Ok... I have a challenge for all of you...

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Jose

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Message 22271 - Posted: 11 Aug 2006, 13:40:24 UTC
Last modified: 11 Aug 2006, 14:02:52 UTC

Please tell me in your own words:

What is the science that is done when we crunch for Rosetta @ Home? I am just curious. (This is not a trick question :) )
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Message 22273 - Posted: 11 Aug 2006, 14:06:54 UTC
Last modified: 11 Aug 2006, 14:14:01 UTC

University have guys with big brains but no money. So each dollar (or Euro or Yen) we can put in this kind of projects helps the ideas of those guys to become real. And thus help (or will help) the whole humanity.
It\'s really different that give money to something. You never know where the money is gone.

(I hope I have well understand the meaning of your question. Sometimes my translation is a bit erroneous).

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Jose

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Message 22276 - Posted: 11 Aug 2006, 14:33:21 UTC - in response to Message 22273.  

University have guys with big brains but no money. So each dollar (or Euro or Yen) we can put in this kind of projects helps the ideas of those guys to become real. And thus help (or will help) the whole humanity.
It\'s really different that give money to something. You never know where the money is gone.

(I hope I have well understand the meaning of your question. Sometimes my translation is a bit erroneous).




I understand what you say :) That is a very sad comment about our wolrd that big brained scients lack the money .... ( Big athelete gets gazillion of moneys to kick a ball or to swat it with a stick but great minds dont) but my question is what are the big brained (and yes with little money ) scientists at Rosetta @ Home doing? What is the purpose of the work units we process?
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Message 22277 - Posted: 11 Aug 2006, 14:37:28 UTC
Last modified: 11 Aug 2006, 14:47:45 UTC

As far as I have well understand, we know the form of some proteins. If Rosetta can find the same form by calculation, that means the same program can find the form of proteins for which the form is unknown.
And if you want to create a drug, the 3-d form is fundamental. So if you know it ....

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Message 22280 - Posted: 11 Aug 2006, 14:57:33 UTC

Very good Thierry, I like that one.

I also like to think of it this way, viruses and many diseases are comprised of proteins. Dr. Baker and his team are working to prove \"protein gets out protein\". i.e. create the technology required to create the proteins needed to target very specific anomolies in the body.

Rather then \"discover\" that the refined sap of a rare tree works as a cancer cure... plan your attack and CREATE a cure that works, without all the tredging around in the forest :)
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Message 22281 - Posted: 11 Aug 2006, 15:17:04 UTC

So if I accept what you two are saying is right: the science is in the software/application ? Am I reading you right?
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Message 22283 - Posted: 11 Aug 2006, 15:32:35 UTC
Last modified: 11 Aug 2006, 15:36:20 UTC

I would say the main science is in the model, i.e. the theory being used to predict protein structures, and the software is the testing part (theories being tested as part of the scientific method, right?) so the model can be improved.

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Message 22285 - Posted: 11 Aug 2006, 15:40:35 UTC - in response to Message 22281.  

So if I accept what you two are saying is right: the science is in the software/application ? Am I reading you right?

The only things NOT in the application are the physical proteins. Those have been around since the beginning of life. The new goodies are in the Rosetta software and the approach it takes to solving the problem. But you\'ll have to go back to a lab and play with the physical proteins to prove if a Rosetta prediction is correct... or close enough to correct to cure a disease.
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Message 22289 - Posted: 11 Aug 2006, 15:50:45 UTC
Last modified: 11 Aug 2006, 15:52:21 UTC

My answer is: We are twisting a chain of amino acids by a set of rules. And the version number (current 5.25) tells what set of rules is being used. After a certain number of random twistings the result is compared to known structure. And based on the result of how close the predicted and known strucres are the set of rules are changed some way (arbitrarily?) hoping it will produce even better match in the next version.

The energy landscape theory is a mystery to me and how is it calculated experimentally.


list of my results
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Jose

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Message 22290 - Posted: 11 Aug 2006, 15:55:39 UTC

So the lower the energy levels and the RMSD, the better the cruncged model is. Am I right in assuming this?
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Message 22291 - Posted: 11 Aug 2006, 16:09:54 UTC - in response to Message 22289.  

...And based on the result of how close the predicted and known strucres are the set of rules are changed some way (arbitrarily?) hoping it will produce even better match in the next version.


Not trying to be picky here, just wanted to further the understanding of the project.

The search is not entirely random. As you say, the search strategy (algorythm) is improved over time. The search START position is randomized, but the strategy is then applied through the rest of the model. And the idea is that if we learn more about how proteins are built, then we get \"smart\" enough to find the correct answer with less of the random starting locations required to find it.

Also, wanted to comment about comparing to known structures. This is the approach now. When you invent a new compass (call it a \"GPS\" perhaps!) you test it first by using a sextant, compass and clock to navigate, and using a GPS on the same journey. Then you compare your ending position, with that predicted by each approach. If the new GPS results in an answer similar to the compass, then we adopt it as a valid means of navigation.

So the hope is, that in the future, you can just pump the amino acid sequence in to Rosetta, and spit out the 3D structures, and safely assume it is the correct structure. With that, you can compare for other compounds that will link up, dock with, and otherwise interact with a disease cell.

Once that is achieved... the field of medicine will be changed forever. Our bodies are regulated by enzymes and chemical messengers. These are all comprised of proteins... which are largely not understood today.
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Message 22326 - Posted: 12 Aug 2006, 8:13:15 UTC - in response to Message 22291.  
Last modified: 12 Aug 2006, 8:50:12 UTC


.....With that, you can compare for other compounds that will link up, dock with, and otherwise interact with a disease cell......

That is exactly what we were doing at FAD with a database of known structures until we ran out of them. I assume we are trying here to create a much larger database of known structures including some that would\'nt necessarily occur naturally, so the type of work done at FAD can continue by many scientific teams and more compounds can eventually be synthesized , plus a few other things can be tried that could probably be seen as more controversial to some further down the line.

But I suppose at this stage, we are mainly trying to improve the software.



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Message 22339 - Posted: 12 Aug 2006, 15:14:34 UTC - in response to Message 22276.  

That is a very sad comment about our wolrd that big brained scients lack the money ....


I think we really need to see some change in what charities and other non-profit organizations do with their money to fight diseases.

Right now the money goes directly to researches in form of grants and while I\'m sure this is helpful (someone needs to pay for Dr Baker\'s pizza deliveries! ;)) we seem to face a completly different bottleneck right now: processing power.

A Japanese University built a 1 PENTAflop computer (which is more powerful than all of Boinc combined) for $7m. That\'s right - 7 millions, not billions. It\'s by far the fastest supercomputer, but it\'s optimized for protein research (what we do here) and not a general computer, so it doesn\'t qualify for the fastest computer ranking. Plus it couldn\'t run BOINC ;) (just imagine that RAC! :p)

Either way, $7m is pocket change to any large organization - quite frankly I still have no idea why there aren\'t dozens (if not hundreds) of them being built right now.

The question is: why isn\'t this being done? Are the people in charge of the research not adequatly informed about technological advances? Is there some missing link between the individual researcher and the Chief Research Officer? Or can those computers just not be built fast enough to satisfy the existing demand? Or maybe there\'s enough money provided for R&D that the researchers can just do it experimentally instead of working on more efficient methods?


Maybe it\'s time someone fires up a charity that collects donations to build and maintain a massive farm of normal PCs. Find a cold place, cheap real estate, cheap labor for maintenance and cheap electricity (Russia?) and get started... how hard can it be? ;)


PS: sorry to derail your thread Jose ;)
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Jose

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Message 22342 - Posted: 12 Aug 2006, 15:40:18 UTC - in response to Message 22339.  

That is a very sad comment about our wolrd that big brained scients lack the money ....


I think we really need to see some change in what charities and other non-profit organizations do with their money to fight diseases.

Right now the money goes directly to researches in form of grants and while I\'m sure this is helpful (someone needs to pay for Dr Baker\'s pizza deliveries! ;)) we seem to face a completly different bottleneck right now: processing power.

A Japanese University built a 1 PENTAflop computer (which is more powerful than all of Boinc combined) for $7m. That\'s right - 7 millions, not billions. It\'s by far the fastest supercomputer, but it\'s optimized for protein research (what we do here) and not a general computer, so it doesn\'t qualify for the fastest computer ranking. Plus it couldn\'t run BOINC ;) (just imagine that RAC! :p)

Either way, $7m is pocket change to any large organization - quite frankly I still have no idea why there aren\'t dozens (if not hundreds) of them being built right now.

The question is: why isn\'t this being done? Are the people in charge of the research not adequatly informed about technological advances? Is there some missing link between the individual researcher and the Chief Research Officer? Or can those computers just not be built fast enough to satisfy the existing demand? Or maybe there\'s enough money provided for R&D that the researchers can just do it experimentally instead of working on more efficient methods?


Maybe it\'s time someone fires up a charity that collects donations to build and maintain a massive farm of normal PCs. Find a cold place, cheap real estate, cheap labor for maintenance and cheap electricity (Russia?) and get started... how hard can it be? ;)


PS: sorry to derail your thread Jose ;)



No problem: It is not derailed...as a matter of fact, it highlights a very important issue: the funding problems , non for profit (read industrial) researchers face in the US.

PS: I belong to XtremeSystems Rosetta Team where a thread that doesnt have at least 10 topics covered is not considered normal ;)
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Message 22343 - Posted: 12 Aug 2006, 15:44:49 UTC - in response to Message 22326.  

[quote]

But I suppose at this stage, we are mainly trying to improve the software.




Exacttly: this is the basic difference in this Project : what makes it unique among the other Boinc Projects. The work Units perse are but a way to test and fine tune the \"real scientific breakthrough\" : the software that is opening new and exiting ways on how to deal with protein structure prediction and with protein manipulation.

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Message 22344 - Posted: 12 Aug 2006, 15:44:51 UTC - in response to Message 22326.  

[quote]

But I suppose at this stage, we are mainly trying to improve the software.




Exacttly: this is the basic difference in this Project : what makes it unique among the other Boinc Projects. The work Units perse are but a way to test and fine tune the \"real scientific breakthrough\" : the software that is opening new and exiting ways on how to deal with protein structure prediction and with protein manipulation.

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Message 22436 - Posted: 14 Aug 2006, 4:59:00 UTC - in response to Message 22271.  

Please tell me in your own words:

What is the science that is done when we crunch for Rosetta @ Home? I am just curious. (This is not a trick question :) )


I have this strange desire to go back to the original question with this one.

Yes, this is an oversimplification of \"reality\". I know that. If you really want that kind of detail, I would point you to several million pages of text books and scientific journals out there.

How do you find a cure for a disease? How do you make a drug that cures a disease? In both cases, historically, we have \"tried things until we find something that works\". Again, historically, most of the \"breakthroughs\" in these areas were \"blind luck\", a combination of the right person noticing some detail at the right time. One example is the discovery of penicillin -- a scientist noticed that one particular mold culture was killing bacteria in petri dishes....

Today, we have found a different path that seems to work better. We try to understand the disease. What happens in the body when a foreign invader (bacteria, virus, cancer, etc.) arrives? How does a foreign invader\'s biochemistry differ from the human host\'s? Has some normal process \"broken down\" or \"sped up\" in a sick person\'s biochemistry?

All of these processes involve chemical reactions in the body, and all of these chemical reactions happen because specific proteins are present to \"help them along\". They help the reactions in several different ways. They may help get the right \"pieces\" to the right places, or they may help a chemical reaction along by holding the two pieces that are supposed to react at just the right distance and angle for the reaction to happen. But all of the different pieces need to be in the right place, at the right time, under the right conditions.

Most commonly, when we try to design a new drug, we try to inhibit one of the reactions in the body. The hope is that it is a reaction that is causing the disease condition we are trying to correct. So, if we can find, and stop, a chemical reaction that a bacteria needs to survive, but a human does not, the bacteria will die, and the human will [hopefully] remain healthy. If we can find a drug to stop the chemical reactions that make blood clot, we can prevent the blood clots that become strokes and heart attacks. If we inhibit the right reaction too strongly, or inhibit the wrong chemical reaction, or inhibit reactions other than the one we are targeting, the person may have other problems [side effects].

One of the critical pieces of this bigger process is the binding of the \"small molecule\" in the reaction to the protein that is going to \"help\" it along. This process is often compared to a \"lock and key\". While not particularly accurate, it is a useful model. The protein is the \"lock\" part, and the small molecule that is reacting is the \"key\" part. The goal now becomes to design a new \"key\" (a drug) to fit into the right \"lock\" (the protein), and hopefully stay around for a while. With the \"locks\" all filled with the drug molecules, the reaction in question is slowed down, and hopefully the person feels better.

So, how do you design a \"key\". One way to start is to get a picture of the \"lock\" in question. There are a couple of different ways that a protein\'s structure can be determined. The two I am most familiar with are x-ray crystallography and NMR. Both have their drawbacks, and not all proteins can have their structures determined using these methods. Both also can take several months of hard work to determine the structure. Both also require several pieces of expensive equipment. Plus, there are way more proteins out there than we are able to determine structures for.

Here, is where software like Rosetta can enter the picture! The ability to accurately, quickly [and cheaply] predict the structure of a protein could speed up the drug discovery processes tremendously! Since the protein structure determination is so very basic and fundamental to almost all diseases and all drug discovery, its value would be incredible!

Again, this is incredibly simplified, but I hope also understandable.
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Message 22444 - Posted: 14 Aug 2006, 12:17:25 UTC

I really think we need a nice, short 200 word summary of what Rosetta does (and a slightly longer one also.) There are tidbits of excellent comparisons and information spread out over the entire forum, usually as a response to a new person in the forum. After reading several such, I believe that I basically understand, but haven\'t seen it all in once place. Maybe ill try to pull it together a bit later.
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Message 22489 - Posted: 15 Aug 2006, 16:25:54 UTC - in response to Message 22444.  
Last modified: 15 Aug 2006, 16:27:39 UTC

I really think we need a nice, short 200 word summary of what Rosetta does (and a slightly longer one also.) There are tidbits of excellent comparisons and information spread out over the entire forum, usually as a response to a new person in the forum. After reading several such, I believe that I basically understand, but haven\'t seen it all in once place. Maybe ill try to pull it together a bit later.
Well, there already are several explanations (each of them in the several hundred words range) of what Rosetta does, linked from the homepage:

What is Rosetta@home? (this is the green link directly at the top of the homepage)
Quick guide to Rosetta and its graphics (read the first few paragraphs)
Welcome from David Baker (the explorer analogy)
Rosetta@home Science FAQ
Research Overview (more detailed)

And if this still isn\'t enough you can go to www.bakerlab.org for additional information, including the full text of their research papers.

I definitely don\'t want to discourage anyone from producing a well written 200 word summary of what Rosetta does, but please try to first have a look at the excellent descriptions which are already there (and linked directly from the top of the homepage). If there are things in those descriptions that are hard to understand I am sure specific questions in the forum will be answerd by the Rosetta team or some of the more knowledgeable participants.
Team betterhumans.com - discuss and celebrate the future - hoelder1in.org
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Message 22490 - Posted: 15 Aug 2006, 16:59:34 UTC - in response to Message 22489.  

The green link doesn\'t look like much of a link.
I must admit, i haven\'t read the info on most of those links...
So when we have a new user in the forum, why does someone always try to explain what rosetta is differently, instead of copy/pasting a short answer from one of those pages with the links to them?
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