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Jetpacks, enzymes and jetpacks!
You spend years waiting for someone to invent a jetpack and then this comes along!
http://news.bbc.co.uk/1/hi/world/7402016.stm
In other news, this is an awesome paper in the current issue of Nature. An enzyme to catalyse a non-biological reaction designed computationally, synthesised and then fine tuned by directed evolution. I'm not actually sure if this is the first example, but it's the first I've heard of. These guys must have some big brains, and some serious computers.
Reactions in synthetic organic chemistry such as the one in this paper (removal of a proton from a carbon atom and its effective transfer to another part of the molecule) are generally pretty tricky - in my hands at least! This is reflected by the fact that a lot of reaction schemes are named after the guy who worked it out, presumably in recognition of their creativity; the one in the paper is called the Kemp elimination. Considering how to accelerate a reaction (or make it possible at all) involves thinking about the transition state(s) - a transient state (TS) somewhere between products and reactants. This will often have a different shape or charge distribution. Enzymes contain active sites which fit, bind and stabilise the TS, which favours progress of the reaction.
Unfortunately, nature is only really interested in making things like amino acids, nucleotides and lipids rather than oil, plastic, cars, money etc., so it hasn't designed (via evolution) any enzymes to do these things. It should be possible to design enzymes to do a wider range of reactions by considering the shape of the TS for the relevant reaction and the properties of an active site that would fit it, but this requires big computers to do the search, as well as a good understanding of the possible shapes proteins can take.
I guess we're getting there, which to me is astonishing. These guys designed their active site taking into account shape, charge, and even positioning a side chain to change the pKa of one of the other bases in the active site. Once they worked out protein backbone sequences (in 3D) that would support this site, they synthesised corresponding genes, whacked them into bacteria and got functional enzymes out. Then they randomly mutagenise their initial genes and look for increased activity to get an even better enzyme, with activity similar to conventional organic catalysis. Ideally enzymes should outperform organic catalysts and I'd hope to see that in future, but it's early days - very exciting. It even involves computers ;) But not jetpacks.
Paper: Röthlisberger et al (2008) Kemp elimination catalysis by computational enzyme design. Nature 453:190-5
http://www.nature.com/nature/journal/v453/n7192/full/nature06879.html
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Great paper!
There are previous examples of designer enzymes made through rational design / directed evolution experiments from the last 15--20 years. Mostly these tend to use some well studied architectures (e.g. the maltose binding protein) which are customised either with computational tools or directed evolution in positions in and around the wanted TS binding site forming part (often both).
This work relies on the Rosetta protein fold prediction algorithm from the Baker group, which was also used in a similar paper to this that was published a few months ago in Nature (an enzyme which handles a non-natural enzymatic reaction after customising it using RosettaMatch). Unfortunately I can't find the issue from anywhere -- I used to love reading that paper in the toilet :) Anyways, Rosetta is the best performing method in the yearly CASP protein fold prediction assessment experiment, and has been for the last two times. It actually predicts some reasonably sized protein structures with no close homology to known folds, which is remarkable!
It's very promising that our understanding of protein folding is reaching the level where it's good enough for not only prediting folds but actually for the purposes of designing new enzymes! Of course the other side that's showing some promise too is computational design of small molecules which bind (to e.g. inhibit activities or interactions of) enzymes. There are some very nice examples of this using for example huge computational and experimentally validated docking experiments -- I shall try to remember to blog about this!
PS. I can do this paper and the earlier similar enzyme design Nature paper in the next Underground Journal Club!