Efficient Prediction of Large Protein Complexes via Subunit-Guided Hierarchical Refinement

Chixiang Lu, Yunhua Zhong, Shikang Liang, Xiaojuan Qi, Haibo Jiang

Keywords: Protein complex structure prediction, AlphaFold3, complex modularity

TL;DR: We introduce HierAFold, a hierarchical pipeline that exploits the modularity of large complexes via PAE-guided (Predicted Aligned Error) subunit decomposition, targeted interface-aware refinement, and confidence-weighted assembly.

Abstract: State-of-the-art protein structure predictors have revolutionized structural biology, yet quadratic memory growth with token length makes end-to-end inference impractical for large complexes beyond a few thousand tokens. We introduce HierAFold, a hierarchical pipeline that exploits the modularity of large complexes via PAE-guided (Predicted Aligned Error) subunit decomposition, targeted interface-aware refinement, and confidence-weighted assembly. PAE maps localize rigid intra-chain segments and sparse inter-chain interfaces, enabling joint refinement of likely interacting subunits to capture multi-body cooperativity without increasing memory. HierAFold matches AlphaFold3 accuracy, raises success rates from 49.9\% (CombFold) to 73.1\% on recent PDB set. While for large complexes, it cuts peak memory by $\sim$25\,GB on a 4,000-token target ($\sim$40\%), successfully models complexes with over $5{,}000$ tokens that are out-of-memory for AlphaFold3, and raises success rates by two-fold compared with CombFold.

Primary Area: applications to physical sciences (physics, chemistry, biology, etc.)

Submission Number: 24657