[quote]Thank you for the updates on the science the project is doing, Dr. Baker.

My main interest in Rosetta@home is so that we can help cure the diseases of aging (the #1 cause of death and suffering in the "western" world), either with a plan like Aubrey de Grey's SENS (see methuselahfoundation.org), or something else.

Work on fibrils (like in Alzheimer's) that accumulate as a toxic byproduct of simply being alive are a good step in that direction, as well as anything that makes gene therapy possible.

Keep up the good work, we'll keep crunching, and please keep updating us frequently.

Thanks![/quote



the updates are very much appreciated

I'll be honest, too: the overwhelmingly greatest reason why I crunch for Rosetta@Home is because I want it to be utilized in the crusade against aging.

Rosetta@home has received a substantial monetary contribution from an anonymous donor! Following the suggestion of the donor, the University of Washington has used the money to start a special “Rosetta@home fund” that will be used to pay part of David Kim’s salary (David is the architect of Rosetta@home and the person who keeps the project running), upgrade the servers as needed, and allow us to make more rapid progress on the disease-releated research Rosetta@home is carrying out. If you would like to make a (tax-deductible) contribution to the project, the link is Rosetta@home fund . David will be adding a link to this from the Rosetta@home home page in the next day or two. Thank you for your contributions to the project!

That's excellent news! If the anonymous donor is reading this, thank you very much!

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Could you offer some more detail on how the money contributed will be used? Specifically, it seems a bit fuzzy between the differences between "Rosetta@home" and "BakerLab", and between public outreach and future research.

How much money are you trying to raise?
Is there a specific initiative, illness or project you are working to fund?
What is the plan to engage the public? Will this be done via Grid Republic, or in association with them?
The site askes for your name and address, how will this information be used?
Are there ways, other than crunching, that people could contribute their time to assist with these initiatives, rather then their money?

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Add this signature to your EMail:
Running Microsoft's "System Idle Process" will never help cure cancer, AIDS nor Alzheimer's. But running Rosetta@home just might!
https://boinc.bakerlab.org/rosetta/

Could you offer some more detail on how the money contributed will be used? Specifically, it seems a bit fuzzy between the differences between "Rosetta@home" and "BakerLab", and between public outreach and future research.


The money will be used exclusively for rosetta@home and the related research in the Baker lab (they are pretty inextricably linked so it is hard to separate the two). I'm going to ask the UW gifts people to remove the "outreach" part, it shouldn't be there.


How much money are you trying to raise?

the more the better! we are always at the limit of available resources.

Is there a specific initiative, illness or project you are working to fund?

not at this point--we are hoping to get support for the whole effort so we can make more rapid progress on all fronts

What is the plan to engage the public? Will this be done via Grid Republic, or in association with them?

we don't have a plan, but I guess we should! what would you suggest?

The site askes for your name and address, how will this information be used?

we won't use it in any way.


Are there ways, other than crunching, that people could contribute their time to assist with these initiatives, rather then their money?

yes--you and others have been and are continuing to help the project immensely by answering questions on the message boards, spreading the word about the project, and in countless other ways. we are extremely grateful for your contributions!

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I have noticed that mods and developers of R@h have a very small RAC. Do you run R@H or Ralph on your PCs or they are used for some internal crunching or else? )

I, for one, do my Rosetta crunching under my personal user ID, rather then my moderator account. Check out the credits from team University of Washington, team ID #2 Housing and Food Services, and team ID #1, Baker Lab.

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Rosetta Moderator: Mod.Sense

That wired article was great, hope it brings more users. personally, I couldn't really get into foldit, but it's nice to hear that it's going well.

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Hi Dr.B.

Good news about the work your doing on the flu, let us know what the task names

to look out for.

pete.

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What will the flu virus work units be called, so we'll know them when we are working on them? How many work units will be sent out to work on this?

Suggest you post a project news item when flu tasks are released. This is just the sort of thing that could dramatically increase project TFLOPs, even if only for the attention span of the public. Some will remain with the project, even after the immediate scare has passed.

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Add this signature to your EMail:
Running Microsoft's "System Idle Process" will never help cure cancer, AIDS nor Alzheimer's. But running Rosetta@home just might!
https://boinc.bakerlab.org/rosetta/

I just got an EMail (and now that I've enabled the new project, a task) from WCG that says it will study influenza.

http://www.worldcommunitygrid.org/projects_showcase/flu1/viewFlu1Main.do

So, that raises the question on how Rosetta's flu research will differ, are you really duplicating efforts (I know you aren't, but a discussion explaining how the research is different would be great). Is theirs more the flu virus in general, and yours more specific to the strain that recently main such big news?

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Add this signature to your EMail:
Running Microsoft's "System Idle Process" will never help cure cancer, AIDS nor Alzheimer's. But running Rosetta@home just might!
https://boinc.bakerlab.org/rosetta/

Any news on the flu research?

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Add this signature to your EMail:
Running Microsoft's "System Idle Process" will never help cure cancer, AIDS nor Alzheimer's. But running Rosetta@home just might!
https://boinc.bakerlab.org/rosetta/

Any news on the flu research?

Yes. We already have designed proteins that are predicted in silico to bind tightly to the virus. we next have to test to see if they in fact bind tightly. This requires getting some of the flu surface protein from our collaborators at Scripps, who are preparing it for us. Next, we will synthesize our designed proteins in the laboratory, and then measure their binding to the flu surface protein. The way this all works out experimentally is interesting; perhaps I should post a full description of the experiment in my journal. in any event, which should be getting experimental feedback in a couple of months on our designs.

The difference between what we are doing and the other project you mentioned is that we are designing proteins to bind to the flu virus, wheras they are searching for small molecules which bind to the virus. Both are interesting and important approaches to take to the problem.

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If you could post details in your journal, that would be great. . . this
is really interesting stuff!


"Yes. We already have designed proteins that are predicted in silico to bind tightly to the virus. we next have to test to see if they in fact bind tightly. This requires getting some of the flu surface protein from our collaborators at Scripps, who are preparing it for us. Next, we will synthesize our designed proteins in the laboratory, and then measure their binding to the flu surface protein. The way this all works out experimentally is interesting; perhaps I should post a full description of the experiment in my journal. in any event, which should be getting experimental feedback in a couple of months on our designs.

The difference between what we are doing and the other project you mentioned is that we are designing proteins to bind to the flu virus, wheras they are searching for small molecules which bind to the virus. Both are interesting and important approaches to take to the problem."

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will do!

If you could post details in your journal, that would be great. . . this
is really interesting stuff!


"Yes. We already have designed proteins that are predicted in silico to bind tightly to the virus. we next have to test to see if they in fact bind tightly. This requires getting some of the flu surface protein from our collaborators at Scripps, who are preparing it for us. Next, we will synthesize our designed proteins in the laboratory, and then measure their binding to the flu surface protein. The way this all works out experimentally is interesting; perhaps I should post a full description of the experiment in my journal. in any event, which should be getting experimental feedback in a couple of months on our designs.

The difference between what we are doing and the other project you mentioned is that we are designing proteins to bind to the flu virus, wheras they are searching for small molecules which bind to the virus. Both are interesting and important approaches to take to the problem."

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So if I'm following the logic, if you are successful in your search for a flu vaccine for the recent strain of flu, since you are focused on invariant portions of the surface protein, you will have actually created a vaccine for thousands of flu strains. In other words, the days of the annual flu shot that may or may not help against the flu strains that actually come to affect the public in a given year, are over. The one shot will be dramatically more effective, and against like future strains as well.

The point I'm trying to surface here is that in pursuit of one specific illness, you end up learning and creating things that are applicable more universally. This is part of why HIV research is important. Whether or not you have or will ever get the HIV virus, the knowledge acquired will help address numerous other maladies.

I am very curious how you create a protein structure that presents the multiple tightly binding strands in the proper orientation. This sounds much more difficult then colorizing a couple lengths of string and then figuring out a way to wind the string into a ball that has all of those colors at very specific points in the completed ball.

In other words, once you know the colored bits of string, how do you fill in the rest of the ball in a way that assures the final orientation of the key elements that you've confirmed have good fit with the target? If they bind well enough, is there some wiggle room there? Where the strands in your counter agent will distort upon docking with the viral cell?

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Add this signature to your EMail:
Running Microsoft's "System Idle Process" will never help cure cancer, AIDS nor Alzheimer's. But running Rosetta@home just might!
https://boinc.bakerlab.org/rosetta/

I am very curious how you create a protein structure that presents the multiple tightly binding strands in the proper orientation. This sounds much more difficult then colorizing a couple lengths of string and then figuring out a way to wind the string into a ball that has all of those colors at very specific points in the completed ball.

In other words, once you know the colored bits of string, how do you fill in the rest of the ball in a way that assures the final orientation of the key elements that you've confirmed have good fit with the target? If they bind well enough, is there some wiggle room there? Where the strands in your counter agent will distort upon docking with the viral cell?

I don't know the answer to this, but I am certain that Dr. Baker has mentioned on several occasions that the ability to design a custom protein that has a desired shape is something that Rosetta is capable of doing. And as we improve Rosetta's ability to determine the shape of a given amino acid sequence, we improve it's ability to design custom proteins.

When determining the shape of a protein, Rosetta lets it fold, measures the energy, "shakes it a bit" measures the energy again, and so on. Each shake adjusts the final shape of the protein from the previous test.

This is now a wild guess on my part, I could be totally wrong. Remember, I'm not a biochemist. ;) However it seems like a plausible idea to me. Suppose they do the following. We know exactly what shape we want. So we try a random amino acid sequence, and see how closely it matches. If it's not quite there, change a residue or two, "shake" it, and try again.

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Will the newly designed protein inhibit neuraminidase? For those unfamiliar with neuraminidase, it's one of the two surface proteins in influenza, and represents the 'N' in 'H1N1' -- the technical name for swine flu. (The 'H' is for hemagglutinin.)

Also, what are the advantages (and disadvantages) of designing a protein to inhibit the virus's surface protein, rather than designing a simpler molecule? My understanding of mainstream anti-influenza drugs like Tamiflu and Relenza is that they are much smaller and simpler than average proteins. Would it be more difficult to engineer and optimize an expression system like E. coli to manufacture the therapeutic protein than the smaller molecular drug? Could small molecules target the invariant regions of influenza surface proteins that the therapeutic proteins being designed will target?

I am very curious how you create a protein structure that presents the multiple tightly binding strands in the proper orientation. This sounds much more difficult then colorizing a couple lengths of string and then figuring out a way to wind the string into a ball that has all of those colors at very specific points in the completed ball.

In other words, once you know the colored bits of string, how do you fill in the rest of the ball in a way that assures the final orientation of the key elements that you've confirmed have good fit with the target? If they bind well enough, is there some wiggle room there? Where the strands in your counter agent will distort upon docking with the viral cell?

I don't know the answer to this, but I am certain that Dr. Baker has mentioned on several occasions that the ability to design a custom protein that has a desired shape is something that Rosetta is capable of doing. And as we improve Rosetta's ability to determine the shape of a given amino acid sequence, we improve it's ability to design custom proteins.

When determining the shape of a protein, Rosetta lets it fold, measures the energy, "shakes it a bit" measures the energy again, and so on. Each shake adjusts the final shape of the protein from the previous test.

This is now a wild guess on my part, I could be totally wrong. Remember, I'm not a biochemist. ;) However it seems like a plausible idea to me. Suppose they do the following. We know exactly what shape we want. So we try a random amino acid sequence, and see how closely it matches. If it's not quite there, change a residue or two, "shake" it, and try again.

Yes, you are right--designing shapes is one of the things we've discovered how to do. we start with just the backbone of the protein folded up into the right shape, but with no sidechains because of course we don't know the sequence. Then we search through the large number of possible sequences for those that have very low energy when the backbone is folded up in this way. then, as you suggest, we check by folding the protein up and making sure it folds up the right way.

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Have you started any work on iron-binding proteins? I currently have a workunit with myoglobin in its name, amd myoglobin contains iron.