Protein folding researcher David Baker to receive Sackler Prize in Biophysics


Dr. David Baker, University of Washington (UW) professor of biochemistry and an investigator at the Howard Hughes Medical Research Institute, has been selected to receive the 2008 Raymond & Beverly Sackler International Prize in Biophysics, along with Dr. Martin Gruebele of the University of Illinois, Urbana-Champaign, and Dr. Jonathan Weissman of the University of California, San Francisco.

Baker is being honored for his seminal contributions to computer-based studies of the manner and the speed in which chains of amino acids fold into protein molecules. Anyone who has tried to put together a cardboard box knows the importance of proper folding to get a useful product. The same is true when the body manufactures proteins.

Creating computer models of protein-folding is essential for figuring out how genetic information directs protein formation, how proteins work, and how misfolded, misshapen, and malfunctioning proteins might underlie serious degenerative diseases.

Baker has developed computer programs to predict protein structures from amino acid sequences in DNA. His program, Rosetta, is among the most accurate. He has combined data from nuclear magnetic resonance imaging and X-ray defraction imaging with his computer modeling to more quickly delineate protein molecule structures. He also researches the ways that molecular configurations of proteins determine their functions in biochemical reactions.


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Dr. Baker's journal archive

Explains the science behind top research on protein folding at the University of Washington's Baker Lab. 3D animations and interviews


http://boinc.bakerlab.org/rosetta

Computer game's high score could earn the Nobel Prize in medicine


Gamers have devoted countless years of collective brainpower to rescuing princesses or protecting the planet against alien invasions. This week researchers at the University of Washington will try to harness those finely honed skills to make medical discoveries, perhaps even finding a cure for HIV.

A new game, named Foldit, turns protein folding into a competitive sport. Introductory levels teach the rules, which are the same laws of physics by which protein strands curl and twist into three-dimensional shapes – key for biological mysteries ranging from Alzheimer's to vaccines.

After about 20 minutes of training, people feel like they're playing a video game but are actually mouse-clicking in the name of medical science. The free program is at http://fold.it/.


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Argonne's Leadership Computing Facility helps researcher win Sackler Prize


"Dr. Baker's work is a significant advance towards developing novel thera­peutics that will improve our everyday life as well as have positive impacts on our environment," said Pete Beckman, director of Argonne's Leadership Computing Facility. "His breakthroughs in predicting and simulating protein structures are invaluable to the community and to accelerating discoveries into practical benefits for society."

Baker conducted his work on the IBM Blue Gene/P at the Argonne Leadership Computing Facility using 12 million computer processor hours awarded by the U.S. Department of Energy's (DOE) Innovative and Novel Computational Impact on Theory and Experiment (INCITE) program. INCITE supports computationally intensive, large-scale research projects that can make high-impact scientific advances through the use of substantial allocations of computer time, resources, and data storage at DOE's global flagship facilities for unclassified supercomputing.

Baker developed computer programs to predict protein structures from amino acid sequences in DNA. His program, Rosetta, is among the most accurate. He has combined data from nuclear magnetic resonance imaging and X-ray diffraction imaging with his computer modeling to more quickly delineate protein molecule structures. He also researches the ways that molecular configurations of proteins determine their functions in biochemical reactions.

"DOE's INCITE program has been critical to the progress made in protein structure modeling using Rosetta," said Baker.



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Computers close in on protein structure prediction


"For more than 40 years, people have known the amino acid sequence of a protein specifies its three-dimensional structure, but no one has been able to translate the sequence into an accurate structure," said senior author David Baker, an HHMI researcher at the University of Washington. "The reason this research is exciting is that we're showing progress in predicting the structure from the sequence. It's not that the problem is solved, but that there is hope."

Proteins are biological machines, and scientists need to determine their structures to understand how the proteins work. Now, scientists determine structures exclusively by measuring the atomic characteristics of proteins in the lab. In contrast, "in this case, we never touched a test tube," Baker said. "We gave it to a computer and said, 'go.'"

In the study, a sophisticated computer program folded 17 short strings of amino acids into 100,000 possible variations. When the researchers compared the best predictions to the actual structures solved earlier by other scientists using experimental techniques, they had the same success rate as the best hitters in major league baseball.


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David Baker, Ph.D.


In early 2008, Baker's group reported successfully creating two brand-new enzymes from scratch. They're not quite as fast as natural enzymes, but as Baker points out, nature has had much longer to get things just right. As his group's techniques improve and other scientists join the effort, Baker envisions a world of potential applications.

Though Rosetta@home began as a way to automate the process of structure prediction, recently Baker added an interactive component.

The Rosetta algorithm uses what computer scientists call the "Monte Carlo Method" to run through possible structures—basically, it flails the amino acids around randomly until it finds something that works. The Rosetta@home interface has an integral screensaver that displays the protein-folding action. Baker remembers that as his volunteers watched their proteins flail, they were writing in, saying "Hey! The computer is doing silly things! It would be great if we could help guide it."


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Project Portal: What is the goal of Rosseta@Home?

DaveBaker: To predict the structures of naturally ocurring proteins, and to create new proteins with new and useful functions.


PP: Is it true that the more times that you run this simulation for a protein, the closer you will likely get to the identical shape of the protein? Why?

DB: Yes. Because it is more likely that we will find the lowest energy structure.

The project runs the simulated folding of a protein many times to find the very low structures for its amino acid sequence. Since the actual structure is the lowest energy structure that exists for the sequence, the lowest energy structure found should be a very close representation of the shape of the protein. The shape of the protein determines how it interacts with everything else, or what it can do.


PP: You are actively seeking new users to run the project. I assume that this is because your results are better with heavier use. If each new volunteer had one new computer running this 24 hours a day, seven days a week, how many more users would you need? If this were a wild dream where anything came true how many would you want?

DB: Yes, the more users the better, because computing the structures of large proteins still requires much more computer power than we currently have. we have set a goal of 150tflops, which would be 5-10 times bigger than the project is currently. this could be achieved by 100,000 new full time users. but in reality, for our broader goal of computing all of structural biology, which would have a huge impact on the world, even this would not be enough. But the project will continue for quite a few years, I expect, so it is not too bad if some problems can't be solved right now!



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Biomedical researcher David Baker wants you to know that the key to an AIDS vaccine or a cure for cancer may be sitting under a layer of dust in your storage closet or on your desk doing nothing but running a screen saver.

Your outdated or idle computer may be just what Baker needs to turn his ideas into scientific breakthroughs.

Baker, 43, a researcher at the University of Washington, realized about two years ago that he had neither the computing power to uncover protein structures at the atomic level nor the money to buy time elsewhere on supercomputers.


Survivors assist


Many of the most active volunteers are cancer survivors or people who have lost close friends or relatives to the disease.

Philip Williams, 53, who writes software for the federal government in Washington, D.C., said he started pulling old Macs out of the closet when he learned more about the Rosetta project. The two-time survivor of Hodgkin's disease has a small wireless network at home and plans to add more computers soon.

Although Williams continues to contribute computer time to a few other projects, his loyalty clearly lies with Baker.

"Baker's group has a way of making people think that they are part of the project," said Williams, who also has volunteered to help diagnose problems other participants are having with the software.

Baker said it's not that users just think they are important to the project — they really are.

"As a scientist, one of the things you're supposed to do is outreach. Outreach has become fundamental to solving the problem," Baker said, pointing out that his team has gotten good ideas about new research angles by involving the public in the research as much as possible. Some of the ideas are generated on the project's message boards.


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Is Rosetta@Home concentrating on a particular disease?


Dr. David Baker "My research group is involved both in fundamental methods development research and in trying to fight disease more directly...

• Malaria: We are part of a collaborative project headed by Austin Burt at Imperial College in London that is one of the Gates Foundation "Grand Challenge Projects in Global Health". Malaria is caused by a parasite that spends part of its life cycle inside the mosquito, and is passed along to humans by mosquito bites. The idea behind the project is to make mosquitoes resistant to the parasite by eliminating genes required in the mosquito for the parasite to live. Our part of the project is to use our computer based design methods (Rosetta) to engineer new enzymes that will specifically target and inactivate these genes.
  


• Anthrax: We are helping a research group at Harvard build models of anthrax toxin that should contribute to the development of treatments. You can read the abstract of a paper describing some of this work at http://www.pnas.org/cgi/content/abstract/102/45/16409
  


• HIV: One of the reasons that HIV is such a deadly virus is that it has evolved to trick the immune system. We are collaborating with researchers in Seattle and at the NIH to try to develop a vaccine for HIV. Our role in this project is central--we are using Rosetta to design small proteins that display the small number of critical regions of the HIV coat protein in a way that the immune system can easily recognize and generate antibodies to. Our goal is to create small stable protein vaccines that can be made very cheaply and shipped all over the world "

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Computers Make Big Strides in Predicting Protein Structure


Computers can predict the detailed structure of small proteins nearly as well as experimental methods, at least some of the time, according to new studies by Howard Hughes Medical Institute researchers.


Proteins are biological machines, and scientists need to determine their structures to understand how the proteins work. Now, scientists determine structures exclusively by measuring the atomic characteristics of proteins in the lab. In contrast, "in this case, we never touched a test tube," Baker said. "We gave it to a computer and said, ’go.’"

In the study, a sophisticated computer program folded 17 short strings of amino acids into 100,000 possible variations. When the researchers compared the best predictions to the actual structures solved earlier by other scientists using experimental techniques, they had the same success rate as the best hitters in major league baseball.

"For about one-third of our benchmark set of small proteins, we generated relatively high-resolution structure predictions, with parts of the structures predicted to near-atomic resolution," said first author Philip Bradley, a postdoctoral fellow in Baker’s lab. "For us, it is a real step forward to achieve structures that are in some way comparable to what you can get by experiments."

The encouraging results come from a refinement of a sophisticated computer modeling program called Rosetta, first developed several years ago in Baker’s lab. The program works on the premise that proteins collapse into their lowest energy state, like a ball that rolls down a hill until it comes to rest on level ground. The energies of hundreds of thousands of possible shapes generated by the computer are computed, and the lowest energy shape is selected as the prediction.


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Because of the large number of possible conformations for a protein chain, finding the lowest energy state is a formidable computational challenge, even with our improvements in the search algorithm. We developed a distributed computing project, called Rosetta@home, to meet this challenge. There are now more than 135,000 participants worldwide whose computers run Rosetta structure prediction and design calculations when not otherwise being used.

The project has sparked considerable interest in biomedical research. Inspired by this, we are working with high school teachers to develop a minicurriculum for students that will explain the science around Rosetta@home. We are also developing a multiplayer, interactive video game version of Rosetta@home that we believe will be an excellent vehicle for learning and, by allowing people to work with each other and with their computers, may allow solution of difficult scientific problems.

Our improvements in Rosetta, together with the large computing power of Rosetta@home, have made it possible to predict, in some cases, the structures of small proteins with near-atomic resolution, and to accurately predict the structures of protein-protein complexes from the structures of the isolated proteins in cases where there are not significant backbone conformational changes upon complex formation. Particularly encouraging after years of work on high-resolution modeling are the close to atomic-resolution predictions of the structures of complexes in CAPRI, the 1.5-Ã… de novo prediction in CASP6, and the close agreement of the Top7 and protein-protein interface design models with the x-ray crystal structures. These results suggest that high-resolution modeling is starting to work.



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Biomolecular Crowdsourcing




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David Baker and colleagues at the University of Washington and the University of Cambridge in England developed a novel computational method for predicting protein structure based only on its amino acid sequence. Thanks to multitudes of users involved with Rosetta@home, a distributed computing project, the group's methodology and its successful application is being reported in the latest Nature.

From the statement issued by the Howard Hughes Medical Institute:

Over the past decade, Baker and his colleagues have made steady progress in developing computer algorithms to predict how a string of amino acids will fold into a given protein's characteristic shape. This intricate folding is molded by the complex molecular side chains that project from the backbone of the protein and can interact in myriad ways, making such predictions far from straightforward. Among the team's chief computational tools is a program called Rosetta that calculates which of a protein's potential shapes is most efficient, or lowest in energy.

One of the thorniest problems Baker and his colleagues have faced with their algorithm is that folding proteins can get stuck in partially folded structures. Predicting protein structure involves finding a structure that has lower energy than any other structures the protein could adopt. "We might have developed a protein structure that is close to the right structure, but not quite there," said Baker. "You might think we could just wiggle the structure around and shake it computationally, but sometimes the energy barriers are so high that the protein just gets stuck in that shape. So, that's where we were stymied in our technique.

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Rosetta@home


My personal favorite, this project is based at the University of Washington and headed by Dr. David Baker. What they're doing is using computer models to design proteins, RNA, and enzymes. Without getting too far into the biology of this, it means that they can take a chain of amino acids and predicts, based on only that information, what the protein/RNA strand/enzyme would look like in 3D. This is extremely useful because the 3D shape of these molecules determines their function.

Rosetta@home has had some funding from the Bill & Melinda Gates Foundation for work on HIV vaccines, and they're also working on influenza, malaria, and biofuels. But more importantly, they are developing a general-purpose tool that can one day be used for biologist working on all kinds of things.

If you volunteer some of your idle CPU time to help this project, you'll not only help them fight the diseases mentioned above, but you'll also help them improve the tool that is used to design these molecules.

Where to get it: This page explains how to join Rosetta@home.



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Gamers Succeed Where AIDS Researchers Could Not


Thousands of people playing an Internet game called Foldit successfully formulated a structure for a key enzyme related to the development of the AIDS virus, coming up with a model that had consistently eluded scientists.

By using a game developed by researchers at the University of Washington, players were able to come up with a viable structure for a protein that's crucial to the early development of AIDS. Foldit allows users to assemble potential proteins out of different molecular building blocks, and video game players ended up accomplishing what scientists couldn't.

The success of Foldit hints at the possibilities of citizen science, a scientific method that involves recruiting large numbers of people to help solve scientific problems. The field encompasses everything from categorizing different types of galaxies to using games, like Foldit, that help users to rapidly gain expertise in a subject.


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I have just been told the very good news that Rosetta@home will be the first project of the BOINC pentathlon, and would like to thank all of the participating teams. I also just learned from the discussion thread that Rosetta@home will be the project of the month for BOINC synergy-this is more excellent news!!

Your increased contributions to rosetta@home could not come at a better time! We've been testing our improved structure prediction methodology in a recently started challenge called CAMEO. For most of the targets, the Rosetta@home models are extremely good, but for a minority of targets the predictions are not good at all. We've now tracked down the source of these failures and it is what we are calling workunit starvation; in the limited amount of time the Rosetta server has to produce models (2-3 days) in these cases very few models were made-this happens because many targets are being run on the server so that only a fraction of your cpu power is focused on any one target. while we are working to fix this internally, by far the best solution is to have more total CPU throughput so each target gets more models.

You can follow how we are doing at http://www.cameo3d.org/. You will see that Robetta is one of the few servers whose name is not kept secret-this is because Rosetta is a public project. Our server receives targets from CAMEO and soon CASP, sends the required calculations out to your computers through Rosetta@home, and then processes the returned results and submits the lowest energy models.

We are excited that the workunit starvation problem may go away through your increased efforts for Rosetta@home. Thanks!!!


A big THANK YOU to all of you who have scaled up your contributions to Rosetta@Home-this is a record level of computing power for us and is super well timed. THANKS!!!


--David Baker


See also: The Baker Laboratory