The new hardware is now being installed, and we are very happy to put the server failures behind us-hopefully we will have no outages this severe again for a long time!

The manuscript I described in my last post on solving crystal structures using Rosetta has now been formally accepted for publication in Nature; the paper will be in an issue on newstands in a month or two.

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In a previous post I described the design of small proteins which bind to and block the function of the key surface protein on the influenza virus, called the haemagluttinin (I can never spell that right!). We are very excited about the possibility of making more proteins that bind to the various strains of the virus that could serve as anti flu drugs (this would only be for very acute infections as you probably wouldn't want to take a dose of these too many times) and are actively working on this. Meanwhile, a manuscript describing the design of the first proteins and how they block the haemaglutinin from the Spanish Flu influenza virus has just been accepted as a full research article in Science magazine. We are excited (and nervous) because we've never been this close to making an actual drug before (as I've explained before, most of what we do is directed more at basic understanding than actual drug development). Still, of course, it is a long road (clinical trials, etc if we get that far) to get something to the point it can be used as a drug. I'll keep you posted as we move along with this.

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The paper on the Rosetta method which allows determination of the structures of a large class of proteins using limited crystallography data has now been published in Nature magazine. Thanks to all of you for making this work possible!

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Graduate student Shawn Yu is now posting on current Rosetta@home efforts to design inhibitors for viruses that cause disease in the "Design of Protein Interactions" thread on the Science message boards. Take a look if you are interested; he is happy to answer questions in the thread as well.

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This week's issue of Science magazine features an article on the use of Rosetta@Home to design novel proteins which bind tightly to the Spanish Flu (H1N1) Influenza Virus. The paper shows that the experimentally determined atomic structure of the complex between one of the designed proteins and the virus is precisely as in the computer model. The designed proteins block the function of the flu surface protein in biochemical tests, and we are guardedly optimistic that the designs will block flu infection. This is an important milestone for computational protein design (and for distributed computing)--the first atomic level accuracy design of a high affinity protein-protein interface, and the designed proteins are exciting leads for new flu therapeutics. In the next few months, we will be using Rosetta@Home to design proteins that bind tightly and hopefully block other pathogens which cause disease. Thanks to all Rosetta@home users for their invaluable contributions to this research!!
(if you want to learn more, the Science web site has a podcast discussing the work:
http://podcasts.aaas.org/science_podcast/SciencePodcast_110513.mp3)

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A recent issue of Nature describes an exciting approach we are taking with collaborators to fight Malaria. The title of the paper is "A synthetic homing endonuclease-based gene drive system in the human malaria mosquito" and the PDF is available at my lab web site. The idea is to use enzymes which cut within critical genes in mosquitos to greatly reduce the number of malaria parasite infected mosquitos. There are still many issues that must be overcome for this strategy to be used against malaria in the real world, but this paper is an important first proof of concept of the strategy.

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This week's issue of Nature magazine has an exciting article (http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10154.html) describing work we are doing with collaborators using Rosetta to design a new class of inhibitors of amyloid fibril formation. Amyloid fibrils have been implicated in Alzheimer's and many other diseases. The designed peptides are not suitable for use as actual therapeutics in their present form, but hopefully will help lead the way to effective drugs.

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Today's issue of Nature Structural Biology reports the determination of the structure of a protein by FoldIt players. This is exciting because it is perhaps the first example of a long standing scientific problem solved by non-scientists. You might read about this in your newspaper; here is a report that does a good job in explaining how FoldIt came out of Rosetta@home:
http://the-scientist.com/2011/09/18/public-solves-protein-structure/

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A recent issue of Nature describes an exciting result from Rosetta@home in collaboration with the NMR spectroscopy laboratory of Lewis Kay in Toronto. Like almost all machines, proteins in order to carry out their functions have to move (change their conformation somewhat) but it has been extremely difficult to determine what these conformational changes are. Lewis Kay's group has developed new methods for getting experimental information on the higher energy very shortlived conformations proteins visit while carrying out their functions. This data is not sufficient to determine the structure of these "excited state" conformations using conventional methods. However, as the paper shows, we can use these experimental data to guide Rosetta and Rosetta@home structure calculations, and produce models of these states. We went one step further than this in the paper by using Rosetta design calculations to stabilize the excited state, and subsequent experiments confirmed the validity of the model. This combination of experimental NMR data, Rosetta structure calculations, and Rosetta design should be very powerful in understanding how proteins carry out their functions.

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Today's issue of Science magazine describes an exciting new approach to HIV vaccine design using Rosetta. In contrast with other viruses such as polio and influenza, inactivated HIV or HIV proteins have not worked as vaccines, and hence as you know there is currently no effective HIV vaccine. Our approach to vaccine design is to take the bits of the HIV surface protein that people make antibodies to, and using Rosetta graft them onto small stable scaffolds that can be made in large quantities and potentially could be useful as vaccines. We've shown earlier that this can be done straightforwardly with Rosetta if the bits of the HIV protein are contiguous along the sequence, but it is much harder if the antibody recognizes multiple bits close in three dimensions but far in sequence. In this paper we show how such "discontinuous" epitipes can be transferred from HIV gp120 to a simple scaffold protein. More work will be required to determine whether this or other vaccine candidates designed using this approach will be effective as HIV vaccines-let us all hope so!!

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In response to requests from many of you, we will be posting descriptions of the many scientific problems currently being tackled with Rosetta@Home on the Science message boards in the next couple of weeks--stay tuned! I also want to describe a new research direction we are now embarking on aimed at future cancer therapies. There are a small set of proteins which are frequently found at much higher levels than normal on the surface of cancer cells. We are starting to design small proteins which bind tightly to these tumor cell markers. If we are successful, we have collaborators who will be testing these proteins for their ability to target cancer cell killing agents to the tumors.

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Last year we described in Science magazine the design of a new enzyme which catalyzes a chemical reaction called the Diels Alder reaction involving the formation of two carbon-carbon bonds. This reaction is interesting because no natural enzymes are known to catalyze the reaction. However, it wasn't a very good enzyme, and we asked FoldIt players to try to improve it. As described in Nature Biotechnology this month, remarkably FoldIt players were able to make the designed enzyme 20 times faster by inserting a completely new loop which helps the enzyme bind the chemicals it links together. The combination of Rosetta@Home and FoldIt is turning out to be powerful indeed for solving challenging problems in biomedicine!

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In the last two months we believe we have made quite a breakthrough in structure prediction, and are excited to test the new method in CASP10. We need your help though--we are now testing many aspects of the new approach and are seriously limited by available CPU cycles. There are now so many flu inhibitor design and structure prediction jobs queued up on Rosetta@Home that there is an eight day wait before they are getting sent out to you. This would be a great time to temporarily increase Rosetta@Home's share on your computers and/or recruit new users--we need all the help we can get! thanks! David

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I've described in the past our work using Rosetta and Rosetta@Home to create new enzyme catalysts. In Nature Chemical Biology last month we describe the design of an enzyme which destroys organophosphate
nerve agents and pesticides. These compounds kill by blocking key enzymes, and our designed enzyme eliminates this toxicity. This illustrates how Rosetta@Home enzyme design work can help to solve current problems, including man-made problems.

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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!!!

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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!!!

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Many common materials such as silk and wool are made out of regular repeating arrays of proteins, and symmetric protein arrays make up the coats of viruses and many other assemblies inside cells. The ability to robustly design self assembling materials made out of proteins would have huge numbers of applications-the naturally occurring assemblies are useful, but imagine if we could make custom materials for 21st century problems. In this weeks Science magazine, we describe the use of Rosetta to design self assembling protein nano structures with very high accuracy. We are now attempting to create many different types of symmetric materials, and you will be seeing more symmetric calculations on your rosetta@home screen server. Thank you for making possible this completely new approach to nanotechnology!

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A recent paper in Nature Biotechnology describes how we have combined computational protein design with the high throughput DNA sequencing methods developed for sequencing the human genome to generate potent influenza virus inhibitors. These designed proteins block infection by the flu virus in cell culture experiments, and they are now going through the (quite lengthy) process of being developed as possible anti-flu drugs.

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We are now testing the latest batch of novel designed proteins that you have helped us create in our brand new Molecular Engineering laboratory at the UW. You can see pictures of the space where the rosetta@home computed designs are being experimentally tested in a recent newspaper article:

http://seattletimes.com/html/localnews/2019068219_molecularlab05m.html

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The native structures are slowly being released for CASP10 targets; all of them will be available by the end of November. In the meantime, you can look at the results of a much larger scale test of prediction methods called CAMEO. CAMEO takes newly solved protein structure before they are published, and sends the amino acid sequences out to structure prediction servers. This happens every week, so it is great to assess new methods as they are being developed. You can look at the results, as well as get more information about CAMEO, at

http://beta.cameo3d.org/modeling/weekly_summary.html

The best number to compare is the "Average accuracy (all targets)" as some servers only model the easy ones. The good thing about CAMEO is that there are many more test cases than CASP, and also that results are released each week so we can see what is working well and what needs to be improved. You will see that ROBETTA, which is now using some of your computing resources, is doing pretty well recently; before this we had problems with some targets not getting enough work units before the server deadline.

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