Originally posted by Brian the Fist
You have all brought up some great points here!
OK, now if someone would care to explain in real simple layman terms what the following "good points" mean, I'd truly appreciate it. First up...

"...the idea of what we are doing is more to really narrow the field, so that other methods can be used to finalize the result. If effective, this would be used more to create "candidates" that can then be more effeciently pursued from other approaches. Kind of a filtering process."

OK, I don't get this at all. Narrow the field? Narrow it to what? Are we striking out into the unknown hoping to come across something useful OR are we taking a cue from someone to look in a certain lagoon for buried treasure? Are we at the start of the whole process or somewhere in the middle? If in the middle, where in the middle? The whole middle? Part of it? If part of it, which part? Early middle? Mid-middle? Late middle? By your statement, we're apparently not at the end of the process.

And candidates for what?

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"If successful, it is possible that Distributed Folding could eventually collaborate with other such projects."

How and in what way? How would it help IBM's Blue Gene? Would IBM even ask for DF's help? And how important would such assistance be to them? Will they come begging for our help or would we have a problem getting them to even return our phone calls?

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"We aren't trying to find the exact structure in microscopic detail (they do that in labs with x-ray crystallography or some other stuff I am not allowed to attempt to pronounce, spell, or understand)."

What!? Why aren't we trying to find the exact structure? I would think that would be exactly the goal of Howard and Dr. Hogue.

And cannot x-ray crystallography be highly automated so ... [Scott tries to do his best Carl Sagan impression] ... billions upon billions upon billions can be done? How long does x-ray crystallography take to do one protein? How expensive is it? Wouldn't it be better to put smart people like Howard and Dr. Hogue to work on making lightning-fast x-ray crystallography technology than this guesstimating software?

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"We are trying to find (and prove) a method for taking an unknown protein and 'predicting' its structure with a certain degree of accuracy."

OK, this doesn't make sense. What do you mean by "unknown protein"? How can you take it if you don't know it? How can you know you predicted it right if you don't know it in the first place?

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"Based upon my limited understanding of the science involved, all of the results (not every single one, but the best of each protein run) in Phase IA were good enough to be of use."

For what?

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"For example, trying to sort/categorize/organize/identify the proteins discovered as a result of the Human Genome Project. You obviously can't do lab work on every single one of them simultaneously, so you either find ways to "sort through" them or you sit around waiting while the limited lab resources are used to find the structures of all of these unknown proteins."

But how do we know which ones are the best ones to devote our efforts to? Or are we simply taking ones willy-nilly and seeing if anything worthwhile comes out of it? If the second one, how would we even know if that simulated protein is worth anything or even what it does?

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"DF also appears to have a good apparatus for implementing very fast tests of both sampling and scoring methods as new methods are discovered/created/shared/etc.

Basically, they have a platform that allows them to test sampling and scoring methods very quickly (a very large number of iterations, a very large "sample set" in a very short amount of time). As the samping and scoring methods become more and more accurate (and robust) the amount of more direct science that they can do with the project should increase. "

Ahhh! Perhaps there's something here. That being "very fast tests". Testing for what? For whom? Why? What value do these tests represent and mean to scientists and the biotech industry?

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"Keep in mind that these pictures are just representations of the actual proteins, in fact just the backbone (they also have side chains sticking out all along the backbone, which are hidden in the picture to make it easier to see). When you view them in spacefilling images with all atoms present, it actually doesn't look too bad (but then its very hard to distinguish which is which without 3-D glasses - hence the simplified representation)."

One, can we see these more detailed pictures?

Two, could you set up some little slide show type thing on the website with a clicker button that would enable us to click back and forth between the real protein and its simulated prediction for us to see the differences ourselves?

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"We are working on the hardest part of the protein folding problem, called 'ab initio' - that is, we have no knowledge of the true structure and are essentially 'guessing' at it based only on our scoring functions."

And this scoring system works how? Also, please remember you're explaining this to a moron.

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"So we expect similar results for novel proteins of comparable size."

I assume "novel" means "unknown". But this just sounds odd as well. I mean how can you fold something you don't know? It doesn't make sense. Do you understand what I'm not getting? Is it that you have a string of protein components you've been told are proteins but they haven't been predicted/folded yet? Is that it? If so, how do you know they know these components make up a protein the first place? Where and how did you get this list of protein parts without knowing its shape? See what I'm getting at? It's like someone comes to me with a dump truck full of vehicle parts and tells me that they'll make a complete working car.

I ask "How do you know they'll make a car?"

The delivery person says "Ummm. Well. Errrr."

"And you expect me to create a car out of these parts? Parts which you've just told me you don't know how they fit together in the first place BUT you're sure they'll all fit together."

"Precisely."

"Right. You stand right there and don't move while I call the funny farm and ask if anyone's missing."

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"As Raj has mentioned in another thread, the current 'king' of ab initio prediction, so to speak, is David Baker in Seattle, WA. I suggest looking at papers from his lab/his web site for details on his methods, if you are interested."

Marketer here. Not scientist. I really doubt I'd be able to understand his papers anymore than I do yours. Thank god for this forum so I can at least ask questions to TRY to understand what's going on.

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"It hasn't been called the most difficult biological problem in history for nothing after all."

Why? Nothing else in biology is this complex of a problem? Nothing? And who has said it was "the most difficult biological problem in history"? And, NO, I will not take Oprah's word for it.

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"As for F@H, as far as I know the only protein we have in common is 1VII. I believe the best structure they obtained was 3.3 A..."

With ours being 2.03.

"...but you will have to ask them if you want to see a structural alignment or the structure itself."

Could someone do this and post it or a link to it here? Even put DF's picture next to it? Due to personal reasons, I really don't want to interact with FAH if at all possible.

"Keep in mind that their goal is NOT structure prediction though, it is to investigate the folding pathway of proteins - i.e. how it gets from unfolded to folded and what all the intermediate steps are."

What?! Isn't their end goal the same as yours? To present the true structure of the protein. If that wasn't their goal as well, their willy-nilly folding of a protein components would be rather stupid and silly.

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"As a final point, our structures are sometimes referred to as 'unrefined'. That is, they are raw predictions straight out of the program. The[y] can be subjected to energy minimization techniques such as molecular dynamics and simulated annealing which could (and should) reduced the energy, and RMSD, further."

Will someone please translate the above? Sorry, I only know English.

"raw predictions"???

"energy minimization techniques"???

"molecular dynamics"???

"simulated annealing"???

"which could (and should) reduced the energy, and RMSD, further"???

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Whether it was a blessing or curse, having been raised by two teachers (father a psychology professor and mother a second-grade teacher), I've long taken the attitude that you're only an idiot if you don't know something and don't try to find out the answers. Or as my father always told me: The only dumb question is the one not asked.

Then again, my father also told me that the more you know, the more you know how little you know. Hmmm. Since I already feel like I know almost nothing, maybe I should stop asking questions now. *insane laugh* Yeah, right! *more insane laughing*