AlphaFold and Protein Folding: Not Dead Yet! The Frontier Is Conformational Ensembles

Like the black knight in the classic Monty Python movie, grand scientific challenges such as protein folding are hard to finish off. Notably, AlphaFold is revolutionizing structural biology by bringing highly accurate structure prediction to the masses and opening up innumerable new avenues of research. Despite this enormous success, calling structure prediction, much less protein folding and related problems, “solved” is dangerous, as doing so could stymie further progress. Imagine what the world would be like if we had declared flight solved after the first commercial airlines opened and stopped investing in further research and development. Likewise, there are still important limitations to structure prediction that we would benefit from addressing. Moreover, we are limited in our understanding of the enormous diversity of different structures a single protein can adopt (called a conformational ensemble) and the dynamics by which a protein explores this space. What is clear is that conformational ensembles are critical to protein function, and understanding this aspect of protein dynamics will advance our ability to design new proteins and drugs.