Hi,
Just a question I have. Will the work my computer has been doing for the last two weeks and will contiue to do possibly lead to some break through? I guess what I'm meaning to say is this important work or just some sort of fad. Please don't mis-understand, every since I've entered this program I've left my computer on 24/7 so it could do more work. I'm just curious about what results we could hope to have from our participation.

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Chuck,

What we're doing now is very useful and does lead to major breakthroughs. Up until now, we have been running Rosetta against proteins whose structures were already known. Someone else had already figured them out, and we were doing this because we were basically calibrating and improving the Rosetta search technique.

The units we're doing until mid August (or so) are for a Bi-annual competition called CASP, and we're trying to predict structures that have not yet been published. That means that we don't know what they're supposed to look like, but various (traditional) labs are nearly done determining the structures.

We have to return our computed structures before they get published to see how good Rosetta's (or Protein Predictor's, or any of the other groups we're competing against) system really is.

The purpose of Rosetta is to one day be able to feed in the sequence and quickly and accurately get the structure back. This is a test of that system. This is how Rosetta can show how good its prediction system is.

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I'm just curious about what results we could hope to have from our participation.

In my opinion... what you should hope for is that at some point in your lifetime, new drugs will be developed in record time to address everything from flu virus, to anthrax. And they will use the science developed here to devise the treatments used. When some new virus, like bird flu, comes up, a cure can be created in a laboratory, and you'll already have some knowledge of any sideeffects it is likely to have, and how effective you will expect it to be at attacking the virus. And rather than a 10-20 year timeframe of trial and error, they will sit down on a computer and CREATE one or more treatments or vaccines for the virus.

If you want to look at it this way, present technology is taking a shotgun approach. They try 1000s of compounds, test if they have an effect on the virus, and work their way down the list and try more. What we're helping to do with R@H is to use this shotgun approach to see which approaches to solving the protein riddle are most effective, and this knowledge will be used to help improve the methods over time, and eventually allow you to go straight to a cure from that point on.

There are literally BILLIONS of proteins that effect our bodies. Studying each of them with the X-ray techniques that exist today will be an endless task.

There's no telling when the golden idea will come that brings the models directly inline with the native form of most proteins. They refine it over time, and are making progress on proteins of a number of different characteristics.

Part of the reason the CASP only runs every 2 years is because that's how long it takes to make visible progress in the field.

Welcome to Rosetta! Crunch long and CASPer.

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Thank you both for replying. You both were way over this layman's head, but I got the general idea. I don't mind pushing my CPU to the max if it is for a good cause. I've seen the one that wants me to do the same thing to monitor signals from outer space to help find intelligent life, and passed. I'd rather do something that will help my children and grandchildren. Thanks for responding.
Chuck

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Chuck,

Someone else had already figured them out, and we were doing this because we were basically calibrating and improving the Rosetta search technique..

I realize this when first time I joined R@H and saw 1FNF in my R@H dir. this is
my fav protein for many reason. Rosetta already performed well in previous casp competition and wish to continue the tradition. But just for curiosity what is the success rate at sequence different identity level during calibration.

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Thank you both for replying. You both were way over this layman's head, but I got the general idea. I don't mind pushing my CPU to the max if it is for a good cause. I've seen the one that wants me to do the same thing to monitor signals from outer space to help find intelligent life, and passed. I'd rather do something that will help my children and grandchildren. Thanks for responding.
Chuck

Chuck,

Perhaps this will help. There are 22 amino acids from which all proteins are built in nature, but they can go together in limitless combinations and virtually unlimited numbers, which can result in almost limitless shapes. Proteins do almost everything for a living organism that makes it alive. Most diseases are in some way or another related to malfunctions of proteins, or proteins running out of control. Even inherited illnesses are protein related because DNA is made of proteins in a particular sequence or order and DNA is where the genes are. Genetic disorders are the result of one or more proteins in the genes failing to perform properly. Even snake venom and viruses are proteins that are harmful to the organisms that have no resistance to them. The resistance them is also a function of protein activity.

Usually illness is caused when either the proteins break or their shape becomes distorted so badly that they can no longer perform properly. In some cases the protein can actually malfunction in such a way that it begins to produce substances that are harmful, or stops producing something that is essential (like too much or too little insulin in diabetics). The shape of a protein often has everything to do with what it does in a living organism like a human.

If science can find a way to determine the shape of properly functioning proteins that is half the battle against a wide range of illness. If we can figure out how and why they change shape, and fail to work properly, that would be a major step as well. But if we can figure out how to fix them, or create new ones that we can use to target broken ones and fix them, we can cure the illness. We could even make a protein that could make a cut in the DNA in a diseased gene, in such a way that the body would replace the bad gene with a new good one and cure illness that way.

So here is where Rosetta comes in.

Rosetta is a computing research project that is targeting the protein problem. Rosetta is looking at three main issues.

First to discover a way using computer modeling to determine the natural shape of proteins.
Second, use the same techniques to find the shape of damaged proteins.
Third, To use that information to design protein based cures.

So what we have here is a basic research project that has broad and deep impact across the entire field of medicine, with the promise of delivering into the hands of medical professionals the tools to cure almost any disease.

So your original thought is correct. We could keep looking for Extra terrestrial (ET) life and hope whoever we find out there can and will provide us with cures. Or we can find a way to solve the riddle of protein based illness ourselves. I for one choose to put my money (and computing time) behind the Rosetta scientists.

One last thing. Right now it takes many years to find the shape of a protein in a laboratory (usually 5-10 years), and it costs millions of dollars for each one. If we succeed with Rosetta, we could cut that time down to a matter of months, weeks or even days, and the cost would be in the thousands not the millions of dollars. Understanding proteins really is about solving the riddle of life and how it works.

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Moderator9
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Chuck,

Someone else had already figured them out, and we were doing this because we were basically calibrating and improving the Rosetta search technique..

I realize this when first time I joined R@H and saw 1FNF in my R@H dir. this is
my fav protein for many reason. Rosetta already performed well in previous casp competition and wish to continue the tradition. But just for curiosity what is the success rate at sequence different identity level during calibration.

See this page for a partial answer to your question. It takes a while to load but it is worth a look.

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Moderator9
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If we can figure out how and why they change shape, and fail to work properly, that would be a major step as well.

And the folding problems are what Folding at Home is studying.

An older version of the Rosetta client is currently being used to help find a cure for disease (Cancer?) at WCG; and with the improvements we're helping create in the Rosetta client, we're helping make the client more precise. The faster the client works, and the more precise it is, the fewer machines that need to running WCG to find new treatments/cures for the various cancers. So we're having a direct effect on finding treatements/cures already. When we've helped improve the client so that it's even more precise and faster - then we'll start seeing more DC projects for the less popular diseases. (HIV/AIDS and Cancer seem to be the most popular diseases for DC study at the moment.)

After a few DC projects that were seeking cures/treatments for various diseases, I was given the following impression of how the current treatment system works:
1. They select compounds to test against various diseases - and note which ones have disease imparing abilities. They can randomly go through the known set of compounds and test them until they find a few that have some negative effect on the disease. Whether that's 10,000 or 100,000 or more compounds - they'll spend a huge amount of time and money searching.

Here's where DC projects can help - they can test a known disease's molecular shape against the 5 million (please verify this number) known molecules that are commercially available and against the 50 or 500 million (also verify) known molecules to create a list of compounds that are likely to have anti-disease properties.

Then they can move on and do a more detailed test of which of these compounds have the best anti-disease properties.

So a DC project can save the medical community years of searching for anti-disease properties in the known compounds - and quickly move them on to the efficiency studies. And by testing ALL the known compounds, we can insure that the best compounds weren't missed by random testing.

Then it gets moved into years of animal studies, and if that passes, then years of trials on humans.. and if things have went well, then it gets FDA approval after a few more years, and it can be prescribed to those with the illness.

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One last thing. Right now it takes many years to find the shape of a protein in a laboratory (usually 5-10 years), and it costs millions of dollars for each one. If we succeed with Rosetta, we could cut that time down to a matter of months, weeks or even days, and the cost would be in the thousands not the millions of dollars. Understanding proteins really is about solving the riddle of life and how it works.

Does experimental protein structure determination actually take 5-10 years and millions of dollars PER PROTEIN ?

I thought it takes weeks, up to over a month. And the cost can be up to ~$100k/each (info from non-authoritative sources).

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And the folding problems are what Folding at Home is studying.

F@H is studying "misfolding" (aggregation-related) diseases, such as Alzheimer's.

An older version of the Rosetta client is currently being used to help find a cure for disease (Cancer?) at WCG;

Human Proteome Folding @WCG, is applying Rosetta "in production", to actually try to resolve unknown (still unsolved experimentally) proteins of the human proteome. Learn more at HPF @ wikipedia encyclopedia

The faster the client works, and the more precise it is, the fewer machines that need to running WCG to find new treatments/cures for the various cancers.

WCG is supposed to start a "cancer project" soon, not to be confused with HPF2.

Personally I'm unhappy with how IBM runs WCG, mainly wrt using ultra-high initial-replication and quorum, which I consider a big waste of donated CPU time (plus some more issues, like not compressing files for BOINC clients).

Apparently, others DC projects are even more wasteful, according to some discussions I've seen posted at UD's site.

When we've helped improve the client so that it's even more precise and faster - then we'll start seeing more DC projects for the less popular diseases. (HIV/AIDS and Cancer seem to be the most popular diseases for DC study at the moment.)

I'm looking forward for Rosetta@home to do some [b]production[/quote] projects, as they have hinted in the past, probably once CASP7 is done.

That's why I recently asked about differences between R and other "docking" apps (AutoDOCK, THINK, LigandFit etc). I'd like to see new R being used for "virtual screening".

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Does experimental protein structure determination actually take 5-10 years and millions of dollars PER PROTEIN ?

I thought it takes weeks, up to over a month. And the cost can be up to ~$100k/each (info from non-authoritative sources).

There's an article about the topic that's more in line with weeks and $K 100s. I think mod9 may have overstated it a bit.

But it also points out that these guys are trying new methods to "mass produce" results in record time. And points out that getting the protein to crystilize is not a given. Sometimes takes months.

I beleive the bottom line is there are billions of proteins, and it is "very expensive" and "very time consuming" using present methods. And the the hope is that Rosetta will be able to produce consistent results at a tiny fraction of the cost and in a consistent and predictable timeframe that is far better than today's physical approaches to finding the 3D form of the protein.

---

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/

One last thing. Right now it takes many years to find the shape of a protein in a laboratory (usually 5-10 years), and it costs millions of dollars for each one. If we succeed with Rosetta, we could cut that time down to a matter of months, weeks or even days, and the cost would be in the thousands not the millions of dollars. Understanding proteins really is about solving the riddle of life and how it works.

Does experimental protein structure determination actually take 5-10 years and millions of dollars PER PROTEIN ?

I thought it takes weeks, up to over a month. And the cost can be up to ~$100k/each (info from non-authoritative sources).

Well the protein must first be crystalized. This process takes a significant period of time. Depending on the protein, a lot of time. Then you have to put it in a Scanning electron microscope. You then move the protein in very small increments, usually less than 2% and take pictures at each angle. You do this for the entire surface (thousands of pictures are involved). You then take the pictures and meld them into a three dimensional image.

I know a very nice young lady who operates a SEM who assures me that this process can take a very long time. Now you might be correct for a small protein (weeks, and $100,000). But even if this was true of all proteins, there are so many that it would take hundreds (or thousands) of years and billions (or trillions) of dollars to do them all.

Imagine shrinking that down to a few weeks run time on a $10,000 computer setup. Now that is a real "WOW" moment.

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Moderator9
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I beleive the bottom line is there are billions of proteins, and it is "very expensive" and "very time consuming" using present methods.

Again, this "billions of proteins" statement is questionable, from what I've read.

Apparently there are about ~400.000 human proteins (naturally occuring). Obviously there can be many more combinations of the aminoacids, allowing for many more "artificially" designed proteins, which apparently is one of the aims of Rosetta.

And, AFAIK, other organisms have a large number of proteins also, many of which evolved from common ancestors, are similar in shape (and function). Which is the type of info the SIMAP BOINC project is trying to organise.

PS: Personally, I hesitate offering answers in Science forum, and stick to offering help on things I know, like computers.

---

Best UFO Resources
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How-To: Join Distributed Computing projects that benefit humanity

I beleive the bottom line is there are billions of proteins, and it is "very expensive" and "very time consuming" using present methods.

Again, this "billions of proteins" statement is questionable, from what I've read.

Apparently there are about ~400.000 human proteins (naturally occuring). Obviously there can be many more combinations of the aminoacids, allowing for many more "artificially" designed proteins, which apparently is one of the aims of Rosetta.

And, AFAIK, other organisms have a large number of proteins also, many of which evolved from common ancestors, are similar in shape (and function). Which is the type of info the SIMAP BOINC project is trying to organise.

PS: Personally, I hesitate offering answers in Science forum, and stick to offering help on things I know, like computers.

Human proteins are not the only ones that must be examined. The cures to many illnesses do not come from human sources.

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Moderator9
ROSETTA@home FAQ
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Does experimental protein structure determination actually take 5-10 years and millions of dollars PER PROTEIN ?

I thought it takes weeks, up to over a month. And the cost can be up to ~$100k/each (info from non-authoritative sources).

There's an article about the topic that's more in line with weeks and $K 100s. I think mod9 may have overstated it a bit.

But it also points out that these guys are trying new methods to "mass produce" results in record time. And points out that getting the protein to crystilize is not a given. Sometimes takes months.

I beleive the bottom line is there are billions of proteins, and it is "very expensive" and "very time consuming" using present methods. And the the hope is that Rosetta will be able to produce consistent results at a tiny fraction of the cost and in a consistent and predictable timeframe that is far better than today's physical approaches to finding the 3D form of the protein.

agreed.

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