These shells bear some striking resemblances to viruses, although they lack the molecular wherewithal to invade cells. “We sometimes call them not-a-viruses,” Dr. Baker said.

    A number of researchers are experimenting with viruses as a means for delivering genes through the body. These genes can reverse hereditary disorders; in other experiments, they show promise as a way to reprogram immune cells to fight cancer.

    But as the product of billions of years of evolution, viruses often don’t perform well as gene mules. “If we build a delivery system from the ground up, it should work better,” Dr. Baker said.

    Gary Nabel, chief scientific officer at Sanofi, said that the new research may lead to the invention of molecules we can’t yet imagine. “It’s a new territory, because you’re not modeling existing proteins,” he said.

    For now, Dr. Baker and his colleagues can only make short-chained proteins. That’s due in part to the cost involved in making pieces of DNA to encode proteins.

    But that technology is improving so quickly that the team is now testing longer, bigger proteins that might do more complex jobs — among them fighting cancer.

    In cancer immunotherapy, the immune system recognizes cancer cells by the distinctive proteins on their surface. The immune system relies on antibodies that can recognize only a single protein.

    Dr. Baker wants to design proteins that trigger a response only after they lock onto several kinds of proteins on the surface of cancer cells at once. He suspects these molecules will be better able to recognize cancer cells while leaving healthy ones alone.

    Essentially, he said, “we’re designing molecules that can do simple logic calculations.” Indeed, he hopes eventually to make molecular machines.

    Our cells generate fuel with one such engine, a gigantic protein called ATP synthase, which acts like a kind of molecular waterwheel. As positively charged protons pour through a ring of amino acids, it spins a hundred times a second. ATP synthase harnesses that energy to build a fuel molecule called ATP.

    It should be possible to build other such complex molecular machines as scientists learn more about how big proteins take shape, Dr. Baker said.

    “There’s a lot of things that nature has come up with just by randomly bumbling around,” he said. “As we understand more and more of the basic principles, we ought to be able to do far better.”

    See the full article here .

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  • richardmitnick 9:51 am on October 2, 2017 Permalink | Reply
    Tags: , , , , Rosetta@home,   

    From U Washington Medicine: “Mini-protein rapid design opens way to new class of drugs” 

    U Washington

    University of Washington

    September 27, 2017
    Leila Gray
    206.685.0381
    leilag@uw.edu

    Scientists at the Institute for Protein Design have created a way to generate thousands of different mini-protein binders as possible drug candidates. The proteins can be custom tailored to specific therapeutic targets. Recently, a set of these proteins were successfully tested in mice against the flu, and another group of these binders was able to protect brain cells against the botulism neurotoxin.

    1
    Artist impression of designed mini-protein binders targeting Influenza hemagglutinin to effectively bind and neutralize the virus. Cognition Studio, Daniel-Adriano Silva, Lance Stewart

    These computer-designed proteins, which did not previously exist in nature, combine the stability and bioavailability of small molecule drugs with the specificity and potency of larger biologics. They would not require refrigeration, and they likely would be simple for patients to take.

    “These mini-protein binders have the potential of becoming a new class of drugs that bridge the gap between small molecule drugs and biologics. Like monoclonal antibodies, they can be designed to bind to targets with high selectivity, but they are more stable and easier to produce and to administer,” said David Baker, who led the multi-institutional research project. He is a professor of biochemistry at the University of Washington School of Medicine and director of the UW Institute for Protein Design.

    Dr. David Baker, Baker Lab, U Washington

    Baker and his colleagues report their findings in article published online Sept. 27 by the journal Nature.

    Aaron Chevalier, Daniel-Adriano Silva and Gabriel J. Rocklin were the lead authors and were all senior fellows at the UW Institute for Protein Design at the time of the project.

    The method used a computer platform, called Rosetta, developed by Baker and colleagues at the University of Washington. They designed thousands of short proteins, about 40 amino acids in length, that the Rosetta program predicted would bind tightly to the molecular target.

    Rosetta@home project, a project running on BOINC software from UC Berkeley


    Rosetta@home BOINC project

    BOINC

    My BOINC

    Because of their small size, these short proteins tend to be extremely stable. They can be stored without refrigeration. They also are more easily administered than large protein drugs, such as monoclonal antibodies.

    Previously, such short, protein-binder drugs were typically re-engineered versions of naturally occurring proteins. These, however, tended not to be significantly better than monoclonal antibodies.

    Because these mini-proteins binders are original designs, they can be tailored to fit their targets much more tightly and are simpler to modify and refine.

    In this study, the researchers sought to design two sets of these proteins: one set that would prevent the influenza virus from invading cells and another that would bind to and neutralize a deadly nerve toxin from botulism. This toxin is considered a potential bioweapon.

    The computer modeling identified the amino-acid sequences of thousands of short proteins that would fit into and bind to the influenza and botulinum targets. The researchers created short pieces of DNA that coded each of these proteins, grew the proteins in yeast cells, and then looked at how tightly they bound to their targets. The targets were Influenza H1 hemagglutinin and botulinum neurotoxin B.

    All told, the method allowed them to design and test 22,660 proteins in just a few months. More than than two-thousand of them bound to their targets with high affinity.

    Evaluation of the best candidates found that the anti-influenza proteins neutralized viruses in cell culture and other designed proteins prevented the botulinum toxin from entering brain cells.

    A nasal spray containing one of the custom-designed proteins completely protected mice from the flu if administered before or as much as 72 hours after exposure.. The protection that the treatment provides equaled or surpassed that seen with antibodies, the researchers report.

    Testing of a subset of the proteins showed that they were extremely stable and, unlike antibodies, did not become inactivated by high temperatures. The small proteins also triggered little or no immune response, a problem that often renders larger protein drugs ineffective.

    Funding for the study came from Life Sciences Discovery Fund Launch grant (9598385), Doctorado en Ciencias Bioquiacutemicas UNAM (R56AI117675), Molecular Basis of Viral Pathogenesis Training Grant (T32AI007354-26A1), Investigator in the Pathogenesis of Infectious Disease award from the Burroughs Wellcome Fund and NIH (1R01NS080833), CoMotion Mary Gates Innovation Fellow; Shenzhen Science and Technology Innovation Committee (JCYJ20170413173837121), Hong Kong Research Grant Council (C6009-15G and AoE/P-705/16), PAPIIT UNAM (IN220516), CONACyT (254514) and Facultad de Medicina UNAM (AI091823, AI123920,AI125704), NIAID grant (1R41AI122431) (1R21AI119258), and Life Sciences Discovery Fund grant (20040757).

    See the full article here .

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    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 11:12 am on July 17, 2017 Permalink | Reply
    Tags: , , Rosetta@home, Synthetic DNA technology and high throughput screening permit large-scale testing of structural stability of multitudes of computationally designed proteins,   

    From U Washington: “Feedback from 1000s of designs could transform protein engineering” 

    U Washington

    University of Washington

    07.12.2017
    Leila Gray
    206.685.0381
    leilag@uw.edu

    1
    A model of a computationally designed mini-protein from a large-scale study to test structural stability. Institute for Protein Design.

    The stage is set for a new era of data-driven protein molecular engineering as advances in DNA synthesis technology merge with improvements in computational design of new proteins.

    This week’s Science reports the largest-scale testing of folding stability for computationally designed proteins, made possible by a new high-throughput approach.

    The scientists are from the UW Medicine Institute for Protein Design at the University of Washington in Seattle and the University of Toronto in Ontario.

    The lead author of the paper is Gabriel Rocklin, a postdoctoral fellow in biochemistry at the University of Washington School of Medicine. The senior authors are Cheryl Arrowsmith, of the Princess Margaret Cancer Center, the Structural Genomics Consortium and the Department of Medical Biophysics at the University of Toronto, and David Baker, UW professor of biochemistry and a Howard Hughes Medical Institute investigator.

    Proteins are biological workhorses. Researchers want to build new molecules, not found naturally, that can perform tasks in preventing or treating disease, in industrial applications, in energy production, and in environmental cleanups.

    “However, computationally designed proteins often fail to form the folded structures that they were designed to have when they are actually tested in the lab,” Rocklin said.

    In the latest study, the researchers tested more than 15,000 newly designed mini-proteins that do not exist in nature to see whether they form folded structures. Even major protein design studies in the past few years have generally examined only 50 to 100 designs.

    “We learned a huge amount at this new scale, but the taste has given us an even larger appetite,” said Rocklin. “We’re eager to test hundreds of thousands of designs in the next few years.”

    The most recent testing led to the design of 2,788 stable protein structures and could have many bioengineering and synthetic biology applications. Their small size may be advantageous for treating diseases when the drug needs to reach the inside of a cell.

    2
    Design model structures from a comprehensive mutational analysis of stability in natural and designed proteins. UW Institute for Protein Design.

    Proteins are made of amino acid chains with specific sequences, and natural protein sequences are encoded in cellular DNA. These chains fold into 3-dimensional conformations. The sequence of the amino acids in the chain guide where it will bend and twist, and how parts will interact to hold the structure together.

    For decades, researchers have studied these interactions by examining the structures of naturally occurring proteins. However, natural protein structures are typically large and complex, with thousands of interactions that collectively hold the protein in its folded shape. Measuring the contribution of each interaction becomes very difficult.

    The scientists addressed this problem by computationally designing their own, much simpler proteins. These simpler proteins made it easier to analyze the different types of interactions that hold all proteins in their folded structures.

    “Still, even simple proteins are so complicated that it was important to study thousands of them to learn why they fold,” Rocklin said. “This had been impossible until recently, due to the cost of DNA. Each designed protein requires its own customized piece of DNA so that it can be made inside a cell. This has limited previous studies to testing only tens of designs.”

    To encode their designs of short proteins in this project, the researchers used what is called DNA oligo library synthesis technology. It was originally developed for other laboratory protocols, such as large gene assembly. One of the companies that provided their DNA is CustomArray in Bothell, Wash. They also used DNA libraries made by Agilent in Santa Clara, Calif., and Twist Bioscience in San Francisco.

    By repeating the cycle of computation and experimental testing over several iterations, the researchers learned from their design failures and progressively improved their modeling. Their design success rate rose from 6 percent to 47 percent. They also produced stable proteins in shapes where all of their first designs failed.

    Their large set of stable and unstable mini-proteins enabled them to quantitatively analyze which protein features correlated with folding. They also compared the stability of their designed proteins to similarly sized, naturally occurring proteins.

    The most stable natural protein the researchers identified was a much-studied protein from the bacteria Bacillus stearothermophilus.

    3
    The researchers compared the stability of some of their designed proteins to a natural protein found in a bacteria that withstands the high temperatures of hot springs like those in Yellowstone. Alice C. Gray.

    This organism basks in high temperatures, like those in hot springs and ocean thermal vents. Most proteins lose their folded structures under such high temperature conditions. Organisms that thrive there have evolved highly stable proteins that stay folded even when hot.

    “A total of 774 designed proteins had higher stability scores than this most protease-resistant monomeric protein,” the researchers noted. Proteases are enzymes that break down proteins, and were essential tools the researchers used to measure stability for their thousands of proteins.

    The researchers predict that, as DNA synthesis technology continues to improve, high-throughput protein design will become possible for larger, more complex protein structures.

    “We are moving away from the old style of protein design, which was a mix of computer modeling, human intuition, and small bits of evidence about what worked before.” Rocklin said. “Protein designers were like master craftsmen who used their experience to hand-sculpt each piece in their workshop. Sometimes things worked, but when they failed it was hard to say why. Our new approach lets us collect an enormous amount of data on what makes proteins stable. This data can now drive the design process.”

    Their study was supported by the Howard Hughes Medical Institute and the Natural Sciences and Research Council of Canada. Rocklin is a Merck Fellow of the Life Sciences Research Foundation. Arrowsmith holds a Canadian Research Chair in Structural Genomics.

    This work was facilitated by the Hyak supercomputer at the University of Washington and by donations of computing time from Rosetta@home participants.

    Rosetta@home project, a project running on BOINC software from UC Berkeley

    Dr. David Baker, Baker Lab, U Washington

    4
    Hyak supercomputer at the University of Washington

    See the full article here .

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    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 9:21 am on May 25, 2017 Permalink | Reply
    Tags: "Unleashing the Power of Synthetic Proteins, , , Rosetta@home, ,   

    From Nautilus: “Unleashing the Power of Synthetic Proteins” 

    Nautilus

    Nautilus

    March 2017
    David Baker, Baker Lab, U Washngton, BOINC Rosetta@home project



    Dr. David Baker


    Rosetta@home project



    The opportunities for the design of synthetic proteins are endless.

    Proteins are the workhorses of all living creatures, fulfilling the instructions of DNA. They occur in a wide variety of complex structures and carry out all the important functions in our body and in all living organisms—digesting food, building tissue, transporting oxygen through the bloodstream, dividing cells, firing neurons, and powering muscles. Remarkably, this versatility comes from different combinations, or sequences, of just 20 amino acid molecules. How these linear sequences fold up into complex structures is just now beginning to be well understood (see box).

    Even more remarkably, nature seems to have made use of only a tiny fraction of the potential protein structures available—and there are many. Therein lies an amazing set of opportunities to design novel proteins with unique structures: synthetic proteins that do not occur in nature, but are made from the same set of naturally-occurring amino acids. These synthetic proteins can be “manufactured” by harnessing the genetic machinery of living things, such as in bacteria given appropriate DNA that specify the desired amino acid sequence. The ability to create and explore such synthetic proteins with atomic level accuracy—which we have demonstrated—has the potential to unlock new areas of basic research and to create practical applications in a wide range of fields.

    The design process starts by envisioning a novel structure to solve a particular problem or accomplish a specific function, and then works backwards to identify possible amino acid sequences that can fold up to this structure. The Rosetta protein modelling and design software identifies the most likely candidates—those that fold to the lowest energy state for the desired structure. Those sequences then move from the computer to the lab, where the synthetic protein is created and tested—preferably in partnership with other research teams that bring domain expertise for the type of protein being created.

    At present no other advanced technology can beat the remarkable precision with which proteins carry out their unique and beautiful functions. The methods of protein design expand the reach of protein technology, because the possibilities to create new synthetic proteins are essentially unlimited. We illustrate that claim with some of the new proteins we have already developed using this design process, and with examples of the fundamental research challenges and areas of practical application that they exemplify:

    2
    This image shows a designed synthetic protein of a type known as a TIM-barrel. Naturally occurring TIM-barrel proteins are found in a majority of enzymes, the catalysts that facilitate biochemical reactions in our bodies, in part because the circular cup-like or barrel shape at their core provides an appropriate space for the reaction to occur. The synthetic protein shown here has an idealized TIM-barrel template or blueprint that can be customized with pockets and binding sites and catalytic agents specific to particular reactants; the eight helical arms of the protein enhance the reaction space. This process can be used to design whole new classes of enzymes that do not occur in nature. Illustration and protein design prepared by Possu Huang in David Baker’s laboratory, University of Washington.

    Catalysts for clean energy and medicine. Protein enzymes are the most efficient catalysts known, far more so than any synthesized by inorganic chemists. Part of that efficiency comes from their ability to accurately position key parts of the enzyme in relation to reacting molecules, providing an environment that accelerates a reaction or lowers the energy needed for it to occur. Exactly how this occurs remains a fundamental problem which more experience with synthetic proteins may help to resolve.

    Already we have produced synthetic enzymes that catalyze potentially useful new metabolic pathways. These include: reactions that take carbon dioxide from the atmosphere and convert it into organic molecules, such as fuels, more efficiently than any inorganic catalyst, potentially enabling a carbon-neutral source of fuels; and reactions that address unsolved medical problems, including a potential oral therapeutic drug for patients with celiac disease that breaks down gluten in the stomach and other synthetic proteins to neutralize toxic amyloids found in Alzheimer’s disease.

    We have also begun to understand how to design, de novo, scaffolds that are the basis for entire superfamilies of known enzymes (Fig. 1) and other proteins known to bind the smaller molecules involved in basic biochemistry. This has opened the door for potential methods to degrade pollutants or toxins that threaten food safety.

    New super-strong materials. A potentially very useful new class of materials is that formed by hybrids of organic and inorganic matter. One naturally occurring example is abalone shell, which is made up of a combination of calcium carbonate bonded with proteins that results in a uniquely tough material. Apparently, other proteins involved in the process of forming the shell change the way in which the inorganic material precipitates onto the binding protein and also help organize the overall structure of the material. Synthetic proteins could potentially duplicate this process and expand this class of materials. Another class of materials are analogous to spider silk—organic materials that are both very strong and yet biodegradable—for which synthetic proteins might be uniquely suited, although how these are formed is not yet understood. We have also made synthetic proteins that create an interlocking pattern to form a surface only one molecule thick, which suggest possibilities for new anti-corrosion films or novel organic solar cells.

    Targeted therapeutic delivery. Self-assembling protein materials make a wide variety of containers or external barriers for living things, from protein shells for viruses to the exterior wall of virtually all living cells. We have developed a way to design and build similar containers: very small cage-like structures—protein nanoparticles—that self-assemble from one or two synthetic protein building blocks (Fig. 2). We do this extremely precisely, with control at the atomic level. Current work focuses on building these protein nanoparticles to carry a desired cargo—a drug or other therapeutic—inside the cage, while also incorporating other proteins of interest on their surface. The surface protein is chosen to bind to a similar protein on target cells.

    These self-assembling particles are a completely new way of delivering drugs to cells in a targeted fashion, avoiding harmful effects elsewhere in the body. Other nanoparticles might be designed to penetrate the blood-brain barrier, in order to deliver drugs or other therapies for brain diseases. We have also generated methods to design proteins that disrupt protein-protein interactions and proteins that bind to small molecules for use in biosensing applications, such as identifying pathogens. More fundamentally, synthetic proteins may well provide the tools that enable improved targeting of drugs and other therapies, as well as an improved ability to bond therapeutic packages tightly to a target cell wall.

    5
    A tiny 20-sided protein nanoparticle that can deliver drugs or other therapies to specific cells in the body with minimal side effects. The nanoparticle self-assembles from two types of synthetic proteins. Illustration and protein design prepared by Jacob Bale in David Baker’s laboratory, University of Washington.

    Novel vaccines for viral diseases. In addition to drug delivery, self-assembling protein nanoparticles are a promising foundation for the design of vaccines. By displaying stabilized versions of viral proteins on the surfaces of designed nanoparticles, we hope to elicit strong and specific immune responses in cells to neutralize viruses like HIV and influenza. We are currently investigating the potential of these nanoparticles as vaccines against a number of viruses. The thermal stability of these designer vaccines should help eliminate the need for complicated cold chain storage systems, broadening global access to life saving vaccines and supporting goals for eradication of viral diseases. The ability to shape these designed vaccines with atomic level accuracy also enables a systematic study of how immune systems recognize and defend against pathogens. In turn, the findings will support development of tolerizing vaccines, which could train the immune system to stop attacking host tissues in autoimmune disease or over-reacting to allergens in asthma.

    New peptide medicines. Most approved drugs are either bulky proteins or small molecules. Naturally occurring peptides (amino acid compounds) that are constrained or stabilized so that they precisely complement their biological target are intermediate in size, and are among the most potent pharmacological compounds known. In effect, they have the advantages of both proteins and small molecule drugs. The antibiotic cyclosporine is a familiar example. Unfortunately such peptides are few in number.

    We have recently demonstrated a new computational design method that can generate two broad classes of peptides that have exceptional stability against heat or chemical degradation. These include peptides that can be genetically encoded (and can be produced by bacteria) as well as some that include amino acids that do not occur in nature. Such peptides are, in effect, scaffolds or design templates for creating whole new classes of peptide medicines.

    In addition, we have developed general methods for designing small and stable proteins that bind strongly to pathogenic proteins. One such designed protein binds the viral glycoprotein hemagglutinin, which is responsible for influenza entry into cells. These designed proteins protect infected mice in both a prophylactic and therapeutic manner and therefore are potentially very powerful anti-flu medicines. Similar methods are being applied to design therapeutic proteins against the Ebola virus and other targets that are relevant in cancer or autoimmune diseases. More fundamentally, synthetic proteins may be useful as test probes in working out the detailed molecular chemistry of the immune system.

    Protein logic systems. The brain is a very energy-efficient logic system based entirely on proteins. Might it be possible to build a logic system—a computer—from synthetic proteins that would self-assemble and be both cheaper and more efficient than silicon logic systems? Naturally occurring protein switches are well studied, but building synthetic switches remains an unsolved challenge. Quite apart from bio-technology applications, understanding protein logic systems may have more fundamental results, such as clarifying how our brains make decisions or initiate processes.

    The opportunities for the design of synthetic proteins are endless, with new research frontiers and a huge variety of practical applications to be explored. In effect, we have an emerging ability to design new molecules to solve specific problems—just as modern technology does outside the realm of biology. This could not be a more exciting time for protein design.

    Predicting Protein Structure

    If we were unable to predict the structure that results from a given sequence of amino acids, synthetic protein design would be an almost impossible task. There are 20 naturally-occurring amino acids, which can be linked in any order and can fold into an astronomical number of potential structures. Fortunately the structure prediction problem is now well on the way toward being solved by the Rosetta protein modeling software.

    The Rosetta tool evaluates possible structures, calculates their energy states, and identifies the lowest energy structure—usually, the one that occurs in a living organism. For smaller proteins, Rosetta predictions are already reasonably accurate. The power and accuracy of the Rosetta algorithms are steadily improving thanks to the work of a cooperative global network of several hundred protein scientists. New discoveries—such as identifying amino acid pairs that co-evolve in living systems and thus are likely to be co-located in protein structures—are also helping to improve prediction accuracy.

    Our research team has already revealed the structures for more than a thousand protein families, and we expect to be able to predict the structure for nearly any protein within a few years. This is an important achievement with direct significance for basic biology and biomedical science, since understanding structure leads to understanding the function of the myriad proteins found in the human body and in all living things. Moreover, predicting protein structure is also the critical enabling tool for designing novel, “synthetic” proteins that do not occur in nature.

    How to Create Synthetic Proteins that Solve Important Problems

    6
    A graduate student in the Baker lab and a researcher at the Institute for Protein Design discuss a bacterial culture (in the Petri dish) that is producing synthetic proteins. Source: Laboratory of David Baker, University of Washington.

    Now that it is possible to design a variety of new proteins from scratch, it is imperative to identify the most pressing problems that need to be solved, and focus on designing the types of proteins that are needed to address these problems. Protein design researchers need to collaborate with experts in a wide variety of fields to take our work from initial protein design to the next stages of development. As the examples above suggest, those partners should include experts in industrial scale catalysis, fundamental materials science and materials processing, biomedical therapeutics and diagnostics, immunology and vaccine design, and both neural systems and computer logic. The partnerships should be sustained over multiple years in order to prioritize the most important problems and test successive potential solutions.

    A funding level of $100M over five years would propel protein design to the forefront of biomedical research, supporting multiple and parallel collaborations with experts worldwide to arrive at breakthroughs in medicine, energy, and technology, while also furthering a basic understanding of biological processes. Current funding is unable to meet the demands of this rapidly growing field and does not allow for the design and production of new proteins at an appropriate scale for testing and ultimately production, distribution, and implementation. Private philanthropy could overcome this deficit and allow us to jump ahead to the next generation of proteins—and thus to use the full capacity of the amino acid legacy that evolution has provided us.

    My BOINC

    See the full article here .

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    Welcome to Nautilus. We are delighted you joined us. We are here to tell you about science and its endless connections to our lives. Each month we choose a single topic. And each Thursday we publish a new chapter on that topic online. Each issue combines the sciences, culture and philosophy into a single story told by the world’s leading thinkers and writers. We follow the story wherever it leads us. Read our essays, investigative reports, and blogs. Fiction, too. Take in our games, videos, and graphic stories. Stop in for a minute, or an hour. Nautilus lets science spill over its usual borders. We are science, connected.

     
  • richardmitnick 11:19 am on September 16, 2016 Permalink | Reply
    Tags: , , , , Hyperstable peptides, , Rosetta@home   

    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.

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    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 .

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    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.

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  • richardmitnick 5:18 pm on August 13, 2016 Permalink | Reply
    Tags: , , , , , Rosetta@home   

    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.

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    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.

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    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

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