MutaStruct: Revisiting Benchmarks for Single-Site Mutation-Induced Structural Change Prediction

Abstract

Predicting the structural consequences of single-site mutations is fundamental to understanding protein function, disease mechanisms, and protein engineering. However, existing benchmarks for mutation-induced structural change prediction are often affected by duplicate mutation events, highly similar structural pairs, and experimental-state confounders, which can inflate reported performance. We introduce MutaStruct, a curated benchmark of experimentally observed single-mutation protein structure pairs designed for rigorous evaluation of mutation-induced structural changes. MutaStruct combines residue-level sequence validation, coordinate-level quality control, context-aware filtering, event-level deduplication, and leakage-aware data splitting to improve dataset reliability and evaluation rigor. We benchmark sequence-only structure prediction, physics-based refinement, and learning-based refinement methods together with a Copy-WT diagnostic control. Copy-WT remains highly competitive on backbone-based metrics, while method rankings change substantially across local and mutation-site measures. These results show that overall structural fidelity does not necessarily imply accurate modeling of mutation-associated structural change, underscoring the need for further methodological development beyond current paradigms. The benchmark dataset is currently undergoing further curation and expansion and will be released in a future journal-version update. The codebase, trained models, and evaluation pipeline are publicly available at https://github.com/HySonLab/MutaStruct