31 replies to this topic

[MichaelGR]

I know this is the folding@home forum, but I figured you guys were more interested in distributed computing advances than the ppl on the biosciences forum..

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Distributed computing Rosetta@home (http://boinc.bakerlab.org/rosetta/) has recently given this update, via David Baker, head of Baker labs at the University of Washington:

"Mike Tyka's results from your calculations over the past two weeks on rosetta@home are truly exciting! Many of you have found, starting from an extended chain, structures that are close to the crystal structure but much lower in energy. When Mike inspects your very low energy structures, in many cases it seems possible that they may be better models than the experimentally determined structure. We never expected to be in this situation so soon! Our next step is to see whether these low energy structures may actually be as or more consistent with the experimental data than the deposited crystal structure. If true, this would be a new step forward for computational structural biology!"

This is promising news, and all that with only 75 teraFLOPs (versus Folding@home's 4,700 teraFLOPS).

Am now looking forward to more info about the Alzheimer's paper recently mentioned by Folding@home. This will help me decide how to allocate my computing power between these projects. I like supporting this team on F@H, but I also want to use my cycles where they'll do the most good. Right now it's a mix between these two projects, with maybe 3/4 on Folding and 1/4 on Rosetta@home (a few months ago it was 100% Rosetta@home).

Cheers,

Mike

[chungenhung]

I use my GPUs for F@H
CPUs for Rosetta and World Community Grid if one server goes down.

[niner]

Thanks, MichaelGR. That is a very interesting result from the Baker group. Accurate computation of structure will probably do more for the progress of medical science than the folding dynamics that seem to be the focus of the Pande group. Since F@H is already so heavily subscribed, we might be doing more for the progress of science to throw some more cycles in the direction of the Rosetta people.

[eternaltraveler]

Thanks, MichaelGR. That is a very interesting result from the Baker group. Accurate computation of structure will probably do more for the progress of medical science than the folding dynamics that seem to be the focus of the Pande group. Since F@H is already so heavily subscribed, we might be doing more for the progress of science to throw some more cycles in the direction of the Rosetta people.

indeed. Every scientist I know is much more behind the Baker group, myself included.

The relative contribution we would make there is much more.

When this was brought up in the past the idea of switching to Rosetta was not popular to say the least for some reason.

Edited by elrond, 20 January 2009 - 05:15 AM.

[kismet]

When this was brought up in the past the idea of switching to Rosetta was not popular to say the least for some reason.

Well, maybe because our team is small enough as it is? Actually we could crunch for dozens of different projects to support different worthwhile scientific goals, but really we wouldn't need to do it under the banner of "imminst" or the "longevity meme", not as a team, because we wouldn't gain much visibility from it anyway.
I don't believe we can be a high ranked team in two distributed computing projects at the moment. Maybe someone could prove me wrong with some hard numbers, though.

[eternaltraveler]

When this was brought up in the past the idea of switching to Rosetta was not popular to say the least for some reason.

Well, maybe because our team is small enough as it is? Actually we could crunch for dozens of different projects to support different worthwhile scientific goals, but really we wouldn't need to do it under the banner of "imminst" or the "longevity meme", not as a team, because we wouldn't gain much visibility from it anyway.
I don't believe we can be a high ranked team in two distributed computing projects at the moment. Maybe someone could prove me wrong with some hard numbers, though.

my point is if immist etc. is going to be involved in one project why pick f@h when Rosetta has demonstrated they can do more even with less resources?

[Traclo]

Hmm... I think I may switch to Rosetta@home.
Sorry Folding@home team if I do, but putting my cycles where they will be most useful is my biggest concern.

Unless I can find information saying why I shouldn't.

[kismet]

my point is if immist etc. is going to be involved in one project why pick f@h when Rosetta has demonstrated they can do more even with less resources?

At this point it's because our biggest team contributes to FAH (and it is simply not feasible to switch for a heterogenous team of this size), but why did the team founder pick folding in the first place? I can only speculate, but I guess folding (~2000) was around before rosetta (~2005) when the team was being formed.

Hmm... I think I may switch to Rosetta@home.
Sorry Folding@home team if I do, but putting my cycles where they will be most useful is my biggest concern.

Unless I can find information saying why I shouldn't.

Both projects are worthwhile, I don't know if Rosetta is "better" in any way (Aubrey d. G. supports Rosetta by the way). However, our folding team is extremely strong so to me it couldn't be any simpler than that: two similar projects, only one seems to help both our exposure and science (FAH). I said anyone could convince me of the opposite with some facts e.g. if 10% of our folding team could help us to rank as a top team in rosetta it may be worthwhile to fight on both fronts - but normally you don't divide sparse resources.
If I simply wanted to support science per se, I'd donate money, not crunch, but with folding it seems we can support both imminst and science.
Although, one could argument that the folding team does not give us any better exposure or something along the lines, but I don't remember anyone saying that? Now does it?

Edited by kismet, 20 January 2009 - 09:03 PM.

[MichaelGR]

My goal with posting here wasn't to create an exodus from the F@H team.

But

I *do* think we need to be very rational about how we try to achieve our goals.

Folding@home no doubts can help with the fight against aging, and they are cutting edge in efficient use of hardware (GPU, consoles, SSEx extensions, etc).

But

Is Rosetta@home a better use of our cycles? It depends.

Is the first goal of the ppl here publicity, or science? If it's science first and publicity second, we need to determine who does the best science.

If it's publicity first, I think we already established that we're not doing very well in that regard, and we should make some changes. I'd be surprised if more than a couple dozen people found longevitymeme.org by seeing the team name in the list and then googling it. We must be after real-world results, not just the abstract satisfaction of climbing in rank.

The PROs of a Rosetta@home team would be:

-Science might be better, or at least more applicable to the SENS platform.
-Smaller project, so we'd have a bigger marginal impact on improving their scientific progress
-Could name the team "LongevityMeme.org" for better publicity
-In BOINC project, team pages can have a clickable URL, a graphic logo and a text. There we could put pro-longevity science stuff to educate ppl.

CONS:

-Can't use consoles or GPUs (though that might change with the new generation of GPGUs)
-Need to start from scratch, though I suspect rankings don't work the same over in BOINC. It's not total credits, but rather Recent Average Credits, so maybe we'd climb fast (edit: confirmed, see list here: http://boinc.bakerla...a/top_teams.php what matters is daily production, not total credit. We could probably get in the top 50 in no time)

SUGGESTION:

A compromise might be to create a team over at Rosetta@home and just let people pick their team, so they can support longevitymeme.org either way, instead of either folding or totally leaving. If the science is our primary concern, then that seems to be the best way to do it. People with lots of GPUs might stick with folding, ppl with lots of CPUs might pick Rosetta..

My 2 cents,

Mike

Edited by MichaelGR, 20 January 2009 - 10:21 PM.

[MichaelGR]

Both projects are worthwhile, I don't know if Rosetta is "better" in any way (Aubrey d. G. supports Rosetta by the way).

That's interesting. Can you source that info about Aubrey? Did he say that in some interview?

[MichaelGR]

I've contacted Aubrey de Grey to ask what his preference is. He replied like 30 minutes after my first email... Will let you know what I find out when our conversation reaches a conclusion.

[Anthony]

I've contacted Aubrey de Grey to ask what his preference is. He replied like 30 minutes after my first email... Will let you know what I find out when our conversation reaches a conclusion.

Could I add the Rosetta program to my computer and let the Folding and Rosetta programs run simultaneously?

Anthony

Edited by Anthony, 21 January 2009 - 01:07 AM.

[eternaltraveler]

I've contacted Aubrey de Grey to ask what his preference is. He replied like 30 minutes after my first email... Will let you know what I find out when our conversation reaches a conclusion.

ya, he answers email faster than most people answer their phone usually

[MichaelGR]

I've contacted Aubrey de Grey to ask what his preference is. He replied like 30 minutes after my first email... Will let you know what I find out when our conversation reaches a conclusion.

Could I add the Rosetta program to my computer and let the Folding and Rosetta programs run simultaneously?

Anthony

If you have a CPU with 2 or 4 cores, you could always split it between the two (1 core Folding, 1 core Rosetta, f.ex.). But it's not a good idea to run the two programs on the same core(s).

[kismet]

Well, there are dozens of people who joined imminst only because of the folding price, even if people just read "longevitymeme" on the stats it may already help to alter their perception in the longterm. Personally I believe the name is disastrous (no .org) and something's going awry at Stanford if they don't allow name changes once in a while. Still it's a project with a lot of potential (if we somehow managed to change the name for instance).

The PROs of a Rosetta@home team would be:

-Science might be better, or at least more applicable to the SENS platform.
-Smaller project, so we'd have a bigger marginal impact on improving their scientific progress
-Could name the team "LongevityMeme.org" for better publicity
-In BOINC project, team pages can have a clickable URL, a graphic logo and a text. There we could put pro-longevity science stuff to educate ppl.

CONS:

-Can't use consoles or GPUs (though that might change with the new generation of GPGUs)
-Need to start from scratch, though I suspect rankings don't work the same over in BOINC. It's not total credits, but rather Recent Average Credits, so maybe we'd climb fast (edit: confirmed, see list here: http://boinc.bakerla...a/top_teams.php what matters is daily production, not total credit. We could probably get in the top 50 in no time)

Not that I dislike Rosetta (it was the first project I ever ran on my PC), but to add to the CONS:
Smaller community, whatever exposure we get (even with the better team name, etc) will reach a smaller audience.

SUGGESTION:

A compromise might be to create a team over at Rosetta@home and just let people pick their team, so they can support longevitymeme.org either way, instead of either folding or totally leaving. If the science is our primary concern, then that seems to be the best way to do it. People with lots of GPUs might stick with folding, ppl with lots of CPUs might pick Rosetta..

I'm pretty sure a R@H imminst team should already exist?! At least that's what I've heard.

Aubrey's opinion:

1. It's somewhere on the mfoundation's "what can you do to help our cause" page, it says e.g. run Rosetta.
2. There was a discussion on the mfoundation board which scratched the surface of this topic, a guy talks about Rosetta and Aubrey answers "We don't yet have the funds to support this project, but it's top of our list."

Edited by kismet, 21 January 2009 - 03:32 PM.

[ihatesnow]

Well, there are dozens of people who joined imminst only because of the folding price, even if people just read "longevitymeme" on the stats it may already help to alter their perception in the longterm. Personally I believe the name is disastrous (no .org) and something's going awry at Stanford if they don't allow name changes once in a while. Still it's a project with a lot of potential (if we somehow managed to change the name for instance).

The PROs of a Rosetta@home team would be:

-Science might be better, or at least more applicable to the SENS platform.
-Smaller project, so we'd have a bigger marginal impact on improving their scientific progress
-Could name the team "LongevityMeme.org" for better publicity
-In BOINC project, team pages can have a clickable URL, a graphic logo and a text. There we could put pro-longevity science stuff to educate ppl.

CONS:

-Can't use consoles or GPUs (though that might change with the new generation of GPGUs)
-Need to start from scratch, though I suspect rankings don't work the same over in BOINC. It's not total credits, but rather Recent Average Credits, so maybe we'd climb fast (edit: confirmed, see list here: http://boinc.bakerla...a/top_teams.php what matters is daily production, not total credit. We could probably get in the top 50 in no time)

Not that I dislike Rosetta (it was the first project I ever ran on my PC), but to add to the CONS:
Smaller community, whatever exposure we get (even with the better team name, etc) will reach a smaller audience.

SUGGESTION:

A compromise might be to create a team over at Rosetta@home and just let people pick their team, so they can support longevitymeme.org either way, instead of either folding or totally leaving. If the science is our primary concern, then that seems to be the best way to do it. People with lots of GPUs might stick with folding, ppl with lots of CPUs might pick Rosetta..

I'm pretty sure a R@H imminst team should already exist?! At least that's what I've heard.

Aubrey's opinion:

1. It's somewhere on the mfoundation's "what can you do to help our cause" page, it says e.g. run Rosetta.
2. There was a discussion on the mfoundation board which scratched the surface of this topic, a guy talks about Rosetta and Aubrey answers "We don't yet have the funds to support this project, but it's top of our list."

[ihatesnow]

can someone tell me what accomplishments folding at home has achieved or at least its greatest accomplishment so far ? i crunch for rosetta at home however i would like to know more about folding at home ..........thanks

Edited by ihatesnow, 23 January 2009 - 09:45 AM.

[ihatesnow]

i did a search at rosetta and found this http://boinc.bakerla...php?teamid=7054

[ihatesnow]

this article mentions rosetta @ home http://www.nytimes.c...ml?pagewanted=1 http://boinc.bakerlab.org/rosetta/

Edited by ihatesnow, 25 January 2009 - 08:38 AM.

[Ghostrider]

People with lots of GPUs might stick with folding, ppl with lots of CPUs might pick Rosetta..

My 2 cents,

Mike

I run Rosetta@Home on my main desktop system. I would run it on my work laptop as well, but having trouble so I am running FAH on the laptop. Basically, since Rosetta@Home cannot make use of GPUs, I feel like I am getting more bang for my CPU buck there. If I had a powerful GPU, then I would run FAH. But since 30 days of CPU time on my machine is equivalent to 1 (or less) FAH day on a GPU, I think my contribution will be best contributing to Rosetta for now. Basically, whichever team can develiver results the quickest or looks most promising, that's what I will go with. Until then, I'll contribute my computing resources in the most efficient manner.

Edited by Ghostrider, 25 January 2009 - 05:57 PM.

[EmbraceUnity]

I have been running Rosetta@Home through the BetterHumans group for years now. They are more open than F@H and I think more productive. Certainly they could use our help more than F@H.

[kismet]

I have been running Rosetta@Home through the BetterHumans group for years now. They are more open than F@H and I think more productive. Certainly they could use our help more than F@H.

But the mfoundation can use our help even more and what about the starving children in Africa for that matter (!?) There's no reason not to support both projects and as of now no one really bothered to discuss the biggest pro of folding, which is said to be exposure, in depth. There are pros and cons to both projects, we cannot deny the facts.

I've contacted Aubrey de Grey to ask what his preference is. He replied like 30 minutes after my first email... Will let you know what I find out when our conversation reaches a conclusion.

What about the update? 

Edited by kismet, 26 January 2009 - 12:48 PM.

[ihatesnow]

[kismet]

I'm sure you have read http://en.wikipedia....at_home#Results ?
I'll try to find out the relevance of their results if it helps.

[MichaelGR]

Hi everybody,

Been a while since I was here. Some very interesting news to report today. The Rosetta@home team (http://boinc.bakerlab.org/rosetta/) is working on two new papers about advances in computational protein structure prediction (with distributed computing software that you can run on your PC or Mac).

Here are the abstracts, straight from David Baker's journal:

The first manuscript is called "Simultaneous prediction of protein folding and docking at high resolution". It reports your exciting results with the "fold and dock" runs set up by Rhiju and Ingemar several months ago. Here is the abstract:

Despite recent successes in high resolution de novo modeling, computational methods have yet to achieve blind predictions of proteins in their most commonly occurring functional forms, symmetric homomultimers. Building on the Rosetta framework, we present a general method to simultaneously model the folding and docking arrangements of multiple chains. A benchmark study on large alpha-helical bundles, interlocking beta sandwiches, and interleaved alpha/beta motifs demonstrates the method’s generality, near-atomic accuracy, and potential use in molecular replacement phasing. Further, we present blind tests on a crystallized coiled-coil as well as two dimers with more complex geometries solved by NMR. These results indicate that high-resolution modeling of multimers is within the reach of the structure prediction community and may have immediate practical use for crystallographic phasing and the rapid structure determination of multimers with limited NMR information.

The second manuscript I am working on is titled "Alteration of Enzyme Specificity by Computational Loop Remodeling and Design". It describes a new approach using Rosetta to redesign enzymes in the human body to catalyze new reactions. Graduate student Paul Murphy not only developed the new method, but also in the manuscript shows how it can be used to create a new enzyme for gene therapy.

Here is the idea. Suppose a patient needs a transfusion of cells from another person to recover from a disease. There is a small chance that these cells will, rather than helping you, actually cause some new problem. In this case, it is important to be able to selectively kill these cells. For this purpose, special drugs have been developed which are not themselves toxic, but become toxic when broken down by a particular enzyme. If this enzyme is put into the introduced cells, then they can be killed if necessary by giving the drug to the patient.

The problem is--where does this enzyme come from. If it is a human enzyme, then the patient will convert the drug to the toxic compound in his/her normal tissue which would be very bad. If it is an enzyme from bacteria for example, that humans don't have the patient will be safe from the drug. However, our bodies are made to destroy anything that looks foreign, and this bacterial protein certainly will.

Our solution is to take a human enzyme, and keep the outside the same, so the patient's immune system thinks it is a human protein and doesn't destroy it, but change the catalytic site on the inside so that it converts the drug to the toxic compound. In the manuscript, Paul shows how a human enzyme that deaminates guanine can be redesigned by remodeling not only the sidechains but also the protein backbone to deaminate cytosine. While not quite ready for prime time, with some optimization this enzyme could be used in gene therapy as described above.

In this case I don't have much more work to do--the manuscript is already accepted for publication in the Proceedings of the National Academy of Sciences, but it is a bit over their length limit so we have to figure out how to cut out a few words.

Very exciting!

Edited by MichaelGR, 07 March 2009 - 07:50 AM.

[MichaelGR]

More info on other papers:

The third manuscript I am working on is called "Blind docking of pharmaceutically relevant compounds using RosettaLigand". This describes the current state of our efforts towards improving methods for designing new small molecule drugs to combat diseases. The challenge addressed by this paper is to predict how drug molecules bind to proteins--determining how they bind is necessary to improve their efficacy and to identify good candidate molecules in the first place. In two earlier papers we had described the incorporation of small molecule modeling into Rosetta to create the new RosettaLigand drug docking methods, and tested the method on publicly available data sets. However, many of you will not be surprised that much of current drug discovery is being carried out in pharmeceutical companies, and the compounds they are testing are generally not made public (they are akin to trade secrets). We wanted to learn whether RosettaLigand was successful in docking drug compounds in actual drug discovery efforts, and were very fortunate when a large drug company agreed to let Ian Davis, who is working on the project, visit one of their company sites and analyze the results they had gotten with RosettaLigand on their private set of compounds. The results are described in this paper and are very encouraging, not only does RosettaLigand appear to be one of the best current methods for this crucial step in drug design, but also there are some clear avenues for improvement (which weren't evident with the public datasets) which we are now starting to work on.

The fourth manuscript describes rosetta@home predictions in CASP8. as you know with your great help we were again the top ranked group in CASP this year. The manuscript begins:

The CASP8 experiment provided an invaluable opportunity to extensively benchmark the Rosetta protein structure prediction method on a wide range of comparative modeling and free modeling targets. For the targets for which a sequence-detectable structural template existed, target-template sequence alignments were generated, and the Rosetta rebuild and refine protocol was used to generate low energy models. For the small number of targets for which a reliable template could not be identified modeling was carried out using the Rosetta de novo modeling protocol. All targets were subjected to extensive high resolution refinement with the physically realistic Rosetta all-atom forcefield using Rosetta@home.

this one has a due date--March 15--so we have to hurry up a bit!

[ihatesnow]

http://boinc.bakerla...ead.php?id=1177

[ihatesnow]

http://www.scienceda...90310152351.htm

[MichaelGR]

Details on 3 more papers (they're working on 7 manuscripts right now!):

The fifth manuscript describes a very exciting recent discovery made in collaboration with another research group. As many of you know, a large number of diseases, including Alzheimer's, are associated with the folding of a protein not into its normal active state but instead into long repeating fibrils. These are called "amyloid fibrils" and the associated diseases are referred to as "amyloid" diseases. We used Rosetta to design molecules predicted to block the formation of the fibrils, and, strikingly, when these molecules are added to the disease state protein under conditions where it normally forms fibrils, none are formed. We are very excited about this amyloid blocker, but as always I must stress that there are a lot of steps before a finding like this leads to an actually distributed drug.

The sixth manuscript describes our recent results on designing new DNA cutting enzymes that can cut the DNA double helix at very specific target sites. The enzymes we design only cut at one particular 20 base sequence. Remember that DNA is made of four different bases, A T G and C so a particular 20 base site might for example be AGAATAGGATCCAGATCGTC. This long a sequence is extremely unlikely to occur more than once in the human genome, so if we design an enzyme to cut at a particular place in the genome it is likely to cut only at that site (of course we can check this because the sequence of the human genome is known).

why would we want to do this? suppose you have a mutation in a gene and it is making you sick. if we can make an enzyme which cuts near the site of mutation and introduce this enzyme and a "correct" copy of the gene into your cells, the enzyme will cut the DNA and the cut will be repaired likely by copying the correct version we have added as well (cells repair breaks in DNA by copying the most closely related piece of DNA around). thus, with such enzymes we can potentially cure diseases by "gene therapy".

the manuscript describes progress towards this long range goal. we show we can design new enzymes that cut at new sites, and by examining how they work in detail we reveal some pretty big surprises in how the naturally occurring enzyme works which are fascinating in their own right and provide considerable insight into how to achieve the longer term goals of using redesigned enzymes for gene therapy.

he seventh paper is also related to your CASP8 predictions. The assessors asked us and a couple of other groups who made models that were geometrically and energetically nearly indistinguishable from native structures to write a paper describing how we were able to consistently able to generate physically plausible structure models. This was much less work for me than the preceding six manuscripts--I had only to describe the key concepts behind rosetta@home and the search for very low energy structures that are familiar to those of you who follow the screen saver from time to time.

Another good news: When I first posted in this thread, Rosetta@home (http://boinc.bakerlab.org/rosetta/) had 75 teraFLOPS of crunching power. It's now closer to 88 teraFLOPS, and with the results above, I hope that will keep growing.

Edited by MichaelGR, 13 March 2009 - 02:04 AM.

[MichaelGR]

Good news! Dr. David Baker wrote in his journal:

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!