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September 26, 2012
Free the Labels
When you talking assays, "label-free" is a magic phrase. The more thingies you have to stick onto your molecules or targets to see them, the less confidence you'll have that you're actually looking at the system the way you really wanted to see it: as if you weren't looking at it at all. And while we're not quite quantum mechanics, the observer effect is very real in molecular and cell biology - too many interesting techniques perturb the system in the process of reading out.
And there are no perfect label-free assays, otherwise we'd all be using them. In vitro, NMR can tell you an awful lot, but it can require an awful lot of work if you want to correlate structural information with binding events. And mass spec is getting ridiculously sensitive, and can be used to detect compound binding. But even when that works, it doesn't give you any structure (or much spatial resolution after a certain point, if that's what you're looking for - say, in cells). SPR is a great technique for getting kinetic information right out of the primary assay (instant off-rates!) But it's not quite label-free, because you have to immobilize something to a chip to make it work. Thermal shift is an interesting assay, too - but it uses up a fair amount of protein, and some proteins are more sensitive to it than others. No structural information there, either.
There are a couple of techniques that I don't have much experience with that sound intriguing. Capillary electrophoresis for binding is one - you look at mobility changes with your protein when something is bound to it, as you'd imagine. It's supposed to be pretty sensitive. And BLI (bio-layer interferometry) reminds me a bit of SPR, in that it uses an immobilized protein. I'm not sure what the advantages/disadvantages of that one are, but I see it turn up in the literature.
The ideal assay? If you could do NMR, with the sensitivity to detect very small amounts of a compound, with spatial resolution well below subcellular. You'd get binding, localization, and structure all in one shot. That's probably not even possible, but I'd love to be wrong about that.
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