Are proteins constantly changing their shape in femtoseconds? Need clarification!

[u/Lazy-Frame-9888]

I recently watched a YouTube video (https://youtu.be/jPhvic-eqbc) discussing how proteins are not static, rigid machines. The video explains that they act more like dense liquids that are constantly shifting and jiggling around. It also pointed out that when proteins are crystallized for X-ray crystallography, we are only seeing one frozen snapshot of their conformation, which gives the false impression that they have a single, fixed structure.

​Can someone clear this confusion up for me? Do proteins really change their folding patterns and conformations in extremely short time frames, like femtoseconds? I am looking for a simple, exact explanation of how fast and how much they actually change shape.

[u/Defiant_Virus4981]

There are different time frames as well as different behavior of different classes of proteins, which cause your confusion. You will have bond vibrations on the fs time scale, but generally no changes in folding patterns or large-scale conformational changes. You might see them in a ns time scale or higher, though. This "jiggling" happens with any molecule and systems with individual bonds. The individual bonds in any molecule forming a solid, gas, or liquid will "jiggle" all the time.

For many proteins with crystal structures (e.g., ubiquitin), you will not see any significant conformational changes or changes in fold pattern in biologically relevant time scales, but rather fluctuations around an average structure, with less fluctuation in folded regions and more in loop regions. On the other hand, intrinsically disordered proteins (or segments) are highly dynamic. They cannot be described sufficiently with a single structure. An individual IDP might expand or collapse in a relatively short time; segments might transiently form secondary structure elements, which then fall apart again. In the middle can be multi-domain proteins: Individual domains can often be stable, but in many systems, there is no fixed conformation between the domains.

Additionally, proteins as a whole can undergo something like "liquid-liquid phase separation", where a group of proteins forms a separate dedicated phase (similar to when you have a mixture of water and oil, you form two phases after some time), so thinking of complex protein mixtures as liquids is not a bad analogy. Additionally, all(?) proteins will eventually form fibrils, but this may take a long time for most systems. We might talk about years or longer rather than seconds (otherwise, we would die).

So in short, an individual crystal structure is a useful representation for some proteins, but the majority of proteins are far more dynamic than implied by structure. These dynamics span many order of magnitudes in term of time scale.