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arXiv · 2607.00180

SF-Cluster: Frustration-Guided MSA Subsampling for Alternative Protein Conformation Recovery

Hanqun Cao·Zijun Gao·Chunbin Gu·Ge Liu·Pheng Ann Heng·Pranam Chatterjee
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Abstract

Deep-learning structure predictors are sensitive to their multiple sequence alignment (MSA) input, making MSA subsampling a practical route to recovering alternative conformations. Existing approaches such as AF-Cluster operate in sequence space, providing limited control over which conformational basin is sampled. We introduce SF-Cluster, which subsamples MSAs using patterns of predicted local energetic frustration, a representation largely independent of sequence similarity. Across a benchmark of 48 cases spanning fold-switching, allosteric, oligomerization-coupled, and intrinsically disordered systems, and using an AF-Cluster-style dual-reference RMSD criterion, SF-Cluster improves target-state recovery of the alternative conformation over AF-Cluster across the two-state classes, with the largest improvement observed for allosteric systems (+15.5 percentage points). The selected MSAs transfer to an architecturally distinct predictor, indicating that the conformational signal resides in MSA composition. Mechanistically, matched-depth controls show that this recovery advantage is largely explained by the effective depth of the selected subsets, which frustration-pattern selection reliably reaches. At the same time, highly frustrated residues are enriched at sites supported by deep mutational scanning and NMR two-state exchange, and frustration covariation is enriched at state-switching contacts while remaining distinct from coevolutionary coupling. Together, these results identify frustration patterns as a transferable representation for conformational prediction and position MSA subsampling as a representation-guided reweighting problem.

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Hanqun Cao, Zijun Gao, Chunbin Gu, Ge Liu, Pheng Ann Heng, Pranam Chatterjee. 2026-06-30. SF-Cluster: Frustration-Guided MSA Subsampling for Alternative Protein Conformation Recovery. https://arxiv.org/abs/2607.00180

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