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Designing Proteins In Silico

Posted by michael on from the computer-control dept.

Fluorophore writes "In a recent issue of the scientific journal Nature, scientists in the lab of Homme Hellinga at Duke University reported designing proteins using a cluster of 20 computers. These proteins were then tested in the lab and shown to bind their intended targets including TNT, serotonin and lactate. This is a tremendous step for computational biology, nicely reviewed in C&E News' top story. Designer proteins such as this can be developed for bioremediation of weapons dump sites (TNT) and sensitive sensors of drugs/contaminants that can easily be grown in bacteria."

14 comments

  1. Cool by icemax · · Score: 1
    Using a computer, Duke University chemists have redesigned proteins to perform entirely new, unnatural functions. Then, the scientists have created these customized proteins in the lab and showed that they do their assigned jobs well.
    How soon untill they make a self-replicating protien that accomplishes ~s/bad_trait/good_trait ?
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    __________
    Love conquers all... except CANCER
    1. Re:Cool by frenchs · · Score: 4, Interesting

      One of the mantra of proteomics is that structure equals function. So increasing protien function increases the exactness of what structure must be.

      Creating a self replicating protien would require insertion of a encoding sequence of dna of the host. And the self replication would involve that protien doing something like functioning as a promoter for that sequence, thus requiring a portion of the structure of the protien be able to recognize a specific sequence of DNA.

      Creating a malicous or beneficial protien indicates that it has a specific target (such as a specific receptor on the HIV protien coat). This also requires a specific structure to be able to recognize that.

      The problem with computationally designing a protien that both self replicates and serves a malicious or beneficial purpose is that the computation involved increases exponentially when adding a new function to a protien.

      This is because you may get a structure that works well for one of the two targets, but then you have to check it against the other target, and it may work horribly for that second one. So then you repeat the cycle until you find something that works well for both.

      So while it is technically correct that they could do it, it's going to be a difficult thing to do by computational methods (and probably even harder by conventional methods).

    2. Re:Cool by diaphanous · · Score: 2, Informative

      How soon untill they make a self-replicating protien that accomplishes ~s/bad_trait/good_trait?

      There's no need for self-replicating proteins because we already have something that is much easier to manipulate than proteins and which replicates readily (although not without help from proteins): DNA

      This is the basic idea behind genetic engineering: alter the DNA of a gene so it will code for a protein that will take over the function of a defective protein or do something else useful, insert it into a cell where it will be replicated everytime the cell divides, and you'll end up with many copies of the gene which can be expressed (in parallel) as the protein you are interest in.

      ~Phillip

  2. More Info by Bowling+Moses · · Score: 4, Informative

    The actual Nature article is "Computational design of receptor and sensor proteins with novel functions," in the May 23, 2003 issue (Vol 423 No 6936 pp101-205). It is important to note that they are not making fully functional enzymes yet, but have accomplished the rather daunting task of designing/directing the evolution of a given protein binding substrate A and making it bind a new, completely different substrate B. Their wild-type substrate interacts with 12-18 residues, so multiply that by your 20 standard amino acids across these interacting residues and you have a crapload of sequences to deal with (10^15 to 10^23; I'll take their word for it). I thought the statement "Designer proteins such as this can be developed for bioremediation of weapons dump sites (TNT) and sensitive sensors of drugs/contaminants that can easily be grown in bacteria." was kind of cute as when you search Pubmed with "TNT reductase" you get back a number of articles on bacterial enzymes that allow them to munch TNT. A few years back I got to work on a project to solve the structures of enzymes that pop NO2 groups off of TNT and related compounds; the bacteria that these proteins were subcloned out of were found in the heavily contaminated soil of a former World War 2 munitions plant. Pretty cool what evolution can do when you add a new component to the environment of some organism.

    1. Re:More Info by Inverarity · · Score: 4, Interesting

      Well put. If your analysis of the paper is correct I am surprised that the paper was accepted to Nature. Nature Structure or Nature Biotechnology would have been more appropriate. Now if they had gotten significant levels of enzymatic activity then I would be impressed. However, your math for the interacting amino acid residues while probably correct can be dealt with with various algorithms. Namely the Dead-End Elimination algorithm, which if I recall, will, with accurate rotamer library, elimate all possible combinations of interacting rotamers and thus energetically unfavorable amino-acid combinations. This I believes seeks a desired global energy minimum and a cuts down on the overhead of needless computational paths.

    2. Re:More Info by Fluorophore · · Score: 5, Informative

      Just a tiny factual correction to the above post. For those searching for this article, its in the May 8th issue of Nature. The remainder of the above reference is accurate.

      What makes this success deserve the superlative 'humongous', imho, is twofold. One, as Bowling Moses refers, the size of sequence space is 10^15 to 10^23. However, you combine this with the number of possible rotameric conformations certain sidechains can adopt, and your search space climbs to 10^50 to 10^70 in size. Make things even more formidable by thinking about the rotational and translational degrees of freedom within an active site pocket and you're trying to find the best solution from among 10^110 states!! Only because of novel improvements to Dead End Elimination, which were outlined in an earlier article by Looger and Hellinga in the Journal of Molecular Biology, are such huge problems able to be solved in 3 days. The second major triumph of this paper is the design of polar specificity. While not the first example of designing polar interactions, a strict rule of satisfying all possible hydrogen bonds has greatly improved both Dead End Elimination selection and the specificity of the resulting active site. Up until now, the best designed small molecule binders were shape matching grease with grease.

      When using a higher resolution search scheme (e.g. more states), Looger and colleagues were able to design a TNT binding protein with nanomolar binding, while preserving specificity. It seems possible that Hellinga may be at the top of the pack in designing useful enzymes. If the proteins are designed to target a substrate transition state, it may be possible to design artificial biocatalysts.

      While plenty of TNT degrading enzymes have been developed either by natural evolution or by artificially directed processes, the advantages of an in silico approach are obvious. Hellinga could make one design in 3 days ... and computers will only get faster.

      --
      --- I am NaN, I am a free man!
    3. Re:More Info by Xookliba · · Score: 1

      Quote: "Their wild-type substrate interacts with 12-18 residues, so multiply that by your 20 standard amino acids across these interacting residues and you have a crapload of sequences to deal with (10^15 to 10^23; I'll take their word for it)" That's a good point. The paper notes that this problem is not soluble by the combinatorial method as you described it. It is a combinatoric process to start blindly investigating every possible combination, in this case that's 10^76 possible combinations. To make these proteins would require more material than exists in the universe! In rational design, you attempt to "fit" the ligands by designing complementary van der Waals surfaces and other non-covalent interactions. The actual strategy employed in the paper was somewhere inbetween, by building a search tree and eliminating dead ends. I think this is why the paper received so much attention. There has not been much success in rational design, a field which has failed horribly since it's inception. A fact that is especially galling considering the money that was thrown into it by many organizations. Still, it's a very sophisticated discussion of the paper by this group!

  3. At the same time... by Inverarity · · Score: 2, Interesting

    While this is a big step forward, it is not a humongous breakthrough. The big accomplishment is that the proteins were engineered to bind to socially relevent substate. There has been success in protein engineering for quite a while. Two big researchers are Stephen Mayo at CalTech ( http://www.mayo.caltech.edu ) and William DeGrado at the University of Pennsylvania. The true holy grail of this field is to create a functional protein from the ground up i.e. predict the three dimensinal structure from the amino acid sequence.

    1. Re:At the same time... by jeeves99 · · Score: 0

      Being a DeGrado employee, I applaud your praise of my boss. :-)

      Just wait till we get our new cluster. In between Unreal Tourney lan parties, we might just one-up our caltech friends. :p

  4. Well... by Mensa+Babe · · Score: 2, Informative

    These (somewhat controversial, I might add) news are not, in fact, new (at the very least, they are not new to anyone, who reads scientific press). Still, I'm surprised and, I can't deny it, somewhat disapointed, how little interest in this subject the Slashdot has shown. I was expecting an interesting debate, but I guess we have much more important things to discuss right now. (Street Fighter Anniversary, anyone?) For anyone, who would like to read much more about the subject, I suggest checking out links on The Google News Service. There's a lot of great articles there. It is important to read many stories with different bias on this interesting subject.

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    Karma: Positive (probably because of superiour intellect)
    1. Re:Well... by Anonymous Coward · · Score: 0
      These (somewhat controversial, I might add) news are not, in fact, new (at the very least, they are not new to anyone, who reads scientific press).

      The noun "news" is plural, but singular in construction.

  5. A new weapon in the War on Terror! by Alsee · · Score: 3, Funny

    These proteins were then tested in the lab and shown to bind their intended targets including TNT, serotonin and lactate.

    Exactly what we need to target those pregnant depressed suicide bombers!

    -

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    - - You can't take something off the Internet! That's like trying to take pee out of a swimming pool.
  6. no need to interact with a genome by QuantumG · · Score: 1

    There are proteins that have the function of causing similar proteins to refold into a configuration similar to themselves.

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    How we know is more important than what we know.
  7. Milking proteins from silicones by Muhammar · · Score: 1

    ...Some people have all the fun.

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    I doubt that we will ever figure out - and I suspect that even if we did figure out we couldn't do much about it