Marc BaadenLet's bring molecules to life! 🌟 Proteins aren't static structures, but dynamic entities in constant motion. It's time to move beyond single snapshots and explore the epic molecular movie unfolding between them. What do you think?
Konrad Hinsen@baam93 It was time 20 years ago!
@khinsen that's a fair point. And it is a bit sad, but it's still time, because the idea IMHO has still not sufficiently sunk in, or has it?
Guillaume Gaullier@baam93 The idea has sunk in at different speeds within different communities.
I think NMR spectroscopists have understood that proteins move for a very long time. But they're generally too easily excited about the physics and maths underlying NMR, while the rest of us not as much. 😅 So maybe they haven't been the ideal messengers to disseminate this idea 😇 (and I mean no offense to any NMR spectroscopist).
Nowadays with #cryoEM we can literally take pictures of proteins in different conformations, and correctly modeling this conformational heterogeneity is a very active sub-field within the broader field.
Pictures seem to be a much more efficient way to communicate the idea to non-specialists.
@Guillawme That's a good summary. Put differently, subcommunities are aware of dynamics if and only if their preferred toolbox give access to dynamical information. It's the dominance of crystallography that has probably held back progress towards a dynamical understanding of proteins.
I just hope that Alphafold will not set us back to focusing on static structures.
@khinsen To be fair, some crystallographers know full well that proteins are dynamic. But they notice it at a different scale: they only get to see the dynamics that can coexist with a crystal lattice. Mostly loops, not domain motions that tend to make proteins impossible to crystallize (for an example, see video 4 from this paper I worked on a couple years ago: https://elifesciences.org/articles/71420/figures#videos ; of course there is no time information in there, but the pictures already tell a good part of the story about dynamics!).
The issue is not structural biologists / biophysicists being unaware of dynamics: very often they know a lot about it! The issue is how they are able to communicate it to non-specialists in adjacent disciplines, either because it is objectively difficult (see NMR), or because their tools don't equip them well to do so; often it's a combination of both.
We cryoEMists are extremely lucky because imaging is much more intuitive than other structural methods! Most people easily understand that 2D projections in different orientations can give a 3D reconstruction. Most biologists understand the concept of heterogeneity at the scale they study (individuals in a population, cells in a tissue, molecules in an ensemble, etc.). So when we explain that our images of single particles are good enough to distinguish different conformations in a heterogeneous ensemble, most people get it relatively easily, and protein dynamics can finally enter the discussion.
Figures and data in Structure and dynamics of the chromatin remodeler ALC1 bound to a PARylated nucleosome
Analysis of conformational heterogeneity in cryo-EM data by a recently developed deep learning method reveals the structure and dynamics of the oncogenic chromatin remodeler ALC1 bound to a poly-ADP-ribosylated nucleosome.
@Guillawme Crystallographers have indeed always been aware of dynamics, but it was mostly a nuisance to them, an obstacle to better structures.There were occasional attempts to extract useful dynamic information from crystals, but they remained marginal.
Theoreticians unfortunately often went too far in searching for dynamics in crystal structures, in particular by interpreting B factors as (nothing but) thermal fluctuations. A great example for miscommunication.