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[–]ren5311Neuroscience | Neurology | Alzheimer's Drug Discovery 1197 points1198 points  (209 children)

Unequivocally, yes.

I do drug discovery. One important part is knowing the molecular target, which requires precise knowledge of structural elements of complex proteins.

Some of these are solved by x-ray crystallography, but Folding@Home has solved several knotty problems for proteins that are not amenable to this approach.

Bottom line is that we are actively designing drugs based on the solutions of that program, and that's only the aspect that pertains to my particular research.

[–]TokenRedditGuy[S] 278 points279 points  (153 children)

So what are some drugs that have been developed or are being developed, thanks to F@H? Also, what are those drugs treating?

[–]ren5311Neuroscience | Neurology | Alzheimer's Drug Discovery 514 points515 points  (148 children)

Alzheimer's. Here's the reference. That's from J Med Chem, which is the workhorse journal in my field.

Drug development usually takes at least ten years from idea to clinic, and Folding@Home was only launched 12 years ago.

Edit: If you have questions about Alzheimer's drug discovery, I just did an AMA here.

[–][deleted] 28 points29 points  (21 children)

How accurate are simulations of protein folding? I took a course for fun in biological chemistry and the prof. talked a little bit about CASP/ROSETTA.

[–]Afronerd 25 points26 points  (14 children)

Once you have a solution from folding@home you could probably double check that solution using X-ray crystallography.

Note: this was a guess, thank-you leonardicus and YoohooCthulhu for your insight.

[–]leonardicus 32 points33 points  (6 children)

It's a very good idea to verify your simulated structure with crystallography or NMR, however this is both expensive, time consuming, and for some proteins, very very difficult. Rosetta offers a computational solution that does a pretty good job and is orders of magnitude quicker to generate a possible structure than it would be to derive from the crystallography.

[–]YoohooCthulhuDrug Development | Neurodegenerative Diseases 25 points26 points  (5 children)

It's not going to work for a substantially novel fold, though :P

The point is you never really know how accurate an MD folding solution is absent experimental evidence. The best usage for folding @ home is docking/peptide binding where there's a simple experiment that can be done to validate the model, and for generating search templates for molecular replacement on difficult crystal structures.

[–]leonardicus 8 points9 points  (0 children)

I agree complete, however I was speaking more to ROSETTA than the Folding @ Home, because it can be coupled with other useful tools for homology-based modelling so the structures aren't completely "de novo" per se, because the protein may have some subdomains that have known crystal structures, etc.

[–]stumblejack 1 point2 points  (0 children)

There are some very accurate force field parameters out there today, though. And, this is particularly true for biological systems.

[–]deadpanscience 1 point2 points  (4 children)

They are generally not very good except in cases of small proteins or highly identical proteins. For things like novel G-protein Coupled Receptors they are essentially useless, with RMSDs >2.5 angstrom even for backbone atoms, which are generally the most similar in related structures.

[–]MillardFillmore 2 points3 points  (0 children)

My advisor always says "Crap in, crap out"

In fairness, there still is a lot of work in developing accurate force calculations, better numerical techniques, and most of all, bigger computers. They've came a long ways from the first MD simulations of DNA which, well, exploded all of its atoms.

[–]edibleoffalofafowl 17 points18 points  (9 children)

Do you know if there is a significant difference in quality or focus between folding@home and rosetta@home?

[–]znfingerBiomathematics 39 points40 points  (8 children)

The aims of the two projects are slightly different. Rosetta@home aims at quickly identifying the native structure of proteins using an array of heuristics whereas Folding@home is aiming at understanding the folding process, that is, what steps are taken by an unfolded protein to reach the native ensemble. Each of these general aims has a slew of ancillary aims associated with it. The Baker Lab (Rosetta) has reformulated the problem of fold prediction into an array of related problems such as inverse folding (given a protein backbone structure, which sequence would fold to make that structure) and various forms of protein design that has direct application to vaccine development (see Bill Schief's new lab at Scripps), chemical catalysis, novel antibody prediction/design (Jeff Gray's Lab), RNA structure prediction and a few others.

The best analogy for the difference is, I think, mountain climbing. Rosetta tries to tell an observer where the highest peak is, Folding@Home tries to ascertain things like the best route, the fastest route, how gravity affects which routes are accessible to a climber and how fast the process of climbing takes.

[–]TourettesRobot 9 points10 points  (2 children)

So would it be accurate to say that both projects are necessary and assist one another?

[–]zu7iv 6 points7 points  (0 children)

I absolutely would. You should realize that there are many many many other related projects going on though, all of which help increase the knowledge base of protein folding and related problems.

[–]znfingerBiomathematics 5 points6 points  (0 children)

In a way. Some of Baker's recent work has been centered around bootstrapping our way to more accurately parameterized potential energy functions (...which are then used by groups like Pande and Shaw, etc.) and correcting for crystallographic artifacts such as incomplete context problems (when you crystallize a protein and its native fold is contingent upon a binding partner or even a whole complex that isn't present in the crystal, the structure you get out is not going to be correct).

[–]zu7iv 3 points4 points  (2 children)

That is an awesome analogy! I bet you've practiced that one before...

[–][deleted] 2 points3 points  (1 child)

The analogy of an "energy landscape" is commonly used in the field of protein folding (all puns intended).

[–]TokenRedditGuy[S] 41 points42 points  (65 children)

I still don't really understand what's going on, and it's probably not within my reach to understand it without heavy studying. However, you seem to know what you're talking about based on your AMA, so I'll take your word for it! Thanks for the responses.

[–]jokes_on_you 169 points170 points  (63 children)

Finally there's a question that's my exact field.

Proteins are huge macromolecules made of a linear arrangement of amino acids that is folded in 3D. The one I'm studying is about 70,000Da, so about the mass of 70,000 hydrogen molecules. It's composed of ~609 amino acids, which are fairly complex molecules themselves. Here is an amino acid. Here's a short peptide sequence composed of 4 amino acids. This looks pretty simple, but imagine 600 in a row. There are 20 different "R" groups which makes it more complex. There are two angles that can rotate freely, phi (NH to alpha carbon) and psi (alpha carbon to carbonyl carbon). Diagram of these angles here. So you have a huge linear molecule that folds in hundreds of places and all the atoms can interact with each other.

To get a 3D image, a protein must be crystallized, meaning it has to from a regular lattice structure. This is very hard to do. You need to isolate your protein very well and have rather large quantities of it because you never know which solution will work. First you have to get it started (nucleation) and get additional proteins to join in. I won't get in to how this occurs but it often involves cat whiskers. It's pretty much an art. Then, once you have a crystal structure, you beam it with x-rays, and predict the structure by how the x-rays are diffracted. You often don't get a good "view" of what's on the inside of the protein. Here are 3 representations of a small and simple protein.

Folding@Home predicts the structure without having to do this long and difficult to achieve process. You have to account for favorable and unfavorable interactions and bond angles and are able to achieve a good estimation of the structure.

EDIT: If you're interested, here's a good 17 minute video on x-ray crystallization. I've been working towards crystallization of my protein for 5 months and still have a ways to go.

EDIT2: Reading more about F@H, I learned that it also aims to find insight in to how proteins fold. This is still a mystery to us. An unfolded protein has an astronomical number of possible conformations. Cyrus Levinthal calculated that if a completely unfolded protein is composed of 100 amino acids, there are 10143 possible. If each conformation is "tried out" by a protein for a millisecond, it would take longer than the age of the universe to try them all. I'm sorry but I'm very busy tonight and can't get that deep into protein folding, but we do know that it starts with a nucleation (here it means you first form a very stable part of the protein) and then the the more unstable parts form but it is still largely a mystery. What makes it even tougher is that the most stable conformation is not always the native/active one. Also, Structure and Mechanism in Protein Science by Alan Fersht is a very good book for biochemists and is what I use as a desk reference.

[–]bobtentpegMicrobiology 24 points25 points  (16 children)

Out of curiosity, what protein are you working on?

[–]jokes_on_you 106 points107 points  (15 children)

I don't want to reveal my identity, sorry. But it is a very good potential drug target for a third world disease that kills many.

There's an idea floating around that started at Yale called the Health Impact Fund that I'd like to bring up. It gives drug companies two options when they discover a drug. They can patent it normally so only they can produce it for a certain amount of time (often 10 years, but some lobbying can increase it). They can pretty much charge what they want for it. Or they can patent it with the Health Impact Fund. The drug is produced by another company and sold as cheaply as possible, while the drug company will be paid an amount determined by the total health impact of the drug by the HIF. So there is an incentive to create drugs that benefit third world diseases and those that suffer from them are much more likely to be able to afford it. Here's a TED talk about it. They are trying to get $6 billion funding to get it started.

[–]bizzykehl 5 points6 points  (1 child)

I've been looking for a reason to go back to college and this actually sounds extremely interesting to me. Where should I go and what should I study?

[–][deleted] 2 points3 points  (0 children)

Look at Biochemistry and to a lesser extent biological chemistry and biology, if you're interested in these areas. also check out medicinal chemistry. Just to warn you though, the field is brutally competitive once you get to the point of actually doing research. Most drug companies have been down sizing their R&D departments and most government funding has been relatively flat.

[–]thehollowman84 2 points3 points  (3 children)

So the HIF would basically be saying, create these drugs and you'll be compensated through this fund, instead of via sales?

[–]jokes_on_you 1 point2 points  (2 children)

Yeah. You're compensated based on how much it improves lives of people of the world. So if it is no increase over what patients would normally receive, you get no money. But if you make a drug for something and it prevents many illnesses/deaths then you are compensated a lot.

[–]Augustus_Trollus_III 3 points4 points  (3 children)

I might be having a slow day, but why would big pharma take that deal? By going with the Health Impact Fund, don't they lose money by allowing cheap drugs out onto the market?

[–]jokes_on_you 17 points18 points  (0 children)

Say you made a drug for malaria. No one would be able to afford it if you sold it through the traditional route. But if it's sold at cost, people can afford it and if their lives are improved you get money.

[–]selflessGene 14 points15 points  (0 children)

A fund like that would likely focus on diseases that are primarily found in the developing world.

If a disease doesn't have a high prevalence in wealthy countries, that disease simply will not be a priority area for research/development. This makes sense as the process of developing a drug is VERY expensive, and pharma companies (or any other company) aren't in the business of doing charity work.

Something like the Health Impact Fund tells pharma companies: "hey, we both know that poor people won't be able to cover the cost of development, but these non-profits and donors have come together to give you a $200 Million bounty if you can treat this illness that poor people get and rich people don't". This gives a financial incentive to create drugs that would not have been created otherwise.

[–]raygundan 1 point2 points  (0 children)

People who are alive buy more Viagra than people who are dead.

[–]bobtentpegMicrobiology 1 point2 points  (0 children)

I don't want to reveal my identity, sorry. But it is a very good potential drug target for a third world disease that kills many.

Thats just no fun! Don't worry about it, I understand not wanting to share for privacy reasons.

[–]feureau[🍰] 11 points12 points  (28 children)

Welp, You got me. Installing Folding@Home as we speak.

Anyway, if I got the gist right, it seems folding@home calculates every possible permutations then save the result so you can just check with the reference for each possible input?

[–]FearTheWalrus 3 points4 points  (25 children)

Keep an eye on the temps of the CPU, I had to uninstall F@H because my CPU ran at about 90º C.

[–]tamcap 16 points17 points  (21 children)

This might indicate that the cooling system for your CPU is not well chosen. You might want to look into it.

[–]FearTheWalrus 8 points9 points  (20 children)

It's a laptop so that's not much of an option. High CPU temps seems to be common according to other comments on the thread.

[–]TailSpinBowler 15 points16 points  (0 children)

The folding client has a cpu % slider, which you can draw back, to give the cpu an easier time; and cooler temp.

[–]tamcap 13 points14 points  (8 children)

yeah, if it's a laptop, that's often a problem - they are not really intended for 100% long-term CPU use

[–]Kelvara 5 points6 points  (8 children)

You can ameliorate that by elevating it and placing a fan underneath. Also, it's probably there's dust or hair in the vents as well, which can be cleaned somewhat with pressurized air.

[–]cosine_of_potato 3 points4 points  (2 children)

F@H eventually started to overheat my laptop and caused two emergency shutdowns--until I opened it up and removed a small dust bunny that had accumulated between the fan and heatsink. Now that the dust bunny isn't clogging up the fan, the laptop's current CPU temp (with F@H running) is 58.5 C.

(Your mileage may vary.)

[–][deleted] 3 points4 points  (7 children)

So is this why people want quantum computers? From what I gather they would be able to do it much much quicker

[–]zu7iv 8 points9 points  (3 children)

This is why I want quantum computers. Other people want them for other things, which they probably think are equally important (ex atmospheric simulations to predict long term weather patterns, or simulations of the big bang etc.)

[–][deleted] 7 points8 points  (2 children)

Cracking codes is another big guy.

We want quantum computing because we all want faster computers.

[–]fatcat2040 1 point2 points  (1 child)

Computational fluid dynamics problems also, though I doubt that is nearly as big as code cracking or atmospheric simulations. Still, it is vital for many types of green energy to move forward.

[–]frezik 3 points4 points  (2 children)

Quantum computers only make certain classes of problems faster. I don't know if protein folding is one of them or not, but it shouldn't be assumed that QC will magically make everything faster.

[–]Skithiryx 1 point2 points  (0 children)

It sounds like they are generating permutations and then testing them against some kind of verifier algorithm to check whether or not the permutation is physically possible. If true, this would be exactly the type of problem QC would make easy.

[–]Lentil-Soup 1 point2 points  (0 children)

Protein folding is definitely one of them. It's basically, try every possible combination until something works. Perfect application of QC.

[–]nyaliv 2 points3 points  (3 children)

My field too, I'm just late to the party!

But don't forget about the advances of NMR, which is also a dominant force in structure determination. As magnets get bigger/stronger and pulse-sequences/methods more refined, visualizing larger macromolecules is becoming more and more common.

[–]znfingerBiomathematics 1 point2 points  (2 children)

Are you at Vanderbilt and if so do you know of the Meiler Lab?

[–]jimmy17[🍰] 1 point2 points  (0 children)

I'm not sure if this is getting a little off topic but does the inhibition of the formation of amyloid plaques actually help treat alzheimers? I was under the impression that the plaques were just a symptom of a wider issue of neurodegeneration in the brain and that breaking the plaques down may even have a detrimental effect.

[–]funnynoveltyaccount 2 points3 points  (2 children)

I'm curious to know what a "workhorse journal" is. I'm in academia (but an operations researcher, not a scientist) and I've never heard the term.

[–][deleted] 2 points3 points  (0 children)

He's probably using that term to distinguish it from a flagship journal. For most chemists, the flagship journal would be Journal of the American Chemical Society, but each subfield has its own journal specific to them. For me, that journal would be Inorganic Chemistry.

[–]athreex 6 points7 points  (2 children)

Greetings:

As a side note, there are several @Home projects active. Folding@home, Einstein@Home, SETI@home, just to name a few.

One important discovery in Astronomy was a radio pulsar using the Radio Telescope at Arecibo, Puerto Rico. The pulsar was successfully discovered thanks to Einstein@home.

Source

Second source, straight from the National Astronomy and Ionosphere Center, better known as NAIC

[–]Derkek 3 points4 points  (1 child)

Thanks for sharing these, they seem interesting. :)

funny story aboot SETI@Home. The former IT director in my school district was fired for installing it on the district's pcs. Apparently it cost them a pretty penny in electricity overnight.

Edit: found some info https://www.google.com/?q=brad+niesluchowski

[–]guysmiley00 2 points3 points  (0 children)

Looking at that story, it sounds more like the school superintendent pulled a number out of her ass to justify firing the guy. $1 million in added utility and replacement parts? That's a suspiciously round number. She also claimed that SETI@Home "slowed down" the computers (hard to do with a program that only uses idle time, isn't it?), and showed remarkable ignorance about the program itself.

This reminds me of people claiming that distributed computing programs "stole" their processing cycles. It just don't work like that. You might as well claim that someone walking down an unused highway lane is "stealing" traffic capacity. You can't loop time and put rush-hour cars into lanes that are empty at 3 AM. People seem to have a really hard time with this concept.

[–][deleted] 1 point2 points  (0 children)

I think the more important thing is even if folding @home didn't lead to a single, solitary useful target (and apparently it has), protein folding is seriously valuable stuff. It requires a lot of CPU cycles to computationally solve the iterative energy minimizations that go into folding a protein (you just can't do it analytically), and protein structure is one of the most fundamental pillars of Biochemistry.

[–]whotherewhatnow 24 points25 points  (3 children)

Hi,

I work in cancer drug discovery, and my impression is that the predictive models (docking, etc.) are useful for initial screening efforts, but that the sheer computing power necessary for true predictive solutions (i.e. replacing old-fashioned screening) relegates distributed computing efforts to a supporting role in drug discovery. Computational solutions are useful to eliminate relatively obvious non-useful compounds--at least, that's how we use them--but we still need fairly high-throughput molecular biological screening to find lead compounds. And from our docking collaborations, I am of the opinion that computing cores (using non-distributed computing) provide enough power for virtual screening. It certainly worked well for us, reducing our compound list over 100-fold.

This is from working with kinases, which are perhaps even simpler (read: inhibition more easily predicted) than the proteins you work with. If you're going to shoot me down, feel free to start with this, as I think the differences between the types of inhibition we're attempting might be why you put more stock in Folding@Home.

Basically, I think distributed computing solutions leverage "inefficient" home computer usage to solve problems inefficiently. If I may be so bold: the only thing worse than high-throughput screening is a computer pretending to do high-throughput screening.

I can't read your paper at the moment (not at work); did you identify your lead compound directly from its predicted docking to the predicted protein structure? Or did you have to do/have a grad student do some actual screening first?

Here is a computational and predictive paper that neatly identifies the pharmacophore and suggests potential inhibitors for a kinase, without a mention of any distributed computing that I can find in the methods section. What I'm trying to establish is that you can relatively easily do all the computational parts without distributed computing. At least in drug discovery.

EDIT: Oh god I followed the formatting help too literally (I had an "!" in the link).

EDIT2: Ok, so I thought about it some more, and realized that a very strong criticism of using that paper I posted as evidence would be that the structure is already solved. So, I'll retract it; see strikethrough. My primary point, though, is still important: computational structure solving is only a supporting aspect of drug discovery. I just don't want readers to think that F@H is a lean, mean solving machine that helps us churn out new drugs better than ever before. It occasionally solves a fold, and sometimes that fold will help us find a drug. But randomly attempting folds is no better than us randomly trying compounds to get an effect, and the latter can at least net you a useful lead drug, which I will take over a potential structure.

[–]Augustus_Trollus_III 4 points5 points  (1 child)

We should have a reddit drive to get out the message about this, maybe have a competition site wide to see how many installs we could get.

It's such a simple thing to do, and yields amazing results.

[–]blueshiftlabs 5 points6 points  (0 children)

Or we could all just start plugging /r/folding as often as we can.

[–]zu7iv 1 point2 points  (0 children)

In my view, its a primarily academic server. And it's not too inefficient for academia. I mean think of how much time the only people who actually know whats going on spend doing nothing but applying for money. So while I agree that it is not that great a tool for drug discovery YET, I think that discouraging people from using it based solely on that point is maybe misleading.

[–]zlozlozlozlozlozlo 12 points13 points  (17 children)

Some of these are solved by x-ray crystallography, but Folding@Home has solved several knotty problems for proteins that are not amenable to this approach.

Could you give an example?

[–]earfoCardiovascular Research | X-ray Crystallography | Pharmacology 14 points15 points  (15 children)

So a brief example would be membrane bound proteins. Many of the receptors that your body uses to communicate with various cell types are found associated with a membrane.

When the author says "knotty" problems, thats in reference to what are called protein fold motifs example. Some of these fold motifs are knots and they have a biologically diverse function.

The other intrinsically difficult example would be proteins with a coiled-coil domain.

I hope this helps, if you want to discuss further, just reply and ill get back with you.

[–]AzurphaxPhysical Mechanics and Dynamics|Plastics 5 points6 points  (0 children)

I love how there's an X-Ray crystallography question, and BAM, there is an x-ray crystallography specialist in the house.

Thank you for existing, earfo.

[–]HowToBeCivil 0 points1 point  (0 children)

This is a very important question. I hope it gets a response since it is the essence of OP's question and was sort of answered with a wave of the hand.

[–][deleted] 5 points6 points  (0 children)

There is also the Help Conquer Cancer project on the World Community Grid that is attempting to develop a statistical model on how proteins crystalize and also develop a high-throughput mechanism to sort the images taken of the crystalization trials. They are hoping to cut the time needed to get a quality crystal by a significant margin. It is a good complement to Folding@Home and Rosetta.

[–]PhilxBefore 4 points5 points  (2 children)

I hate to hijack the top comment, but reddit has it's own Folding@Home team. If you'd like to join and make a difference, we're over here in r/Folding.

[–]BugeyeContinuumComputational Condensed Matter 3 points4 points  (4 children)

I heard a talk recently where a research group was studying correlations between charge density distributions on protein molecules and changes in base pair sequences. For example, they'd have ---ATTGC--- on one and ---ATAGC--- on the other, and they were investingating the effects this would have on local charge density.

I didn't get to ask the speaker, but how well is this stuff understood ? It seemed like it would be interesting if you could do the reverse, i.e. infer base pair sequences based on charge densities.

Also, do people have a 'modular' understanding of protein folding in some sense ? I.e. if you knew how chain A folds and how chain B folds, could you predict the behaviour of something that looks similar to A and B joined head to tail ?

[–]znfingerBiomathematics 4 points5 points  (2 children)

I know this was one thing that was a subject of interest to Barry Honig at Columbia, who was also the person responsible for developing methods to calculate electrostatic potentials of biomolecules.

Comically enough, reading DNA on the basis of charge densities is an active area of research and central to a number of third generation sequencing projects, such as the Oxford Nanopore Sequencer.

[–]zu7iv 1 point2 points  (1 child)

That's the most fucking ridiculous thing I've seen all day. I was just about to answer "You could infer the sequence, but there are no good ways to measure the charge distribution over the length of the molecule". Showed me.

[–]zu7iv 2 points3 points  (0 children)

The answer to your modular question would be "usually". If we have good starting structures for the two, we would probably just throw the two joined together into an MD simulation, heat it, and cool it, and repeat, and then gather statistics based on our results, and then get a low energy structure for protein AB. IF they're too big, this won't work. If they're too small, we probably should not start from native folds and instead use a generic folding algorithm.

[–]Toppguy 2 points3 points  (1 child)

Your job sounds fantastically interesting, would you mind sharing what you studied in college (major) like was it a science degree in _____. Im currently considering making the switch from nursing to pharmacy because human metabolism captivates me... but how, how can I get into something like:

I do drug discovery

[–]tryx 3 points4 points  (0 children)

Not OP, but I imagine a PhD in pharmacology or medical chemistry is a good starting point

[–]redditaccountforme 1 point2 points  (2 children)

I do work with solid state NMR, but from the more physics side and not really with proteins... would ssNMr work where x-ray crystallography failed?

[–]deadpanscience 2 points3 points  (1 child)

Solid state NMR people have been saying it could be used to solving large protein structures and membrane proteins. They haven't been successful. The vast majority of protein structures are done by x-ray crystallography and then a small minority by NMR. You can see all of these statistics at the pdb.

[–]MJ81Biophysical Chemistry | Magnetic Resonance Engineering 5 points6 points  (0 children)

I think it should be noted that it wasn't until 10 years that the biological solid state NMR community were able to do a de novo short peptide structure determination as seen here. There had been some earlier preliminary results of interest (partial assignments for hydrated BPTI is the one that comes to bind, along with a laundry list of functional, typically site-specific, studies of various proteins ), but since, the field has been maturing rather nicely in terms of preparing to do entire membrane proteins.

After all, the first protein structure was published in 1958 - the first integral membrane protein structure wasn't published until 1985. I don't see that it's going to be any easier for ssNMR - while crystals aren't required, doing all of those assignments is going to be burdensome. As I recall, when Wuthrich was starting in on his structural efforts on soluble proteins as early as the late 1970s, that was just when the basics for much of what's done for biological solid state NMR was being established (for those interested - Schaefer & Stejskal's first Cross Polarization/Magic Angle Spinning experiments were right around then, as the Waugh group had introduced cross polarization in the early 1970s). Clearly, of course, the static/oriented samples group in the bio-ssNMR community don't really require the sample spinning.

Of course, the cool thing is that people are already looking ahead - doing solid state NMR of integral membrane proteins in intact cells, as was recently published here. There is of course earlier work in this vein, but this was something recent that just made its way across my desk for a timely example.

[–][deleted] 1 point2 points  (0 children)

I understand this is not a recent post but it's probably the clearest and most concise reasoning for users to run folding@home I have ever read. I hope you don't mind but I quoted this when posting to my facebook timeline to promote F@H.

Thankyou for being a sussinct voice in a sea of scientific complexity.

[–]ihaque 212 points213 points  (26 children)

Qualifications: I'm a alumnus of the Pande Lab at Stanford, the group behind Folding@home. It might make me biased; take that as you will. (I'm not in the lab anymore, though, so I can't answer questions about your current work units, and nothing I say should be taken as official :).)

TL;DR: Yes!

The answer is, as ren5311 said, definitely yes. One misunderstanding I see a lot in this thread is the idea that FAH is all about predicting the final "native" structure of a protein. While that's occasionally true, that's not the main focus. FAH projects are mostly directed at learning about the dynamics of proteins and other biological macromolecules. Put more simply: it's about the journey, not the destination. Other projects, like Rosetta@Home and the FoldIt game (both from the Baker lab at the University of Washington, who are also awesome people) focus more on the latter question of final structure. I can't quite ELI5 this, but maybe I can ELI16 it, or so.

Why are dynamics important (or, why should I care about the journey)?

Lots of reasons. To keep it concrete, let's take Alzheimer's and Huntington's diseases, two of the main driving goals of the project. In both diseases, a major clinical finding is the accumulation of protein aggregates or "plaques" in the brain -- basically, a bunch of protein fragments stick to each other and form protein masses. The underlying proteins are different (beta-amyloid and tau in Alzheimers, huntingtin [sic] in Huntington's), but both are plaque-formers. A critical thing to understand is that these plaques are (it is believed) fairly unstructured: it doesn't really matter what the particular configuration of the final result is; what matters is figuring out how the plaque got started in the first place. Many, many work units on Folding@home have been (and probably still are) dedicated to answering these questions. By simulating the early stages of aggregation, we can work out the molecular mechanisms by which this happens. This then allows us to try to make modifications to the system that can prevent aggregation. Eventually, after enough simulations, you make your compound, and actually try it for real in a test tube, and then (when you're really lucky), you publish a paper showing that it works.

Alzheimer's

That's exactly what happened in the paper cited by ren5311. An earlier student (Nick Kelley, among others) in the lab did a huge amount of work with molecular dynamics simulating structural modifications to the amyloid peptide (peptide = protein fragment). This work was then experimentally followed up by another student (Paul Novick, with others), who demonstrated that a small molecule with a similar structure to part of Dr. Kelley's peptide could also inhibit aggregation.

(Here is a good place to point out something that can be immensely frustrating to the layperson: science is slow. The initial simulations were run probably five or six years ago, maybe more; the experimental work took years; and only now the paper is coming out. There are a number of reasons for that (example: Paul had to do to LA to run some lab tests, because construction at Stanford put a lot of metal dust in the air, which makes a-beta aggregate really fast, and only skipping town made the assay work). I know it's really annoying as a contributor wondering exactly where your CPU time is going. Believe me, it's worse as a grad student wondering where your life is going... :))

Flu

Dynamics are important to other processes as well. Peter Kasson did a number of projects (which will probably be familiar to some contributors as "bigadv" projects) looking at how lipid vesicles fuse with one another. Why? Because that's a major process in viral infection: enveloped viruses fuse their membranes with those of the target cell to gain entry. Example: this paper. Fusion inhibitors are a relatively new class of antiviral agent, and the hope is that understanding the dynamics of the fusion process can help design new ones.

Fundamentals of macromolecular dynamics

On a more abstract level, no one actually understands how proteins "fold", or reach their final structures from a linear chain of amino acids coming off the ribosome. Work done by my former labmate Greg Bowman has shown that several models of protein folding are actually wrong -- it's not the case that proteins proceed linearly along from one state to the next in a direct chain of events from unfolded to folded; rather, they often get trapped in so-called "metastable" conformations (of which there can be many), leading to a state diagram with a large number of hubs between the unfolded and native state. Greg was awarded the Thomas Kuhn Paradigm Shift Award by the American Chemical Society in 2010 for this work, which really changed the understanding of how proteins fold. None of this would have been possible without the massive CPU time donations from users of Folding@home!

We've made a lot of big advances in methods too, but I'll split that into another post since this is getting pretty long.

[–]TokenRedditGuy[S] 18 points19 points  (8 children)

So it seems like our computers go through all the different possible ways a protein can fold. How do you or our computers know which way is correct? Also, exactly what information is inside a completed working unit?

[–]KnowLimits 12 points13 points  (1 child)

My understanding is that they're computing the energy of a given configuration. (Basically, parts of the molecule that are being held closer or further apart than they "want" to be contribute to the energy.) This is useful, because in general, the correct configuration is the one with the lowest internal energy.

[–]ihaque 1 point2 points  (0 children)

This is almost correct. The thermodynamic hypothesis is that the native state of a protein will be that one with the lowest free energy (not the internal energy; entropy matters as well). However, we're not usually trying to just find a native state; in fact, we run many simulations that start at the native state and try to "melt" the protein backwards to find near-native states. We're usually more interested in the dynamics of the system than the end result.

[–]ihaque 1 point2 points  (1 child)

Well, the number of possible configurations of a protein is astronomically large (think 1040 or so), so no - we don't sample every possible configuration. What we do try to do is sample all the (kinetically accessible) pathways through protein states - a large number of individual protein shapes might all correspond to the same state.

"How do you know you're right" is a great question! The best way to check is to compare your results to experiment. This has traditionally been a problem from both the experimental and the simulation sides, but is now being overcome. The experimentalists are devising faster-and-faster experiments to reach shorter timescales, and we're building better simulation methods to meet them in the middle. A good example is this paper by the Pande lab, which shows comparison between simulation and experiment for a particular observable called triplet-triplet energy transfer.

A completed work unit has a number of "snapshots" of the configuration of the protein (and sometimes solvent) during the time it was simulated on your machine, which lets us rebuild what the trajectory looked like.

[–]Exnihilation 3 points4 points  (3 children)

I'm not familiar with how AMBER (the program used to make the calculations in F@H) works, but I do know that most computational chemistry programs calculate the total energy of the specific orientation of the molecule. The goal is to minimize this energy. The lower the energy the more stable that configuration is.

The program will shift the atoms in the molecule little by little, recalculating the total energy at each step. The calculation knows to stop when it compares the energy of the current step with the previous step. If it differs by less than a parameter set by the user (usually a really small number) then the calculation has found the "optimum" configuration.

There are several methods used to calculate these energies and each of them has their advantages and disadvantages. Computational chemistry is really an art form, knowing when to use certain methods and what criteria you want to examine.

Edit: After some investigation, it turns out F@H doesn't use AMBER. They use Tinker, Gromacs, and QMD to do their calculations.

[–]znfingerBiomathematics 1 point2 points  (1 child)

Has the Pande group done any work on functionally disordered or conditionally ordered proteins? I was on a binge reading about them for a while, but never really followed it up.

[–]BeatLeJuce 1 point2 points  (3 children)

Great answer. OUt of curiosity: why is F@H not open-sourced?

[–]ihaque 1 point2 points  (2 children)

Most of the software we use is, actually. The majority of our simulations are run using GROMACS or OpenMM, both of which are open-source software. We've also put out a lot of open-source in our other research projects:

  • MSMBuilder (builds Markov state models of protein dynamics)
  • PAPER and SIML GPU-accelerated chemical similarity code (this stuff was a large part of my thesis!)
  • MemtestG80 and MemtestCL Video memory testing code for GPUs

[–]florinandrei 1 point2 points  (0 children)

What Pande should do is explain it in a more simple language for those who are not initiates. You go to their site to the Project Results page and, if you don't understand what's all about, your eyes glaze over. Well, at least mine do, this not being my field and whatnot.

They should put 3 or 4 simple items on a page: "know this disease? well, this medicine (or this treatment) was created based on the CPU cycles you folks donated to us". Show a picture of the drug, or something.

It's not dumbing it down. But poor innocent folks like me, who try to understand what exactly is it that we donate to, we read the existing page, and there's this PhD-level wall-of-text, beat-you-on-the-head-with-science thing that is incomprehensible for outsiders unless they spend a lot of time to parse that stuff. Sure it's easy for those who work in the field, but advocacy for such a project is not directed towards those people, but towards the general public.

You said you've been there. Well, could you email them, tell them that plain-clothes dudes like me are a bit puzzled as to what exactly the outcome is?

Currently, I have two CPU cores crunching F@H round the clock, and another core a few hours a day; once in a while I do one round of simulation on the PS3 or on the GPU. Been doing this for a few years. I'd like to see the project grow even more.

[–]NBegovich 16 points17 points  (2 children)

Can any science types comment on any of the BOINC projects like Rosetta@home?

[–]expert02 6 points7 points  (1 child)

Btw, so everyone knows, there is a way to run BOINC and have it run any project that has joined them.

I wish they had two things: a quick client (which installs as a service in a few steps and subscribes to the All BOINC project) and a screensaver which will do the same thing (but crunches when the screensaver is active and shows you what it's doing).

[–]Broan13 6 points7 points  (0 children)

Why not tell them about your ideas for it? They might like them.

[–]Peopie 29 points30 points  (26 children)

I'm still kinda confused as to what exactly we are calculating when we are folding, or what we are sending

how would they interpret what we send?

[–]jackskelingtonz 95 points96 points  (24 children)

Don't overcomplicate it in your mind. Proteins are basically 3D puzzle pieces. That is an almost perfect analogy by the way. The atoms that make up any structure never actually touch one another, and this is just as true for proteins as it is for a 5000 piece jigsaw, so you can think of them literally as miniature puzzle pieces. 'Lock and Key' is another great analogy. You have receptor proteins embedded in the membranes of your cells, most of the cells in your body have hundreds of them. These are like molecular 'locks' that change shape when their 'key' fits perfectly onto them, at which point this 'lock' or 'switch' is activated and causes some type of action to occur in the cell. Many drugs are molecules of a very specific shape that work by fitting into and unlocking these receptors and allowing them to perform their function (pain relief, hormone release, appetite stimulation, etc. etc.). All proteins are formed as a chain of amino acids that are then 'folded' or 'bent' into a 3-dimensional shape that will fit into a receptor, and by looking at the DNA contained in any cell we can determine the exact sequence of the chain that composes a specific protein. What we cannot determine is how the protein will be 'folded' into 3 dimensions, as you can basically fold up a long chain into an incredible number of 3D forms. Imagine every possible 3D structure you can make out of this chain with only a few links in it. So your playstation is calculating thousands and thousands of possible shapes that a particular chain of amino acids sent to it by the researchers can take, sending them back to the researchers, and allowing them to cross check the keys against different receptor 'locks'.

TL;DR Your PS3 makes hundreds of thousands of cellular 'keys' that the researchers can then test on known cellular receptor 'locks' or 'switches' which cause some type of action within the cell.

ANALOGIES ARE THE BEST WAY TO LEARN YEA!

[–]ItsDijital 47 points48 points  (17 children)

So we are essentially brute forcing the "passwords" for receptor proteins?

Isn't there a more efficient way to go about this? With most passwords, brute force attacks are considered a huge waste of time. I wonder if there are any cryptographers out there who have taken a jab decoding protein folds.

[–]Comedian 13 points14 points  (2 children)

Isn't there a more efficient way to go about this? With most passwords, brute force attacks are considered a huge waste of time.

The fold.it project uses a combination of computer calculations and human brain power, to attempt to speed things up versus the brute force method.

I wonder if there are any cryptographers out there who have taken a jab decoding protein folds,

DNA isn't really "encoded" in the same sense as in cryptography. The rules for decoding a DNA sequence (a gene) to a protein is basically simple -- they are just the laws of physics. It's the raw amount of calculations needed which complicates matters immensely.

[–]Kimano 9 points10 points  (0 children)

That's reasonably analogous to one-way hashes in cryptography. It's just a huge amount of prime factors.

[–]jackskelingtonz 29 points30 points  (0 children)

That is an excellent way to put it, and the answer to the efficiency question is actually the entire point of the project! The answer is yes and no. I suspect the researchers are also using something called 'motifs' or 'domains' which is simply a way to refer to a structure within a protein that is repeated often, and whose corresponding portion of the lock is also repeated often (think of jigsaws and how you see the same shapes sometimes over and over, but never in the exact same combination! this is basically the same principle). DNA is handed down from common ancestors, so many of the motifs and domains are repeated or are extremely similar to one another because they haven't had to change much over the course of evolution. I suspect that the researchers take advantage of this fact to make the process a littttle bit more efficient, but essentially you are still brute forcing away because there are tons of 3D configurations you can make even with conserved portions of the structure!

[–]Sui64 9 points10 points  (2 children)

By my understanding, it's not quite brute-forcing it, seeing as they're not trying to fit any particular molecular lock. The program does not check the folded protein against a theoretical receptor: it attempts to find the most stable shape(s) for the protein.

The amino acids he mentioned, the ones that make up the protein chain, are of different sizes and charges, so they'll attract and repel each other, meaning that there will be one (probably with some exceptions) protein conformation that requires the lowest amount of energy to be applied to it before it maintains its shape. On the way to that shape, researchers will obtain plenty of data on how the protein behaves in other conformations. Most proteins spend time in at least two conformations — something that represents an active state and that represents an inactive state. Think of one as a slinky in a thousand dimensions.

[–]jackskelingtonz 7 points8 points  (1 child)

This is an excellent way of thinking of this problem, and really illustrates how there are several different ways to go about using the DNA amino acid chain code that is easily derivable from any cell in the body. I really like analogies as a learning tool for those who are not quite as immersed in the subject as students or experts (if you couldn't tell!) and to carry mine further: The slinky analogy is awesome and I am quite impressed and wish I could have come up with it! Essentially this is my logic in reverse. Rather than finding the perfect key to fit a lock, you find the 'most probable' or 'most easily folded' configuration for a key, and then find the perfect lock to fit it instead, thus learning about a new type of lock and the actions in the cell that it initiates! I feel like a non-expert can easily understand the approach explained in this way, which is why I prefer it :)

[–]MillardFillmore 4 points5 points  (1 child)

I wouldn't say they're brute forcing it in the sense of running columns of A-Z, a-z, and 0-9 for the password, because there are certain regions of optimization that one can take. For instance, you don't have to calculate the force between two atoms on the complete opposite side of the molecule because their interaction should be close to zero.

Then you can get into things like having an implicit solvent, which is like replacing the fluid around the molecule being represented by some function instead of simulated water molecules. By the end of the day, you'll end up in my lab, which runs "spherical cow" physics simulations on long DNA-protein systems. You can get rid of the water and most of the atoms and still end up with decent predictions.

[–]jackskelingtonz 2 points3 points  (0 children)

These kind of technicalities are very interesting and cool to me, but end up being just that: technicalities. It is a discussion for the best way to create the puzzle pieces, but I was more aiming for an easily understandable model of the situation. Reddit scientists sometimes forget that the best way to understand an unfamiliar problem is to create the most simplified model possible to explain how it works; the rest of the details are for fleshing out once you've become an expert and want to actually do something terribly useful with your knowledge :)

[–]znfingerBiomathematics 7 points8 points  (2 children)

This is exactly what Rosetta is. Whereas the Pande Lab simulates all the atom by atom forces in a biomolecule as well as as with solvent, Rosetta seeks to take short cuts, such as approximating solvent effects, simplifying proteins (this is done by treating protein side chains as simple spheres that have roughly the same physical characteristics as that amino acid) and using statistical measurements to assess how good a pose is rather than calculating intramolecular forces.

That aside, Folding@Home isn't "brute force". It simply aims to solve the problem the same way nature does it, which is in a very parallel way. Brute force would require much more time than the lifespan of the universe for most proteins (see Levinthal's Paradox ).

[–]ItsDijital 2 points3 points  (1 child)

Is there any talk between Rosetta and Pande Lab? Like Rosetta lays out a group of candidates and then Pande Lab puts those candidates through Folding@Home to narrow them down even more?

Are the two even working towards the same thing?

[–]znfingerBiomathematics 1 point2 points  (0 children)

I don't know if things have changed since I was last following this field really closely, but as I understand, they have no involvement with each other and there's no joint pipeline that uses both technologies.

[–]keepthepace 3 points4 points  (1 child)

Isn't there a more efficient way to go about this? With most passwords, brute force attacks are considered a huge waste of time. I wonder if there are any cryptographers out there who have taken a jab decoding protein folds.

As far as I know (I'm on the algorithmic side, not biological side) this is still an open problem. However, cryptographers won't be of much help, what is more needed is people with mathematical skills to describe and solve analytically 3D problems.

[–][deleted] 2 points3 points  (0 children)

x-ray crystallography has gotten very good at determining the "passwords" directly for some types of protein (especially soluble proteins which can be crystallized). Other types like membrane bound proteins are much more difficult and require attempts like folding at home.

There is also research into taking crystallography further or in modifying other techniques to determine the structure directly rather than computationally, but FAH still fills an important niche.

[–]zu7iv 2 points3 points  (0 children)

Pretty much everybody who works on this stuff is either a mathematician, a physical chemist, or a computer science student by training. They usually work in a "biophysics" lab.

SO its not just a brute force search. A less oversimplified version would be to say that it uses some approximation to the known laws of physics to find how a bunch of balls which like each other different amounts will settle best over a long period of time, if they're always moving by some amount (corresponding to the temperature). There are many, many tricks to find (probably) the best 3D structure without exhausting all permutations.

There are ways to guess the best structure based only on the sequence and not doing any actual physics, but they're pretty bad. They basically just take all the known 3D structures, and predict a likelihood that one building block will end up next to another one. You can get reasonable structures, but the chances that its right aren't nearly high enough for anybody to use them seriously unless there are no other options.

[–]MindoverMattR 1 point2 points  (0 children)

Those are excellent questions. From a worst-case scenario perspective, we could assume that every bond between atoms is able to move freely (but not change distance), which basically restricts every bond to a two dimensional surface (theta and phi, per bond). That means that, if you allow overlaps, you could have a 2n dimensional spectrum of different protein folded states (n is the number of bonds in the molecule, so probably in the 1000-10000 range). That's an incredibly hard thing to calculate the energy of each state perfectly for all (or even a representative sample of) states, even for a small number of bonds.

Therefore, one common (and oft-used) mathematical trick is to pick a random point on our 2n space, which would correspond to a certain folded state of the protein. Then, calculate the energy of that state. Chances are, you fucked up. it is probably super high energy because you picked a state where lots of atoms are super close to one another. BUT, you can calculate the energy with relatively few calculations (1 iteration so far, versus [a reasonable smattering between 0 and 180 degrees, lets say 10] ^ 1000 iterations (this would be for 500 bonds, due to 2 degrees of freedom).

So, once we have our energy, we just wiggle a bit. Wiggle? Wiggle. change a few of the angles, in whatever pattern you feel like, really, and recalculate. If we're at a lower energy (more stable), start the process over from that new answer. If not? we'll get there in a second. For now, let's say we reject that answer and try a different wiggle.

So, now we have a process to take us from a high energy protein (bad) to a low energy protein (more likely to be the folded state in nature). We run our simulation a few thousand times, and we hit a minimum energy. This should be our folded state, right? Not quite. The problem with this method is that certain folding states are like intermediates: stable in a short term sense, but there is a more stable long term fold that is even lower energy. However, to get there, you'd have to fold to less favorable transition states first. How would we do that?

We would accept the occasional 'bad' fold in our algorithm. So now, our algorithm looks like: start at a certain fold. change a little bit, see if energy lowers. If yes, repeat. If no, then MAYBE keep the higher energy conformation (usually the chance that you keep it is based on how much less favorable it was. small upticks in energy are more acceptable than big honking YOU-SHOULDN'T-HAVE-DONE-THAT upticks). with that, you run your code a few thousand times, with/without different starting points, and see where your walk in 21000 space takes you. Hopefully, it's mostly the same place, which you then speculate is your answer.

Hope anyone read that. I'm drunk.

[–][deleted] 2 points3 points  (1 child)

Does the PS3 also compute whether the shape fits into the lock?

[–]jackskelingtonz 3 points4 points  (0 children)

I wish I knew, I just read the FAQ from ap0theosis and they don't go into deep enough detail. It would not be difficult for them to do this, however, and I suspect that they do.

[–]Madsy9 2 points3 points  (0 children)

If I may add an interesting side note, 'errors' with the protein folding cause diseases like Creutzfeldt–Jakob disease in humans, and mad-cow disease in cows. In which case the haywire protein is called a prion. It seems so alien that the shape of something contribute to its properties. So while the concept is easy to understand vaguely at face value, it is still complicated since chemistry at that level works very differently compared to the macro world we live in.

[–]rafikki 1 point2 points  (0 children)

Since you mentioned the 3D puzzle aspect, you might find this interesting: http://fold.it/portal/ Someone made a game out of protein folding.

[–]hospitalvespers 74 points75 points  (32 children)

To piggyback on this thread, what about SETI@home? Obviously we have not found intelligent life or anything, but has the data being crunched yielded anything interesting?

[–]bobtheterminator 51 points52 points  (7 children)

Depends how you define interesting. Every so often they identify interesting bits of the sky that seem to be emitting interesting frequencies, like this one. Nothing really shocking yet, but keep in mind it's only been going for 11 or 12 years, and there's a lot of sky out there.

[–]econleech 8 points9 points  (5 children)

At the rate we are going, how long will it take to do a full scan?

[–]bobtheterminator 20 points21 points  (1 child)

I'm moving dangerously close to the realm of speculation here, but it's not just a one-and-done scan. If there is an alien signal out there, it could come from anywhere, at anytime. SETI@home will continue as long as there is interest and funding, or until we establish contact with an alien race. This doesn't exactly answer your question though, so hopefully someone who knows how they collect their data can talk about that.

[–]capn_awesome 12 points13 points  (21 children)

SETI@home scans the same data again and again hoping to find radio waves (seriously, they dont' always have new data, so they go through old data again).

Think of all of the interesting things we shoot into space - radio waves are neat, but what about other emissions? If there were an advanced civilization shooting "hello universe" out into space, did they do it with radio waves, or did they do it with something else. Lasers, perhaps?

I'm a fan of thinking about life elsewhere in the universe. And I guess I think there should be people listening and watching for it in the various ways we can (though I stress various - not the same way over and over) - I just don't get my hopes up about SETI. Sorry SETI. Wouldn't it be cooler to help diseases related to the one Michael J Fox has?

In all seriousness - if Folding at Home did a special project for Parkinsons, I'd spin up a lot of of computers for it. If you're watching this thread Folding at Home, consider the publicity you'd get for it.

[–]Broan13 12 points13 points  (9 children)

Radio waves are less obscured than almost any other wavelength. Optical and IR pose HUGE problems, and its more easy to send data in radio waves.

[–]life036 -1 points0 points  (6 children)

Lets not be so shit-sure of ourselves, though. There could be anther medium that we haven't discovered yet that is way faster and clearer than radio waves. The aliens we're trying to contact may think radio is useless and are broadcasting their SETI on this other medium entirely.

[–]Skellyton 5 points6 points  (1 child)

Well, if its way faster than radio waves we are going to have some very, very serious relativity problems. Amongst other things...

[–]Broan13 1 point2 points  (0 children)

We can only act on what we currently know. Considering radio telescopes will probably be build by any civilization, it seems likely to send radio transmissions.

[–]tnoy 1 point2 points  (1 child)

Exactly this. You have to remember that we've only been using radio technology for the past 130 years or so, and in another 130 years, we could be using a completely different form of technology that doesn't emit nearly as much RF as we do now. Its not like we're going to be broadcasting an ultra-powerful signal over RF saying "HERE WE ARE!"

Even an alien planet was in that 'detectable' range for 1000 years, the reality is 1000 years is a completely insignificant timeframe when you compare it to the age of the universe. Having a planet in a close enough range to detect their signal, have them be in their technological timeframe so that their signals would be reaching earth at the same time we'd be looking, is pretty slim. We would also see the signal hundreds, if not thousands, of years after they sent it.

Given that we've gone from no radio to a complex network of communications satellites in 130 years, its anyone's guess as to what would be discovered 10,000 years from now.

Our understanding of modern physics is relatively new, too. To think that we really understand the laws of the universe is incredibly ego-centric.

[–]TheCookieMonster 5 points6 points  (4 children)

If there were an advanced civilization shooting "hello universe" out into space, did they do it with radio waves, or did they do it with something else. Lasers, perhaps?

If they intended it to be recieved by an unknown civilization, they would send it near a frequency that a civilization interested in the stars would most likely be looking at. Hence radio - it's not because humans historically used radios to communicate, it's because the Hydrogen line means people interested in the sky will have radio telescopes (if they are able).

(That was my understanding of some of the thinking behind SETI)

[–]capn_awesome 2 points3 points  (2 children)

I'm not sure I agree. I think that by the time you're ready to listen to "the space phone" you probably have a complete and total paradigm shift of what "the space phone" is.

[–]TheCookieMonster 2 points3 points  (1 child)

I may have explained it poorly - a reason to send a signal via radio is that you don't need the target civilization to be "listening" for alien signals, you just need them to be interested in astronomy.

EDIT: Was hoping to head off two common misconceptions: that we listen to radio because it's how humans historically communicated and we're stuck in that mindset, or that we are listening for communication leakage and thus assuming aliens also use radios to communicate - the power needed to send a signal between star systems is so enormous that we will only recieve something that was intended to be recieved.

[–]pirateninjamonkey 1 point2 points  (5 children)

I always wondered what would would hear first. Like we produced telegraph radio waves first right? Wasn't the telegraph the first thing we did over radio waves? If so, if we hear anything, it would probably be a series of dots and dashes assuming that the aliens develop technology in the same way we did.

[–]bobtheterminator 2 points3 points  (4 children)

That's a pretty giant assumption. The reason they're scanning radio waves is in the hope that another advanced civilization is sending out a "Hi guys" signal that we can pick up on, and we think radio would be the most logical choice for that kind of signal. It's almost guaranteed that if we did find a signal, we wouldn't what it meant or how to decode it, but we'd know it wasn't natural.

[–]hahano111 20 points21 points  (6 children)

The worst part of the folding@home project is that they use several pieces of open source software, they redistribute them, yet they don't give away their code as required. Instead, they asked for a special license, going against the whole notion of academic fairness. They have their special tool and they don't want to share, despite building on the backs of others.

http://folding.stanford.edu/English/FAQ-OpenSource

[–]haladura 7 points8 points  (3 children)

I'm a participant in this project, and other distributed computing efforts. My concern with folding@home is that the information derived is going to support the production of drugs that may then be sold at a profit by large pharmaceutical companies. Is this a concern for others?

[–][deleted] 5 points6 points  (0 children)

Are they also doing research on Multiple Sclerosis? If not, are the results from Folding@Home at least indirectly useful for research on MS?

[–]drenesh 3 points4 points  (0 children)

If nothing else, this thread reminded me to install it on my most recent PC build. I haven't had it installed in years.

[–]rush22 3 points4 points  (0 children)

There's also a game called FoldIt you can play. It, too, has solved some mysteries and accomplished things.

For example Fold It players came up with the way an AIDS-related enzyme was folded which scientists had been working on for 10 years. The proteins are downloadable content for the game--it took players only 3 weeks to "beat the high score" and come up with a more optimal fold than the scientists had.

[–]ComradeSmithers 5 points6 points  (0 children)

Check out the end of this TED talk, it talks about not only protein folding, but also why technology like this will change the world.

[–]dtfgator 2 points3 points  (2 children)

I've gotten about 300k pts so far on my 2 GTX 480's and QX9650, but haven't folded recently due to stability issues. Planning to come back during the next OCN foldathon.

Hopefully my work as well as others is paying off!

[–]Sidicas 2 points3 points  (1 child)

Buy EVGA cards in the -AR series and they have lifetime warranties.. Also, Team EVGA rewards everybody who folds for them.. $10 in EVGA bucks for every 350k points. You can use these earned EVGA bucks to buy yourself a faster graphics card for gaming as well as folding@home.

http://www.evga.com/folding/

[–]GenericEvilDude 2 points3 points  (1 child)

Does f@h account for pH and temperature when it does these calculations? i know that proteins can have different shapes depending oh different environmental variable, what can mean the difference between something useful or unusable junk

[–]Sidicas 2 points3 points  (0 children)

Yes. It uses Gromacs at the core. http://www.gromacs.org/

[–]BugeyeContinuumComputational Condensed Matter 4 points5 points  (0 children)

In the same vein, there's also the clean energy project. They have a paper out based on some findings here (4.7MB PDF).

[–]mrstinton 7 points8 points  (12 children)

There is an argument that the power cost of folding@home (some $12.5 million annually) outweighs the benefit we derive from it.

[–]ldpreload 29 points30 points  (5 children)

So,

1) That article seems to underestimate the qualitative benefit. The author, who admits he's not a biologist, is incredulous that 11 years have produced so few results. Elsewhere in these comments, someone who says they're familiar with the field points out that ten years from research to market is actually quite normal, so one would extrapolate that in 11 years we shouldn't actually expect to see results. I'm all for evidence-based approaches to knowledge, but only if the evidence is being interpreted in an informed way.

2) That article seems to underestimate the quantitative benefit. $12.5 million a year seems a fairly low number to go into a medium-sized research lab. (You can't pay a huge number of researchers alone with that annual revenue, even if you don't count for the cost of the things they're researching and the equipment they research with.)

3) The argument would equally well apply to that just about any public scientific project is better spent throwing the money directly at saving lives. This is an incredibly shortsighted view; the only reason that we are able to save lives at that cost today is because of billions of dollars of scientific research spent in years and decades past. For the cost of paying Watson and Crick to sit in their ivory tower, we can buy untold numbers of maggots for bloodletting. Our medical techniques today, especially those we can apply in places far from state-of-the-art hospitals, will seem as crude as bloodletting to those one hundred or two hundred years from now.

If there's an argument that Folding@Home is in fact less productive than other scientific projects that cost millions of dollars annually amortized over lots of citizens (i.e., any taxpayer-funded research), then I'd like to hear it; until then he's faced with the difficult position of arguing that all taxpayer-funded research costs more than the benefit we derive from it.

[–][deleted] 4 points5 points  (0 children)

For the cost of paying Watson and Crick

And Rosalind Franklin, for the sake of completeness.

[–]znfingerBiomathematics 1 point2 points  (0 children)

Important to note is that these projects that are undertaken are often aimed at understanding disease process, misfolding in Alzheimer's for example. The second part is figuring out what to do with a good understanding of a disease and how to leverage that understanding into a viable treatment. Even though F@H has increased our understanding of how misfolding contributes to AD, that's no assurance that we can figure out how to treat it as a result and even if there is, there will be a lag time between understanding and developing a treatment IN ADDITION TO the ~10 year journey to FDA approval.

TL;DR - Diagnosis of a problem doesn't insure a solution, but it certainly helps.

[–]PostPostModernism 23 points24 points  (2 children)

I can certainly see where they're coming from for that, but if people are donating their power voluntarily, and it's being spread among lots of people, it shouldn't bother anyone.

[–]Baron_von_Retard 3 points4 points  (0 children)

Even if it was true, any success with the desired result would be worth much more than the sum of that money.

[–]KaosKing 3 points4 points  (0 children)

on the other hand, you could consider it we're donating money to a good cause.

[–]rz2000 2 points3 points  (1 child)

I really wish that this, or something related, were the top comment on any issue relating to distributed computing projects. Good intentions don't make deeds efficient, or even a net "good. Some of the worst tragedies of the last century, whether Stalin's collectivization or Mao's Great Leap Forward, were based on flawed methods meant to achieve positive goals.

Anyway, I kind of wish people were more disciplined about applying rationality to good deed doing to make sure that they are not causing more harm. If people wanted to serve this cause then they could probably pay for unused cycles on servers, that are more efficient than their home computers, and therefore produce more computations per unit of energy. However, because the power waste is easily ignored, or often not even realized, it goes on.

Here's a LessWrong discussion thread on distributed computing with references to a few other discussions on the subject.

It is easy to dismiss this type of issue as subjective and not possible to address with critical thinking. However, that is confusing the issue. Whether or not we want to advance the public good is a subjective issue, how much different methods advance a hypothetical goal is an objective issue whether or not the effectiveness can be reliably predicted or measured.

[–][deleted] 3 points4 points  (0 children)

i get where you are coming from but this is black and white science. we are learning more about the world around us. the only other option is closing our eyes.

stalin and mao aren't really fair comparisons.

[–]panzerkampfwagen 1 point2 points  (0 children)

At the very least projects such as this one increase the public's interest in science. That's a positive.

[–]Predditor_drone 1 point2 points  (0 children)

Now I know I'm doing good by allowing my PS3 to run folding @home constantly instead of wishing it. I just wish my internet was faster so it could do more. Thank you for this post.

[–]LordBling 1 point2 points  (0 children)

Thanks for reminding me about this program! I used to run it a lot when I first got my PS3, but I sent it off for repairs about a year ago and when I got it back, I never really thought about it again. Now I've updated Life with Playstation, joined the Reddit team, and it's running right now.