AlphaFold 2 and NMR Spectroscopy: Partners to Understand Protein Structure, Dynamics and Function

The artificial intelligence program AlphaFold 2 is revolutionizing the field of protein structure determination as it accurately predicts the 3D structure of two thirds of the human proteome. Its predictions can be used directly as structural models or indirectly as aids for experimental structure determination using X-ray crystallography, CryoEM or NMR spectroscopy. Nevertheless, AlphaFold 2 can neither afford insight into how proteins fold, nor can it determine protein stability or dynamics. Rare folds or minor alternative conformations are also not predicted by AlphaFold 2 and the program does not forecast the impact of post translational modifications, mutations or ligand binding. The remaining third of human proteome which is poorly predicted largely corresponds to intrinsically disordered regions of proteins. Key to regulation and signaling networks, these disordered regions often form biomolecular condensates or amyloids. Fortunately, the limitations of AlphaFold 2 are largely complemented by NMR spectroscopy. This experimental approach provides information on protein folding and dynamics as well as biomolecular condensates and amyloids and their modulation by experimental conditions, small molecules, post translational modifications, mutations, flanking sequence, interactions with other proteins, RNA and virus. Together, NMR spectroscopy and AlphaFold 2 can collaborate to advance our comprehension of proteins.