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February 4, 2013
Single-Cell NMR? How About Single-Protein NMR?
Two different research teams have reported a completely different way to run NMR experiments, one that looks like it could take the resolution down to cellular (or even large protein) levels. These two papers in Science have the details (and there's an overall commentary here, and more at Nature News).
This is not, as you've probably guessed, just a matter of shrinking down the probe and its detector coil. Our usual method of running NMR spectra doesn't scale down that far; there are severe signal/noise problems, among other things. This new method uses crystal defects just under the surface of diamond crystals - if a nitrogen atom gets in there instead of a carbon, you're left with a negatively charged center with a very useful spin state. It's capable of extraordinarily sensitive detection of magnetic fields; you have a single-atom magnetometer.
And that's been used to detect NMR signals in volumes of a few cubic nanometers. By comparison, erythrocytes (among the smallest of human cells) have a volume of around 100 cubic micrometers. By contrast, a 50 kD protein has a minimal radius of 2.4 nm, giving it a volume of 58 cubic nanometers at the absolute minimum. This is all being done at room temperature, I might add. If this technique can be made more robust, we are potentially looking at MRI imaging of individual proteins, and surely at a detailed intracellular level, which is a bizarre thought. And there's room for improvement:
By implementing different advanced noise suppression techniques, Mamin et al. and Staudacher et al. have succeeded in using near-surface NVs to detect small volumes of proton spins outside of the diamond crystal. Both authors conclude that their observed signals are consistent with a detection volume on the order of (5 cubic nanometers) or less. This sensitivity is comparable to that of the cryogenic MRFM technique and should be adequate for detecting large individual protein molecules. Both groups also project much smaller detection volumes in the future by using NVs closer to the diamond surface. Staudacher et al. expect to improve sensitivity by using the NV to spin-polarize the nuclei. Mamin et al. project that sensitivity may eventually approach the level of single protons, provided that the NV coherence time can be kept long enough.
I love this sort of thing, and I don't mind admitting it. Imagine detecting a ligand binding event by NMR on an individual protein molecule, or following the distribution of a fluorinated drug candidate inside a single cell. I can't wait to see it in action.
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