Wednesday, May 23, 2007

Details in structural biology

(Apologies to my general non-scientist readers in advance for a very specific science mini-post. And this post was written about an hour after a terribly boring NMR talk, so might be biased)

Structural biology is a major, interdisciplinary branch of biology that worries about what biological macromolecules (read: proteins, DNA and RNA) look like (or at a broader scale, what organelles look like).

Anyway, when it comes to proteins and nucleic acids (RNA and DNA), the two major methods used to study them are X-ray crystallography and Nuclear Magnetic Resonance (NMR). Both methods have their advantages and disadvantages, have revolutionized biology (starting from the structure of the DNA double helix, and the structure of hemoglobin), and there are plenty of debates on those.

But for the general biologist, those differences are meaningless. Show them a structure, and molecular insights into protein function, and they're quite happy. The details of the experiments, and all the difficulties of solving the structure are incidental, and not particularly interesting. And I think this is where the X-ray crystallographers have really understood what it's all about.

In general (and there certainly are exceptions), when speaking to a broad audience (like say a biochemistry department somewhere), most X-ray crystallographers skip through the actual experimental nitty-gritty, like the particular problems in obtaining phases, or the details of the Ramachandran plot, and go right to the structure itself, and the implications that follow it. So, at the end of the talk, the audience (which would perhaps have a small percentage of crystallographers, and a majority of diverse biologists) will go back happy, feeling like something has been learnt.

The NMR folks though don't seem to have really received this message. In all their talks, they cannot resist going into details about the NOE spectra, or unique angle restraints, or exchange of somethingortheother. More often than not, at least I don't leave the seminar having appreciated the bigger picture.

Getting your message across to a broader audience is a big aspect of science. Could this be just one reason why there are a lot more X-ray crystallographers out there than NMR spectroscopists? And does anyone else feel this is true?


Anonymous said...

I dont think this is a fair generalization - most NMR talks I have been to do talked about the structural/dynamic features and not the technique.

As for why there are more crystallographers - I think it just has to do with the power of the technique. Especially with the molecular biology/biochemistry becoming easier with kits, and high throughput methods for crystallization conditions, X-ray crystallography is best we have for high resolution structures. NMR is good for small dynamic and/or flexible regions but not so useful for large proteins. IMO thats the main reason for more crystallographers.

Wavefunction said...

I think I largely agree with you, and think that part of the reason why many protein NMR spectroscopists talk about the details is because protein NMR spectroscopy is still not as established a technique as X-ray crystallography (even after Wuthrich won the Nobel). They may want to actually talk about what they did differently, and part of this may be a sense of pride. Many NMR spectroscopists write their own pulse sequences, and they want to actually say this, although I agree that it does not make much sense to an audience of biochemists. Also, especially in case of NOE data, the devil often is in the details. It usually does not matter for rigid molecules like proteins, but for highly flexible portions and especially small molecules like peptides, the NOE data is an average, and some tricky deconvolution methods can be needed to tease it apart into individual conformational contributions (not that everyone realises this). That could be another reason why they stress the data. But in general, I do agree that one can still pitch only the results and the main conclusions to an audience who may not be interested in these details.

Anonymous said...

excellent views

Sunil said...

bongopondit....i did put up that disclaimer that this post was written in after a rather frustrating nmr seminar :-). Anyway, yes, I know there are plenty of advantages of crystallography particularly with larger macromolecules.....but both techniques have their own pluses and minuses. But like Ashutosh says, the devil is in the details, but those details are most important to the scientist executing the project, not necessarily to everyone else. I think NMR spectroscopists are overly fascinated by the details, and cannot tear themselves away from it, and that's just too bad.