Accurate Conformation Sampling via Protein Structural Diffusion

Accurately sampling of protein conformations is pivotal for advances in biology and medicine. Although there have been tremendous progress in protein structure prediction in recent years due to deep learning, models that can predict the different stable conformations of proteins with high accuracy and structural validity are still lacking. Here, we introduce Diffold, a cutting-edge approach designed for robust sampling of diverse protein conformations based solely on amino acid sequences. This method transforms AlphaFold2 into a diffusion model by implementing a conformation-based diffusion process and adapting the architecture to process diffused inputs effectively. To counteract the inherent conformational bias in the Protein Data Bank, we developed a novel hierarchical reweighting protocol based on structural clustering. Our evaluations demonstrate that Diffold outperforms existing methods in terms of successful sampling and structural validity. The comparisons with long time molecular dynamics show that Diffold can overcome the energy barrier existing in molecular dynamics simulations and perform more efficient sampling. Furthermore, We showcase Diffold’s utility in drug discovery through its application in neural protein-ligand docking. In a blind test, it accurately predicted a novel protein-ligand complex, underscoring its potential to impact real-world biological research. Additionally, we present other modes of sampling using Diffold, including partial sampling with fixed motif, langevin dynamics and structural interpolation.