Integrating diverse experimental information to assist protein complex structure prediction by GRASP.

Abstract

Protein complex structure prediction is crucial for understanding of biological activities and advancing drug development. While various experimental methods can provide structural insights into protein complexes, the knowledge obtained is often sparse or approximate. A general tool is needed to integrate limited experimental information for high-throughput and accurate prediction. Here we introduce GRASP to efficiently and flexibly incorporate diverse forms of experimental information. GRASP outperforms existing tools in handling both simulated and real-world experimental restraints including those from crosslinking, covalent labeling, chemical shift perturbation and deep mutational scanning. For example, GRASP excels at predicting antigen-antibody complex structures, even surpassing AlphaFold3 when using experimental deep mutational scanning or covalent-labeling restraints. Beyond its accuracy and flexibility in restrained structure prediction, GRASP's ability to integrate multiple forms of restraints enables integrative modeling. We also showcase its potential in modeling protein structural interactome under near-cellular conditions using previously reported large-scale in situ crosslinking data for mitochondria.