While this is a breakthrough within the field of cryo-electron microscopy it is important to appreciate that for many questions in structural biology we also need to understand how protein structure changes over time.
With the presented method the structure sampling time seems to be O(10 s) which easily is about 10 orders of magnitudes slower than the dynamics we're interested in seeing.
A direct consequence of this is that for achieving atomic spatial resolution they needed to use a "rock-solid" protein -- one that has an exceptionally stiff structure (one that does not wiggle a lot). The presented method is great and cool, but this is a pretty severe limitation. Most proteins wiggle a lot :-).
Background: protein structure-function relationship can often be well understood only when considering the structural dynamics of the protein (key words: conformational changes, the entropic contribution to free energy).
That is, in the ideal case we would be able to measure molecular structure not only at high spatial resolution, but also at high temporal resolution.
How can one make such a measurement much faster, by ~10 orders of magnitude? By irradiating a lot of light. Via X-ray free electron lasers (XFEL).
XFEL-based techniques are expected to revolutionize structural biology (as always, also still a long way to go):
> XFEL protein crystallography not only determines high resolution structures of proteins, but also reveals the time-stamped conformational changes of proteins.
You're glossing over the advantages specific to cryo-EM though, which is it can give you a good picture of large ensembles of small things at this accuracy, with a lot less computational/interpretation hardship than X-ray crystallography or NMR. So for seeing structures of large protein complexes and how the super structure varies with heteromeric variation this is a really big deal. If you wanted to see what viral capsids in-situ looked like down to the atoms this is what you'd use. There are a lot of places this is going to be useful, there is no one method to rule them all in structural proteomics simply because nothing can offer all of the spatial and temporal scales one might need. Plus cryo would only give you the surface hull of these complexes, you'd still need a different method to fill in all the exact structures inside. Writing up these methods as if there is some competition for "best" is an entirely false impression to a lay person reading. The best is all methods improve and researchers collaborate to provide every possible scoped view. Even mass spectrometry is doing crazy things for investigating the structure of disordered proteins. You'd never use that for something you would use cryo-EM for.
Thanks for this reply and the additional level of detail. I didn't mean to imply that one method is generally better than another. The combination of a variety of methods applied to the same problem space is certainly the way to go whenever we really want to unravel molecular mechanisms.
To add on, another promising technique is ultrafast electron diffraction (UED). You can get atomic space and time resolution (sub-angstrom and 100 fs) already. It's just a matter of scaling up beam quality to the point we can study complex macromolecules. UED will also fit in a single room while the worlds only XFEL is miles long.
(I work on instrumentation improvements for XFELs and UED.)
But don't forget that these methods use class-averaging and each class represents members of a frozen structure. One of the beauties of cryoEM is that if your structure is dynamic, cryoEM will actually capture the ensemble in each class, which if you have enough images of each class you can solve each states' structure. One caveat is that if there are no local minima, you may have a huge number of states which means you won't get high resolution structures of each, but typically you'll have a few conformations that are reasonably stable. The other cool thing is you can throw in literal cell lysate and let the computers "purify" the sample for you. This allows the native environment to participate in the thermodynamic landscape of dynamic proteins, possibly showing more meaningful dynamic states.
With the presented method the structure sampling time seems to be O(10 s) which easily is about 10 orders of magnitudes slower than the dynamics we're interested in seeing.
A direct consequence of this is that for achieving atomic spatial resolution they needed to use a "rock-solid" protein -- one that has an exceptionally stiff structure (one that does not wiggle a lot). The presented method is great and cool, but this is a pretty severe limitation. Most proteins wiggle a lot :-).
Background: protein structure-function relationship can often be well understood only when considering the structural dynamics of the protein (key words: conformational changes, the entropic contribution to free energy).
That is, in the ideal case we would be able to measure molecular structure not only at high spatial resolution, but also at high temporal resolution.
How can one make such a measurement much faster, by ~10 orders of magnitude? By irradiating a lot of light. Via X-ray free electron lasers (XFEL).
XFEL-based techniques are expected to revolutionize structural biology (as always, also still a long way to go):
> XFEL protein crystallography not only determines high resolution structures of proteins, but also reveals the time-stamped conformational changes of proteins.
- https://www.nature.com/articles/nmeth.3070.pdf?origin=ppub
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678726/
(PhD in structural biology/bioinformatics, investigated dynamics of proteins with molecular dynamics simulations)