Science. 2025 Jul 10:eadv9817. doi: 10.1126/science.adv9817. Online ahead of print.
ABSTRACT
Following the sequence and structure revolutions, predicting functionally relevant protein structure changes at scale remains an outstanding challenge. We introduce BioEmu, a deep learning system that emulates protein equilibrium ensembles by generating thousands of statistically independent structures per hour on a single GPU. BioEmu integrates over 200 milliseconds of molecular dynamics (MD) simulations, static structures and experimental protein stabilities using novel training algorithms. It captures diverse functional motions-including cryptic pocket formation, local unfolding, and domain rearrangements-and predicts relative free energies with 1 kcal/mol accuracy compared to millisecond-scale MD and experimental data. BioEmu provides mechanistic insights by jointly modelling structural ensembles and thermodynamic properties. This approach amortizes the cost of MD and experimental data generation, demonstrating a scalable path toward understanding and designing protein function.
PMID:40638710 | DOI:10.1126/science.adv9817
