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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: Twitter: Dereklowe

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« Genetic Optimism | Main | Nobel Time! »

October 9, 2002

The Bigger They Are

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Posted by Derek

The Chemistry Nobel this year doesn't include any household names, even by the standards of my branch of the science. But (as I said this morning,) I think the award is a good one. The ability to deal with large molecules like proteins as molecules is a relatively recent development. Before these sorts of methods were worked out, you stepped into another world when you worked with such things. The precision of "real" organic chemistry (such as it is!) disappeared.

A newly discovered protein might weigh, oh, 60,000 or so give or take a few hundred units (or a few thousand.) That's pretty fuzzy, when you compare it to the world of small molecules, which can be measured out to four decimal places. (Doing that, you have to correct for picky things like the 1% abundance of isotopic carbon-13 atoms rather than the usual carbon-12 - not the sort of thing that kept the protein chemists up at night, that's for sure.) And the 3-D structure of your new beast? Good luck! Maybe it would come to you in a vision. . .failing that, you could try to crystallize it and hope for the best in an X-ray analysis. But many proteins don't crystallize (or at least don't crystallize well on human time scales,) many that do don't give good data, and even the ones that can don't always give you realistic structures. After all, the proteins floating around in your cells aren't packed in a crystal lattice with billions of their identical twins. You'd better hope they aren't, anyway. They're surrounded by water, other proteins, lipids, and who knows what.

So, before the mass spec techniques of today's prize were developed, you could put a big ol' protein into a mass spectrometer, sure - and get an extraordinary mess of fragments out the other end. That's not always bad, of course (one of the points of mass spectra is the information that the fragmentation pattern provides,) but you'd like to be able just to see the mass of the parent, too. Now we can. Ridiculously huge molecules can be made to fly off, intact, into the hard vacuum of the mass spectrometer, there to be sorted by mass and charge. A few years ago, some lunatics even tried this on an intact virus. (PDF file.) They ionized it (without destroying it, thanks to these methods) and flew it down the mass spectrometer. When they collected the virus particles at the other end, they were still infectious - the only viruses to survive an ionizing flight in a vacuum, if that's the verb to use with a virus. (Unless, of course, they're raining down on us from space, a possibility this experiment does not dispel.)

The same goes for NMR, the veg-o-matic analytical technique of the organic chemist (thanks to all the tricks you can play with it.) Here's a brief history: The original method (Nobel Prize!) showed you the hydrogens in a molecule, and that's still the first thing we do. Want to see the carbons, instead? You can tune it for that, as well as plenty of more exotic nuclei. Then, in the 1950s and early 1960s, it was discovered that the splitting of the NMR lines (coupling constants) would tell you the angle between the two adjacent hydrogens that caused it, and suddenly 3-D structural information began to be extracted (as well as another Nobel or two.) Then the nuclear Overhauser effect was exploited (if you don't know how NOE works, I'll need to see payment - in cash or precious metals - before I explain it. Inquire within.) That tells you if particular hydrogens are close together in space, no matter how the rest of the molecule might be connected. More 3-D structural information started to come into focus.

The next big thing was 2-D NMR spectra, where you could extract (among other things) all the possible coupling constants or all the possible NOEs simultaneously. (These sorts of techniques will take most smalleunknown molecules and nail their structure up on the wall in matter of minutes or hours, the sort of thing that used to take years of hair-pulling effort.) Now we're getting to the area of today's Nobel: Applying these techniques to really complex molecules, like proteins, allows a look their real structure. That's the structure in solution, with whatever added molecules you want or need. In short, it gives you a look at the real animal, instead of a stuffed and mounted version (which, as mentioned above, is more like what X-ray crystallography does.)

There are limitations. Some kinds and sizes of proteins don't give good spectra, and many of them live in environments too complex to (yet) be reproduced in an NMR experiment. But the field's moving right along. If we're going to realize the promise of medicinal chemistry, we're going to need as much of this sort of work as we can get. The molecules of the living cell aren't special - they're big, they're complex, they do amazing things - but they're just molecules. It's good to be able to work with them that way.

Note: for a very nice technical discussion of today's prizes, see this PDF from the Royal Swedish Academy. Try to avoid most newspaper articles, since (as usual) the subject matter of the awards will be unrecognizably diluted.

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