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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

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September 25, 2008

Protein Folding: Complexity to Make More Complexity?

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Posted by Derek

Want a hard problem? Something to really keep you challenged? Try protein folding. That'll eat up all those spare computational cycles you have lounging around and come back to ask for more. And it'll do the same for your brain cells, too, for that matter.

The reason is that a protein of any reasonable size has a staggering number of shapes it can adopt. If you hold a ball-and-stick model of one, you realize pretty quickly that there are an awful lot of rotatable bonds in there (not least because they flop around while you're trying to hold the model in your hands). My daughter was playing around with a toy once that was made of snap-together parts that looked like elbow macaroni pieces, and I told her that this was just like a lot of molecules inside her body. We folded and twisted the thing around very quickly to a wide variety of shapes, even though it only had ten links or so, and I then pointed out to her that real proteins all had different things sticking off at right angles in the middle of each piece, making the whole situation even crazier.

There's a new (open access) paper in PNAS that illustrates some of the difficulties. The authors have been studying man-made proteins that have substantially similar sequences of amino acids, but still have different folding and overall shape. In this latest work, they've made it up to two proteins (56 amino acids each) that have 95% sequence identity, but still have very different folds. It's just a few key residues that make the difference and kick the overall protein into a different energetic and structural landscape. The other regions of the proteins can be mutated pretty substantially without affecting their overall folding, on the other hand. (In the picture, the red residues are the key ones and the blue areas are the identical/can-be-mutated domains).
PNAS%20proteins.jpg
This ties in with an overall theme of biology - it's nonlinear as can be. The systems in it are huge and hugely complicated, but the importance of the various parts varies enormously. There are small key chokepoints in many physiological systems that can't be messed with, just as there are some amino acids that can't be touched in a given protein. (Dramatic examples include the many single-amino-acid based genetic disorders).

But perhaps the way to look at it is that the complexity is actually an attempt to overcome this nonlinearity. Otherwise the system would be too brittle to work. All those overlapping, compensating, inter-regulating feedback loops that you find in biochemistry are, I think, a largely successful attempt to run a robust organism out of what are fundamentally not very robust components. Evolution is a tinkerer, most definitely, and there sure is an awful lot of tinkering that's been needed.

Comments (8) + TrackBacks (0) | Category: General Scientific News | In Silico


COMMENTS

1. c on September 25, 2008 10:30 AM writes...

Steric effects and hydrophobicity limit conformational space to a small number of attractors. This article is indeed an impressive reiteration of this fact.

Hopefully scientists interested in protein folding and nonlinear systems will begin migrating across to cellular processing of misfolded proteins. (Nature 454, 1088, for example)

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2. eugene on September 25, 2008 11:25 AM writes...

It's also really impressive (from a chemist's, not a biochemist's point of view) that there is an entire complex giant protein, Chaperonin, dedicated to folding others in the right way.

Permalink to Comment

3. Retread on September 25, 2008 5:28 PM writes...

I'm far from convinced that all (or even most) proteins have a dominant shape. Certainly, to be biologically useful, a protein must limit the shapes it can adopt, and evolution (or something) has provided them. For some details on this see the 7 May '08 Chemiotics post on "The Skeptical Chymist" -- "Why should a (biological) protein have one shape"

Whether most proteins (biological and nonbiological) do have a shape is something we'll never know -- for why see the 15 April post "How many proteins can we make" and the 2 June post "A chemical Gedanken Experiment"


Feel free to comment over there if you wish (or here of course)

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4. john.spevacek@aspenresearch.com on September 26, 2008 7:54 AM writes...

Something I've never understood (maybe it's just me) is why the model the folding for the whole protein at once. It is not biosynthesized at once, so why not model the folding of it from one end to the other?

Permalink to Comment

5. c on September 26, 2008 8:57 AM writes...

John, you're right, folding is likely to occur in a stepwise manner for many multidomain proteins ie. most proteins. However in the context of small 'model' proteins folding transitions suggest a tight coupling of local and long-range interactions. This is common to many complex systems which undergo phase transitions.

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6. Shane on September 28, 2008 8:39 PM writes...

The idea of a single enzyme shape being that useful is definitely fading away. It is the slow scale dynamics of an enzyme that is the key to its catalytic behaviour, and we are only just starting to understand that process. Just as we barely had a handle on structure and folding we have to add an even greater level of complexity to the problem.

Permalink to Comment

7. retread on September 29, 2008 1:05 PM writes...

Shane

Interesting ! Could you elaborate a bit on what you just said (with some pointers to the literature if possible)? Also, would you quantitate what you mean by 'slow scale' -- nanoSeconds microSeconds, milliSeconds etc. etc.

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8. MJ on September 30, 2008 6:18 PM writes...

retread -

I believe what Shane is referring to is the motions of various loops, lids, and other structural motifs of the protein that may regulate ligand binding, product dissocation, substrate rearrangements and other phenomenon. These typically occur at the micro- to millisecond time scale (sometimes a bit slower, sometimes a bit faster). Now, some have suggested that faster dynamics at the "hinges" of such loops/lids/other motifs also play a role (see a paper from the Kern and Karplus groups last year - Nature; 6 Dec. 2007; Vol. 450, pgs. 913-916), but that's perhaps something for discussion later.

I remember a case study from when I started grad school (about six years ago) on the role of a flexible loop in the enzyme triosephosphate isomerase (TIM) in governing catalytic activity. I'll have to dig through the files again, though, but I seem to remember some sort of microsecond to millisecond timescale involved for the opening and closing of this one particular loop.

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