HDOCK-Multimer: integrating docking and combinatorial assembly for structure prediction of large protein complexes

Deep learning methods, such as AlphaFold and RosettaFold, achieve high accuracy in protein structure prediction. However, predicting the structure of large protein complexes remains challenging due to their large size and intricate multi-chain interactions. Docking-based methods can handle large proteins, but are limited by the huge combinatorial binding space of multi chains. Assembly-based approaches offer an alternative, but their accuracy critically relies on the precision of predicted subcomponents. Addressing the challenges, we propose HDOCK Multimer (HDM), a structure prediction framework of large protein complexes by integrating ab initio docking and combinatorial assembly. HDM can efficiently reduce reliance on subcomponent accuracy through docking process, while leveraging the pairwise interactions of subcomponents through assembly strategy. HDM is extensively validated on three benchmarks of 35 large heteromeric complexes, 172 large protein complexes, and 7 CASP15 targets, and compared with state-of-the-art methods including MoLPC, CombFold, AlphaFold-Multimer (AFM), and AlphaFold3 (AF3). It is shown that HDOCK-Multimer substantially outperforms the other methods. In addition, HDM also shows ability to predict the stoichiometry and model the complex without stoichiometry input. It is anticipated that HDM will serve as a powerful tool for study ing large protein complexes or molecular machines. The HDM package is freely available at https://github.com/huang-laboratory/HDOCK-Multimer.