I’m always happy to see new techniques for resolving structures of molecules (large and small) and figuring out their behavior. Even if the latest instrument or method doesn’t seem to have any bearing on what I’m doing, or even on drug research in general, it could end up helping. It’s Sydney Brenner‘s 90th birthday today (!), and one of his famous quotes relates to this point: “Progress in science depends on new techniques, new discoveries, and new ideas, probably in that order”. Freeman Dyson has made the same point, most recently in his book The Sun, The Genome, and The Internet, saying that contrary to popular opinion, many scientific revolutions are tool-driven rather than concept-driven.
This paper has me thinking about such issues today. The authors report using electron diffraction to locate hydrogen atoms in small-molecule crystals, and it’s pardonable to wonder what the big deal about that might be. Don’t we pretty much know where the hydrogen atoms are? After all, when you look at a small-molecule X-ray structure, the hydrogens tend to be an afterthought, usually dealt with by a phrase like “hydrogen atoms were fitted using a riding model” or such. But that’s because X-ray diffraction is nearly blind to hydrogen atoms. They hardly diffract. Just because we can’t see them doesn’t mean that they’re not important, though. We use X-ray data to tell us about all the heavier atoms in a crystal, and it’s great stuff, but what are we missing?
Electron diffraction is XRD’s cousin, but it has its tricky aspects. Recent advances in instrumentation and (especially) processing of the data, though, are making it more and more useful (here’s more). I’ve written about a few very impressive structures that have been generated of proteins by electron diffraction, and that first link brings up another very useful aspect of the technique: it can work on ridiculously small crystals. If you’re going to do X-ray diffraction, there’s a size limitation (even on a bright source like a synchrotron, although that’ll certainly help). This new paper demonstrates a great improvement in handling electron diffraction from hydrogen atoms.
It’s demonstrated first by analysis of a very small single crystalline region of an acetominophen (paracetamol) sample, about 500 nm wide. The method nails the hydrogen positions, including the NH and the OH of the phenol. This structure was already worked out, and confirmed by this route, so they then went on to an unknown structure, a zeolitic cobalt aluminophosphate made by a new synthetic technique. X-ray powder diffraction established the general parameters (unit cell, space group), but also revealed that the cobalt atoms were only partially occupying the positions one would have normally assigned. This kind of thing happens a lot, and it can be a real pain to work out – and it is, as fate would have it, often closely related to catalytic activity and other important properties of such solids.
The electron diffraction work on this one was not without trouble – the first data sets they collected showed signs of the structure having been slightly deranged by the electron beam itself, which is a known problem (these are pretty high-energy electrons). Lower-dose data were more reliable, and the hydrogens were tracked down, although it still took plenty of work. This is really nice to see, though, because in these sorts of solids, X-ray data alone are not going to tell you whether that’s an OH or an O-minus coming off of a given metal atom, if something is an acetic acid or an acetate, a water molecule or a hydroxide, and so on, and these can be (as you’d imagine) rather important distinctions. If we’re going to understand the properties of advanced solid-phase samples, which include hugely important industrial catalysts, photovoltaics, superconductors, and structural materials, we’re going to have to track down every last atom. It looks like we may finally have a way to do that.