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Questions about Dr. Baker's journal?

We have a series of threads over time where you can participate with your questions and comments. Look for a thread in the Science forum with a sticky entitled "DISCUSSION of Rosetta@home Journal". At present, discussion 4 is the active discussion thread.

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Rosetta Informational Moderator: Mod.Zilla

We got some good news today. A manuscript that many of you contributed to through Rosetta@home was just accepted for publication in Science magazine, perhaps the most widely read scientific journal. The paper shows that accurate structures can be calculated using Rosetta for proteins up to 200 amino acids long if even a small amount of experimental data (from NMR experiments) is available to guide the search. This is an exciting advance because it could make it very much faster and easier to experimentally determine protein structures. Thanks everybody for your contributions to this work, and to our ongoing research efforts!

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Sarel has collected many very promising potential flu virus inhibitors from your rosetta@home calculations over the last ten days, and will be selecting a number of them for experimental testing--see his postings in the "design of protein-protein interactions" thread.

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We are entering a very busy and science packed time for Rosetta@home. As described in the "design of protein-protein interfaces" thread, we are now designing proteins to bind to and block several different targets, including the flu virus. At the same time, we are gearing up for CASP9 which will start in May by testing out both our new structure prediction methodology and the improved energy function which underlies it. The new methodology is quite CPU intensive, and we are hoping for as much user participating as possible once CASP starts; whatever you can spare now as well would be great so we can go the last 9 yards on structure prediction methods development before CASP and at the same time proceed as rapidly as possible on the protein-protein interaction designs. thanks! David

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This survey request is from David Anderson, the creator of BOINC, and Oded Nov from NYU

Dear Rosetta@home volunteer:

We are conducting a survey of Rosetta@home volunteers in order to
better understand why people participate in volunteer computing and
contribute computer resources.

We would be extremely grateful if you could help us by filling out a
questionnaire. If you are not interested, ignore the rest of this
email.

The survey is at http://boinc.berkeley.edu/survey/ It should take no
more than 10-15 minutes. Your responses will be used for research
purposes and to improve BOINC.

We will be happy to share our findings with you, and they will be made
available once we complete the data collection and analysis.

With many thanks -

Dr. David P. Anderson
Director, BOINC
University of California, Berkeley
email: davea at ssl.berkeley.edu

Prof. Oded Nov
Polytechnic Institute of New York University
email: onov at poly.edu

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Our paper on solving structures of proteins of up to 200 amino acids using very limited experimental data is in the Feb 19 issue of Science magazine (pg 1014) which is on some news stands now. this wouldn't have been possible without Rosetta@home--thanks again everybody!

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While the results are still preliminary, it appears that Rosetta@home has produced an extremely exciting result! As I described a few posts ago, many of you through rosetta@home contributed to the design of proteins predicted to bind very tightly to the influenza flu virus. We have now completed the first round of testing of the designed proteins, and one of them in the experiments conducted thus far clearly binds very tightly to the virus. Our data also indicate that the binding is at a site critical to the virus invasion of our cells, and so the protein may be able to neutralize the virus. I will keep you posted over the next couple of months as the picture becomes clearer--but for now--thank you all for making this possible!!

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I was asked on the discussion thread about the timescale for learning more about the influenza binding protein I described in my previous post. I'm reposting my answer here:


We are doing a series of tests and control experiments in my lab in the next 2-3 weeks to rule out various possible artifacts. If, as we expect, the design passes with flying colors, we will send it to Scripps research institute where the ability of the design to neutralize the virus in cell based tests and the extent to which the design neutralizes different strains of virus will be measured. I would expect we would know the results of this in several months. We will also work to solve the crystal structure of the design bound to the virus to confirm the design binding mode. This hopefully will not take more than a few months as well.

I will keep all of you posted here about the results from these experiments. I am very optimistic, but one should be cautious about getting to excited too early about results like these--there are very many places where things can go wrong just with the biochemistry, and after this there are very many steps to actually make a protein into a drug--this is why there are so few new drugs for curing diseases being discovered.

For those of you who would like to try your hand at improving designed binders to the influenza virus, we are now posting virus inhibitor design challenges on foldit.

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Experiments this past week have made us even more confident that the designed influenza binder is working as in the design model. we used "directed evolution" methods to identify amino acid changes that make the rosetta@home designed protein bind even more tightly to the virus. we found mutations at two positions: first, at an alanine residue in the design, the evolution process found a valine, and inspection of the design model showed some extra space around the alanine that would be filled by the slightly larger valine. the second amino acid change involved a charged aspartate residue in the design that in retrospect was too close to the virus protein--it was changed to a non charged residue which is less energetically costly to bury upon binding.

we are now combining these two substitutions, and expect that the combination should bind still more tightly to the virus than any protein we have tested so far. we should know later this week--I'll keep you posted!

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We got some good news today in an announcement by Vice President Biden:

http://arpa-e.energy.gov/NewsMedia/News/tabid/83/vw/1/ItemID/21/Default.aspx

We were funded to work with three other research groups to develop a completely new pathway for using solar energy to transform CO2 into the large molecules that the world has grown to depend on (fuels, etc)--this if successful could greatly reduce dependence on fossil fuels and contribute to removing CO2 from the atmosphere.

While the large majority of rosetta@home calculations will remain focused on biomedical problems, expect to see from time to time work units relating to design of enzymes for CO2 capture and conversion.

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We got some more good news today: a manuscript we submitted to Science magazine on rosetta based de novo design of a new enzyme which catalyzes the formation of two carbon-carbon bonds between two small molecules was accepted for publication. The work described in the manuscript is a real step forward in designing enzyme catalysts for reactions not catalyzed by naturally occurring enzymes, and could provide new routes to drug molecules which can be hard to synthesize using traditional methods.

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CASP9 is now in full swing and we need your help! We are being overwhelmed with targets and need as much CPU power as possible!

I just got this from the organizers:

Subject: CASP update - May 7

First week of CASP9 prediction season is over. We have released 14 targets. The vast majority of them were easy TBM targets. Next week you will find some harder targets in the human prediction category.

As of today, we have 125 groups (predominantly servers at this early stage) contributing models to the Prediction Center. You can always find the latest CASP statistics at http://predictioncenter.org/casp9/numbers.cgi .


If you are interested in following the prediction season as it happens, the above web site is a good source of information.

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We are absolutely delighted by the recent increase in the total throughput of rosetta@home, which could not come at a more critical time! we are having to make very difficult choices between CASP9 structure prediction calculations and the next generation of pathogen inhibiting proteins building on our success with the flu virus inhibitor, and the new contributions of computer power many of you are making are helping immensely. Thank you very much!

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We have now confirmed the tight binding of our designed Spanish Flu inhibitor to the flu virus using multiple different methods (it is always good to be totally certain with exciting results like these!). For those of you with some chemistry background, the binding constant is about 20nM.

With collaborators at Scripps research institute we are now trying to determine the structure of the designed complex between the inhibitor and the virus by x-ray crystallography (to see whether binding is as in the design model). With the tight binding confirmed, we are now starting to investigate whether the designed protein prevents the virus from infecting cells.

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A manuscript describing the results on FoldIt, which many of you contributed to, was just accepted for publication in Nature. The idea for FoldIt came from rosetta@home participants who posted on the message boards about wanting to be able to guide the course of the folding trajectory. Please keep letting us know your thoughts and suggestions!

Rosetta@home has now been directly responsible or closely associated with two papers in Science (one on enzyme design, one on new approaches for structure determination) and two papers in Nature (this one on Foldit, and one last year on endonuclease design for gene therapy) in the last 9 months. This kind of impact at the forefront of scientific research is I think a first for volunteeer computing, and perhaps the strongest indication to date of the power and value of volunteer computing for pushing forward the boundaries of scientific understanding.

Thank you all for your invaluable contributions to our collective efforts!

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The most recent issue of Science magazine has our paper on the use of Rosetta to design a new carbon-carbon bond forming enzyme, along with a commentary. This paper has attracted a lot of attention in the press. Thank you all for your contributions to this work and to our ability to move forward with designing enzymes and other proteins that will hopefully be of use to society in not too long.

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There have been exciting developments in our work to develop general methods for designing proteins that can bind to and block the activity of any desired target protein. There are now three targets for which we have designed and experimentally validated binders: a widely used "model" protein called lysozyme, a protein involved in biosynthesis in the bacteria that causes tuberculosis, and a key protein on the surface of the H1N1 flu virus. In the flu case, our collaborators have just solved the structure of our designed protein bound to the virus protein and it is amazingly close to our computational design model.

Now that the methods seem to be working pretty well, we are thinking more about applications. One of these is to make cheaper and more robust diagnostics kits. We are now collaborating with groups interested in developing low cost diagnostics for the flu virus (and other pathogens). our designed proteins are very easy to make in large quantities, and our collaborators are going to test how well they work in place of more expensive and less stable antibody molecules in diagnostic kits.

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In the past I've described a brand new approach using Rosetta to design vaccines for which there are not effective current vaccination treatments. HIV, for example, has turned out to be fiendishly effective at evading the immune system, and as you probably know, despite much work there is no really good vaccine. In collaboration with other groups, Rosetta has been used to design small proteins that present "Achilles heel" regions of the virus to the immune system to stimulate the production of antibodies which recognize these regions. The first papers on this have now been published and, while the designed proteins have not yet elicited strongly neutralizing responses, there is considerable excitement over this new approach. You can read about it at
http://www.nature.com/news/2010/100927/full/news.2010.495.html

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The Gates foundation has just awarded $1,000,000 to a collaborative project to develop specific enzymes that cut within HIV DNA in cells into which the virus has integrated:

http://www.gatesfoundation.org/press-releases/Pages/gce-next-stage-winners-announced-101027.aspx

One of the many nasty things about HIV is that it can reside for a long time in a latent state where it can't be detected by the immune system. If we can generate enzymes that cut up the virus when it is hidden inside a genome, its hiding place will be destroyed. Keith Jerome's lab at the UW is developing methods for delivering enzymes to possibly HIV infected cells, and a graduate student working between our groups is using Rosetta to design endonucleases which cut within the HIV DNA sequence. I'll keep you posted on the progress of this exciting project!

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First, I would like to thank everybody for bearing with us while we recovered from a critical server hardware failure. Over the next month or two we will be installing more powerful and more robust hardware so hopefully this will not happen again.

Second, I'd like to tell you briefly about another exciting success with Rosetta. When structural biologists work to solve protein structures by putting protein crystals into x-ray beams and recording the diffraction pattern, they only have half of the necessary information. The other half (the "phase" information) can be quite difficult to obtain. In the past six months, we've collected about 15 cases where protein crystallographers were stuck and could not solve the structure. Using Rosetta, we built models for these proteins of sufficient quality to allow the inference of the missing information and subsequently the solution of these structures. This opens the door to a much easier way of solving challenging protein structures, and there are lots of scientists excited about using the new method. The new method is described in a manuscript which will likely appear soon in Nature magazine.

Again, thank you for sticking with rosetta@home during our recent server problems -- there is a lot of exciting scientific research that is only possible because of your contributions!

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