Learning millisecond protein dynamics from what is missing in NMR spectra

Many proteins’ biological functions rely on interconversions between multiple conformations occurring at micro- to millisecond (µs-ms) timescales. A lack of standardized, large-scale experimental data has hindered obtaining a more predictive understanding of these motions. After curating >100 Nuclear Magnetic Resonance (NMR) relaxation datasets, the researchers realized an observable for µs-ms dynamics might be hiding in plain sight. Millisecond dynamics can cause NMR signals to broaden beyond detection, leaving some residues not assigned in the chemical shift datasets of ~10,000 proteins deposited in the Biological Magnetic Resonance Data Bank (BMRB). The team made a bold assumption that residues missing assignments are exchange-broadened due to µs-ms motions and trained various deep learning models to predict missing assignments. Strikingly, these models also predict exchange measured via NMR relaxation experiments, indicative of µs-ms dynamics. The best of these models, which the researchers named Dyna-1, leverages an intermediate layer of the multimodal language model ESM-32. Notably, dynamics directly linked to biological function, including enzyme catalysis and ligand binding, are particularly well predicted by Dyna-1, which parallels the authors' findings that residues experiencing µs-ms exchange are more conserved. The researchers anticipate that the datasets and models presented here will be transformative in advancing our understanding of protein dynamics and function.