I linked to this particular XKCD strip when it came out, but it came right back to mind when I saw this paper, on a new kind of intramolecular interaction in proteins (and other systems). Protein folding, macromolecular folding in general, is indeed a famously horrendous problem to attack from first principles. There’s been progress on semi-empirical approaches based on the protein structures that we already know, but there’s still a lot to understand.
It all comes down to the many sorts of interactions (some attracting, some repelling) that the protein can make with itself, compared to what can be had with the solvent. Enthalpic and entropic terms are dueling it out in each case for the final free energy figure, and things like the disposition of single water molecules can make a big difference – and a difference that might totally flip from negative to positive in a different example. To counterbalance those big influences, there are a large number of very small ones, each of which adds little to the binding picture on its own, but which as a collection can send things over into particular paths.
That’s what this latest paper is talking about. Apparently, calculations have suggested that C-H bonds can have a weak interaction with the pi bonds in carbonyls. That’s definitely not one of the the bonding modes that anyone would think of first, but the paper demonstrates actual detection of (very, very small) coupling constants in 2D NMR (HMQC) spectra that are due to through-space interactions of (say) the methyl groups in a valine with the carbonyl of an appropriately situated backbone CO group. There doesn’t seem to be much correlation with the type of CO, what amino acid it’s part of , or whether it’s involved in a hydrogen bond with some other group, etc. This experiment needed some specific isotopic labeling to get the signal/noise up to where the couplings could be detected, and the authors believe that many others will be found in other labeling experiments. They suggest that it’s not going to be just methyl groups, but OH groups and others that will prove to participate another order of weak hydrogen-bond-like interactions.
So this could be a new way to interrogate protein structures in solution, and it seems to represent a new consideration to add into protein folding calculations. There will doubtless be some systems where these interactions are buried down in the noise compared to the other factors, and others where they really do add up to something, but we don’t know much about this yet. It’s worth thinking, though, that this is a phenomenon that until now we haven’t even known about. Every time something like this is discovered, I ask myself what else we don’t know. (Hint: there’s a lot). It’s great. All that stuff is waiting out there for us.