Comment by dekhn
2 years ago
The ribbons and helices you see in those pictures are abstract representations of the underlying positions of specific arrangements of carbon atoms along the backbone.
There are tools such as DSSP https://en.wikipedia.org/wiki/DSSP_(hydrogen_bond_estimation... which will take out the 3d structure determined by crystallography and spit out hte ribbons and helices- for example, for helices, you can see a specific arrangement of carbons along the protein's backbone in 3d space (each carbon interacts with a carbon 4 amino acids down the chain).
Protein motion at room temperature varies depending on the protein- some proteins are rocks that stay pretty much in the same single conformation forever once they fold, while others do thrash around wildly and others undergo complex, whole-structure rearrangements that almost seem magical if you try to think about them using normal physics/mechanical rules.
Having a magical machine that could output the full manifold of a protein during the folding process at subatomic resolution would be really nice! but there would be a lot of data to process.
Thanks, awesome! So what do molecular biologists do with these 3D representations once they have them? Do they literally just see how they fit to other proteins?
There are many uses for structure. Personally, I find the 3d structures to be useful as a mental guide for picturing things, and certainly people do try to "dock" proteins that have complementary structures, but unfortunately, the biophysics of protein complexes suggests that the conformation change on binding is so large that the predicted structures aren't super-helpful.
Certainly, in a corpo like mine (Genentech/Roche) protein structures have a long history of being used in drug discovery- not typically a simple "dock a ligand to a protein" but more for constructing lab experiments that help elucidate the actual mechanistic biology going on. That is only a tiny part of a much larger process to work on disease targets to come up with effective treatments. Genentech is different from most pharma in that their treatments are themselves typically proteins, rather than small molecules.
How bad is our understanding of force fields?
It seems like that's the basic principle to understand.
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A structure is bascially another tool for producing hypotheses. In my case, I often use structures to predict effects of genetic lesions. If your protein has a clearly defined active site, you can get a rough sense of where on the enzyme that active site is relative to other mutations. Often residues that are distant in sequence end up right next to each other in the folded structure, so certain residues can have unexpected roles.
It gives a picture of the enzyme as a machine, and lets you look at specific parts and say “this residue is probably doing this job in the whole system”.
Often the ribbons (alpha-helices and beta=sheets) form "protein domains". Canonically, these are stable, folded structures with conserved shapes and functions that serve as the building blocks of proteins, like lego pieces. These protein domains can be assembled in different ways to form proteins of different function. Different protein domains that have the same evolutionary origin have conserved structure even when the underlying amino acid sequence, or DNA sequence has changed beyond recognition over millions of years of evolution. In other words, molecular biologists use structure as a proxy for function. Looking at how the same protein domains works in different proteins in different species can give us clues as to how a protein might work in human biology or disease.
Basically, the shape of the protein determines how it interacts with other things. So knowing the structure enables better prediction of how the pathways it is involved in work and how other things (say, potential drugs) would affect that pathway.