For the field of protein physical science, the future is at least as compelling as the past. Here are some of the unsolved problems:
We have little experimental knowledge of protein-folding energy landscapes.
We cannot consistently predict the structures of proteins to high accuracy.
We do not have a quantitative microscopic understanding of the folding routes or transition states for arbitrary amino acid sequences.
We cannot predict a protein’s propensity to aggregate, which is important for aging and folding diseases.
We do not have algorithms that accurately give the binding affinities of drugs and small molecules to proteins.
We do not understand why a cellular proteome does not precipitate, because of the high density inside a cell.
We know little about how folding diseases happen, or how to intervene.
Despite their importance, we still know relatively little about the structure, function, and folding of membrane proteins (70, 71).
We know little about the ensembles and functions of intrinsically disordered proteins (72), even though nearly half of all eukaryotic proteins contain large disordered regions. This is sometimes called the “protein nonfolding problem” or “unstructural biology.”