HIV-1 vs Gamers

Of the many things that annoy me about Creationists, one Im going to focus on today is their child-like understanding of biochemistry and what actually goes on inside of a cell.

They put out these pretty animations (well, they put out 'animations' copied from pretty animations) and everything is so cutesy and perfect and multicolored and smooth...

Yeah, stuff dont look like that in real life.

And those 'artistic renditions' are just that. Artistic renditions. We dont stare into our microscopes and see this stuff happening-- its too friggen small. So we go through all of these elaborate contortions to 'see' what is going on at that level. Its really goddamn hard. And sometimes we only have a general idea of what things 'look like' after we do so, in certain circumstances, maybe.

For instance-- the protein I study, HIV-1 envelope-- yeah, I mean, we kinda know what it looks like, sort of. Maybe. Why do we care? Because some anti-HIV antibodies stick to Env and prevent the virus from infecting cells. Antibodies see structures. It would be real nice to know what exactly was going on with individual antibodies-- how they were doing it, so maybe we could figure out what to put into a vaccine so everyone makes those kinds of antibodies.

Another example: HIV-1 integrase (the enzyme that puts the retroviral cDNA into the host cells genomic DNA)-- It would be really nice if we knew what integrase looked like, and we knew how our integrase-inhibiting drugs worked so we could design other drugs (either new ones or second/third generation drugs that worked better). But we dont know what it looks like. We kinda sorta have an idea.

Well, just to reemphasize the connection between biology and computer science-- there is an online game where players and teams work together to help solve protein structures:

Fold It

They just helped figure out (kinda, sorta) the HIV-1 protease structure, and several other proteins:

Crystal structure of a monomeric retroviral protease solved by protein folding game players

Foldit is a multiplayer online game that enlists players worldwide to solve difficult protein-structure prediction problems. Foldit players leverage human three-dimensional problem-solving skills to interact with protein structures using direct manipulation tools and algorithms from the Rosetta structure prediction methodology. Players collaborate with teammates while competing with other players to obtain the highest-scoring (lowest-energy) models. In proof-of-concept tests, Foldit players--most of whom have little or no background in biochemistry--were able to solve protein structure refinement problems in which backbone rearrangement was necessary to correctly bury hydrophobic residues. Here we report Foldit player successes in real-world modeling problems with more complex deviations from native structures, leading to the solution of a long-standing protein crystal structure problem.

From one of the figures for the M-PMV protease:

Starting from a quite inaccurate NMR model (red), Foldit player spvincent generated a model (yellow) considerably more similar to the later determined crystal structure (blue) in the β-strand region. (c) Starting from spvincent's model, Foldit player grabhorn generated a model (magenta) considerably closer to the crystal structure with notable improvement of side-chain conformations in the hydrophobic core. (d) Foldit player mimi made additional improvements (in the loop region at the top left) and generated a model (green) of sufficient accuracy to provide an unambiguous molecular replacement solution which allowed rapid determination of the ultimate crystal structure (blue).

HA! Thats fantastic! And apparently they did it in just 16 days of game play (not 16 days, literally, 16 days worth of game play)! HAHAHA! That is so sweet!

My only complaint is that, once again, scientists determined the structure of a non-HIV retroviral protein, and are plugging it as 'we figured out the structure of an HIV-1 protein!'. What they are doing is using the M-PMV protease as a model for HIV-1 protease. They didnt do this with HIV-1 protease.

But still, HA!

The critical role of Foldit players in the solution of the M-PMV PR structure shows the power of online games to channel human intuition and three-dimensional pattern-matching skills to solve challenging scientific problems. Although much attention has recently been given to the potential of crowdsourcing and game playing, this is the first instance that we are aware of in which online gamers solved a longstanding scientific problem. These results indicate the potential for integrating video games into the real-world scientific process: the ingenuity of game players is a formidable force that, if properly directed, can be used to solve a wide range of scientific problems.


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Abbie, did you reddit foldit?

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Maybe it was Nature's fault. Just . . . maybe.

I'm actually in the same department as the folks working on this, and just got back from our department retreat where the last talk was about this very thing. Was definitely a nifty way to finish things up.

A couple first hand stories (forgive me for not having a chance to read the paper yet, and being slightly buzzed from just getting back from the department retreat):

With regard to Abbie's comments about "scientists... plugging it as 'we figured out the structure of an HIV-1 protein!'. What they are doing is using the M-PMV protease as a model for HIV-1 protease. They didnt do this with HIV-1 protease." This seems like another instance of journalists or scientists to the public one way and scientists talking to themselves another way. The talk I saw was mostly about how they were using all the cool data Foldit was giving them to solve these interesting questions that have stumped the crystollographers - the fact that this could be related to HIV was actually pretty tangential, and in fact when I saw Abbie's post title I was ready to correct things since it was pretty clear this was a retroviral protein but not HIV.

I think one of the interesting things was the question about how many people using the game already are knowledgeable about biochemistry and protein structure (cause who would spend a bunch of their free time trying to fold proteins if they weren't already structural bio geeks right?) But in fact a lot of the players don't have much of a science background, and in fact the speaker pointed out that a lot of the Baker lab people are actually pretty bad at the game.

I'd never heard of Foldit until this story hit the news, but I've spent the last hour playing with it. It's pretty addictive. Rubik's Cube geeks will be all over this.

As a researcher who dabbles in structural biology/molecular modelling myself, I have one major complaint about FoldIt. They've created what appears to be the best engine for this sort of structural "tinkering", bar none - and then restricted it so that it can only be used on protein structures in their proprietary format. I would love to have a program of this caliber in my arsenal of tools to study my particular proteins of interest.

"And apparently they did it in just 16 days of game play (not 16 days, literally, 16 days worth of game play)! "

Good point to highlight. For a typical gamer, "16 days worth of game play" is closer to 17 actual days. So it's not quite as efficient as it first seems.

Does anyone know how the news reporters picked this up and reported on it as "AIDS virus protease", when in fact it was Mason-Pfizer Monkey Virus protease? The crystal structure of HIV-1 protease has been known for years, it is a homodimer. See PDB entry 1ODW for example.

Hi Abbie!

I was just wondering: did you write this before or after I sent you the link to the story? I mean, I wouldn't mind adding "contribution to ERV" on my CV! :p