CASP7 T309

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Profile Leonard Kevin Mcguire Jr.

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Message 18603 - Posted: 14 Jun 2006, 1:04:54 UTC
Last modified: 14 Jun 2006, 1:10:47 UTC

SR415 76 X-ray 1 Jun 7 Jul NESG target SR415, Bacillus subtilis.

I looked this best I can, at.
http://predictioncenter.genomecenter.ucdavis.edu/casp7/targets/cgi/casp7-view.cgi?loc=predictioncenter.org;page=casp7/

It was what my computer started working on. I wanted to make this post to see if I understand what is actually going on better. (I know nothing!)

The CASP7 is a regular deal, to compare and evaluate methods for predicting, computing, or discovering a protiens structor(at least), mabye what it does and other stuff. The CASP7 includes all the current top of the line methods for prodicting protein structor, but it does not include our method(boinc), yet. This CASP7 is to evaluate our method(boinc) in comparision to other methods instead of post-prediction, right - close or somewhat close?

I was mainly asking because I noticed it said, \"X-ray\" as the method and was wondering if I was right why our boinc method was not including, and wondering why multiple methods were not used or submitted to be compared - such as NMR?

(I am completely dumb about any of this!)

SR415 76 (X-ray,NMR,Boinc) 1 Jun 7 Jul NESG target SR415, Bacillus subtilis.

?

---- edit ----
I just read some of the other topics in this forum, and did not realize I was posting to a really advanced discussion group. Sorry! Thought everyone in here was a dummy like me! =) =) =)


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BennyRop

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Message 18606 - Posted: 14 Jun 2006, 2:20:10 UTC

CASP is a competition between prediction techniques. The group that I was providing computer time to for Casp5 and Casp6 isn\'t even taking part in Casp7. Their predictions didn\'t improve at the same rate as the rest of the Casp6 predictors.
Each of the proteins that we\'re working on for CASP7 have been crystalized and their structure has been found and kept a secret until after all the prediction is done.

Each team taking part in CASP7 is given the amino acid chain makeup of the protein - and asked to make a prediction of its native structure. Some teams only make predictions on the smaller structures; but we\'ll be working on all of them this year thanks to all the current participants. (Although Rosetta would love to have several times as many of us here..) Unfortunately, the scientists in the competition don\'t get together and taunt each other anywhere we can see - so we don\'t get to see if scientist taunting inspires creativity. *grin* In 2004, DF finished their last prediction on Oct 4th, and it wasn\'t until mid Dec that the CASP results were released. If I understand the graph of a CASP6 result, Rosetta was represented by a computer only prediction from Robetta; a Distributed computing based prediction, and a 3rd where David Baker and others did something I\'d characterize as looking at the predicted shape, and moving things around to make the curves more artistic and natural looking. i.e. they make changes to the prediction in ways, and for reasons I don\'t understand very well, as it\'s not my field of expertise.

When the Casp7 summit is held, representatives from each of the groups will get to hobnob with all the representatives from the other predictors - and share ideas on prediction. They\'ll get to see what worked best this year, and hopefully try something different if the technique they used this year didn\'t show up in the top 50% of the predictions for the proteins they\'d worked with.

Unfortunately for David Baker and the rest of the Rosetta team - they seem to be the ones everyone should have been aiming to beat from the results from Casp6. Hopefully the improvements that have been created this year will keep them ahead of the pack on all the Casp7 proteins this year. :)
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Message 18608 - Posted: 14 Jun 2006, 3:05:29 UTC

Leonard, firstly welcome to Rosetta! There\'s no wrong place to post. Some of the posts are written by scientific types, and some not. So, you\'ve started something here that will help many of the other participants that have just recently joined.

The website for CASP7 that you saw is showing the list of the proteins they have sent out for analysis by the scientific teams participating in the \"event\". I think of it as a \"contest\". This list is made up of proteins that NOONE actually knows the structure (i.e. the physical shape) of. They know the ordering of the amino acids, but that\'s all. The \"X-ray\" or \"NMR\" is an indication of the technique that is in progress presently. They are presently doing an X-ray analysis of the protein to define it\'s physical structure... but that analysis is not complete yet, or will be kept secret for a few weeks during the contest.

So there are over 200 scientific teams participating in CASP7, trying to predict the structures. The technique called Rosetta has been around long before BOINC. But this is the first time that Rosetta has used distributed computing to crunch the numbers for the event.

...and so the question is \"If we know how to use X-ray and NMR techniques to find the structure, why mess with Rosetta?\". And the answer is that Rosetta hopes to be able to find the structure much faster and cheaper than the current techniques.

Current it can take months for X-ray analysis of a protein to be completed and costs from $10,000 to $100,000. That wouldn\'t be so bad if you only needed to learn about say SARS, HIV, and avian flu virus proteins... but the goal in the end is to learn about all of them, and there are 100s of thousands! It is just not possible to produce results at the pace that will be needed to gain a complete understanding of how all these proteins are effecting our bodies and health.

So, for these few proteins, they will attempt to predict using various techniques from different teams, at the same time as other scientists are using the existing X-ray techniques to solve the structure. This X-ray analysis will then be used to guage which predictions were most accurate, and most useful.
If having a DC project with BOINC is of interest to you, with volunteer or cloud computing resources, but have no time for the BOINC learning curve,
use a hosting service that understands BOINC projects: http://DeepSci.com
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Profile Christoph Jansen
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Message 18619 - Posted: 14 Jun 2006, 6:52:03 UTC
Last modified: 14 Jun 2006, 7:16:53 UTC

Just to show how difficult it is to do an X-ray analysis of a protein:

A colleague of mine was investigating the structure of a protein called \"violet-colored acid phosphatase\". To do so she first had to process hundreds of kilos of sweet potatoes. Then she had to pre-separate the different ingredients by methods I do not really know any more, something like precipitating things with special chemicals. Then the protein containing rest was subjected to gel-electrophoresis and tiny amounts of the protein were isolated. This had to be done with numerous samples until in the end they got 500 mg of the protein.

Next step was crystallization, which again took many samples and a lot of time. Finally they had some single crystals they could use for structure determination, but it turned out the protein tended to disintegrate under X-rays. They finally got time at the DESY where thy could do measurements with synchrotron radiation which worked out (much higher intensity, thus much shorter measuring time).

The step of solving the structure is the next ordeal: carbon, nitrogen and oxygen have almost identical electron densities and will thus show up in the electron density map the x-ray yields as hardly distinguishable \"bulges\". Hydrogen, very important to distinguish those atoms, is hardest to find as it has only one electron and is thus just a speck in a sea of possible bulges and will only be seen, when the electron densities of heavier atoms are assigned correctly. So you just work your work forward, guessing the backbone together, assigning CH, CH2, CH3, NH, NH2, and OH groups where you think the heavier atoms carry hydrogen and slowly go towards your aim of a totally solved structure.

What you also have to account for is water which also shows up the way the backbone- and residue atoms do and often adjacent water molecules emulate structures of the backbone or residues, so you have to separate this from the protein itself (when the assignment of atom species is only a rough one, the atoms seam \"smeared\", so you cannot exactly determine their disctances, which complicates the separation of water and protein a lot).

So it is a long and troublesome thing to do (at least it was ten years ago, maybe things have improved a little with faster PCs and better search algorithms). It mainly depends on your experience, how good you proceed.

The whole thing took three years and three people were working on it in different fields and with different samples (one tried to extract the enzyme from uteri of pregnant pigs). Some attempts were simply fruitless and you need a high frustration threshold to work in that field.

After going through all that labour, trouble and waiting comes the next problem: you have treated the enzyme so brutal and exposed it to so many chemical and physical procedures. Who is now going to guarantee you still have a native enzyme in your crystal? Maybe all those changes in pH and chemical composition of the solution has denaturated your target.

So, to me, the bottom line is: folding is not only much less troublesome, cheaper and faster, it is also much likelier to yield the correct structure. And that is what you finally want.
"I know that you believe you understand what you think I said, but I'm not sure you realize that what you heard is not what I meant." R.M. Nixon
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Profile Leonard Kevin Mcguire Jr.

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Message 18669 - Posted: 14 Jun 2006, 23:43:43 UTC
Last modified: 14 Jun 2006, 23:45:30 UTC

You guys are great, I really do appreciate the time you took to explain in detail the vast aspects of this scientific field!

I am entranced, and enraptured by Christoph Jansen\'s explaination of the x-ray method. I really do enjoy donating my CPU time to this project if it can deflate the cost, and move protein prediction more towards a trivial point in science relative to the treatment of disease among innumerable other biologicaly debilitating problems.

I am also understanding that even if Rosetta is not definite in accuracy it can still exponetialy speed up the many processes such as the X-RAY method(s) to unviel the working of proteins. This project seems to be a gratifying and first-class non-profit non-political effort to place at the least a little volunteer CPU time into.

Thanks so much for replying!

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Message 18675 - Posted: 15 Jun 2006, 0:50:18 UTC

For further reference, the article in Wired is fairly detailed about the X-ray process, and another approach to the problem... which is to make the X-ray crystallography process faster and less expensive. I think if you read the article you will see that no matter how good they get with that approach, when you multiply it by 100,000 or a million proteins that we wish to understand, it is still not going to get us there. However, the technology they are working on should prove helpful if you have one very specific protein (such as Avian flu virus) that you wish to learn about, more or less regardless of cost.

...and yes, now you know why we\'re here too! Help us to inform others so they can see how vital development of this technology is to mankind. You will find that even as a layperson (me too!) you can learn more yourself by following the project links, and continuing to read the boards and post questions. And you can post helpful answers and references to the existing material for others.
If having a DC project with BOINC is of interest to you, with volunteer or cloud computing resources, but have no time for the BOINC learning curve,
use a hosting service that understands BOINC projects: http://DeepSci.com
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