ME: And candidates for what?

HOWARD: Candidate structures - i.e. a structure that is likely to be close to correct.

But, again, candidates for what? Or is this some different definition thing within your field where the common definition for a word isn't the same as one used in your specialized industry? To me, "candidate" means it is up/running for something. What I'm wondering is what that "something" is.

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ME: 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?

HOWARD: The Blue Gene team is aware of our software and may indeed have use for it later on when they are closer to completion.

But in what way would they likely use it? Also, isn't Folding@Home closer to what they're doing than what DF is doing?

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

HOWARD: Well this is a loaded question. Exact structure is an oxymoron in this case. Proteins are DYNAMIC molecules, constantly moving and rolling and vibrating around in solution. The best we can hope to do is find an approximate structure. Even then we can't expect a perfect match to the crystal structure. It is impossible to model reality sufficiently, at present, to ever expect an EXACT prediction.

So what is the RMSD score then? Isn't 0A a perfect match? Or are you saying that we will never see a 0A score?

HOWARD: As for X-ray crystallography the limiting step is making crystals which can take for 3 mo. to 1 year or more for just one protein (protein dependent). There are indeed companies working on high-throughput crystallography, but the catch is, they can only do this on a certain fraction of proteins (maybe 5%) which crystallize easily.

Crystallize? How do you crystallize a protein? You mean make it solid as opposed to a more fluid structure? But you just said: "Proteins are DYNAMIC molecules, constantly moving and rolling and vibrating around in solution." So wouldn't crystallizing them give you a false ... or at least a less accurate idea of the protein?

HOWARD: Also many proteins can never be crystallized (or are extremely difficult) and must be solved another way.

Why can they never be?

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

HOWARD: It is a black box as far as you can see. In goes the structure, out comes the score.

Is that to keep the scores honest?

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HOWARD: Proteins are like beads on a string. It is easy to get their sequence - the order of the beads on the string. But it is hard to get their 3-D shape - how that string folds up into a globular structure. Again, 'unknown' implies unknown structure but known sequence.

So spotting a protein is easy, correct? But how do you get their sequence? Why is that also easy? Isn't there a concern that you straighten it out (or whatever you do to get the sequence) wrong thus end up doing a simulation on a false protein? And since there's "billions" of proteins, how would you know you got it wrong if you did? It would seem it would be rather difficult finding another exact one since there's so many to choose from.

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HOWARD: Keep in mind that their [Stanford's Folding@Home's] 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."

ME: 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.

HOWARD: Nope, Im pretty sure their goal is to investigate folding pathways, not structure prediction.

But, again, this doesn't make sense. How do they know they folded it right if their goal isn't to get the structure right? Wouldn't they need the fold to end up with the correct structure and if it didn't, it would mean they didn't take the correct pathways?

HOWARD: Not sure what you mean by willy-nilly folding though.

Willy-nilly is a derogatory term for randomly. More like "foolishly randomly" or "randomly without care".

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ME: "energy minimization techniques"???

HOWARD: minimize the energy of a protein using some technique

Errr? What? Hmmm. Let me take a stake in the dark and see if I get someone's back. Are you saying that the less energy a protein need to expend to completely fold a certain protein sequence is how nature likely (or exactly?) would fold said protein? Also, what do you mean by energy? Where is this energy coming from? Is the protein a living functional organism before or after it folds? Or does something else fold it for it? If something else, what is that?

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SCOOFY12: "the field" is the set of all the possible (or probable) structures that could be assumed by a given sequence.

Which -- as someone (Howard?) has said -- there are more than there are atoms in the universe, correct?

SCOOFY12: remember those "trajactory distributions"? we have a sort of probability map with the relative likelihood for each direction, and i expect the probabilities in our generation are wieghted to correspond to this map.

One, I don't remember "trajactory distributions". And it is "trajectory" and not "trajactory", right? I couldn't find "trajactory" in my common-usage dictionary, but that's not saying doesn't exist within this specialized field. And I think it is better to ask than assume in this situation.

And the "probability map with the relative likelihood for each direction" is based on what? The before-mentioned energy used as talked about earlier? Less energy used being the most likely route taken, right?

And what do you means by "our generation"? Do you mean our generation of protein structures? And thus "weighed to correspond to this map" meaning how much energy ours took and then comparing that against energy used up by other such predictions by other crunchers?

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ME: "and this scoring system works how?"

SCOOFY12: I dunno but this is neato and im gonna look at it more

Please post your findings here in this thread.

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SCOOFY12: "energy minimization"

I think i have the general idea of this. its sort of a potential energy... i dunno how much chemistry you remember, but you may recall that certain atoms, compounts, molecular structures, etc are said to have higher energy than others.

Last time I took a course in chemistry was in high school ... some 22 years ago. During college all my science courses were in astronomy ... which I aced every single one of. And before you ask, same case with biology. Given this poor foundation of fading knowledge...

Where did this potential energy come from? I don't believe it came out of thin air so it had to come from somewhere. And how did these things get energized with it?

SCOOFY12: the pauli exclusion principle.

???

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ME: "simulated annealing???"

SCOOFY12: hm, i dunno... relevant definition of annealing from m-w.com: to heat and then cool (nucleic acid) in order to separate strands and induce combination at lower temperature especially with complementary strands of a different species.... so it seems like this process might unfold the protein and then let it fold up again? dunno, a quick search of F@H didnt find that word anywhere.

Anyone like to take a shot at this? Or is Scoofy12 close?