Ultrafast and Accurate Selection of High-Quality Protein Complex Models from Large-Scale Prediction

Abstract

In the post-AlphaFold era, advances in protein complex structure prediction have enabled the generation of thousands of candidate models per target, making the accurate and efficient selection of high-quality models from large candidate pools a critical challenge. Existing model-selection approaches commonly employ estimated model accuracy (EMA) methods, which include single-model and consensus-based methods. The former lack cross-model comparative information, whereas the latter often incur high computational costs from pairwise structural alignments and are influenced by candidate-pool quality. Here, we present DeepUMQA-Selection, a two-stage framework combining single-model accuracy estimators for preliminary selection with Ultrafast Shape Recognition (USR)-based structural alignment for consensus selection. Preliminary selection enriches the candidate pool with high-quality models and reduces subsequent structural comparisons, while USR-based structural alignment enables efficient consensus selection without explicit structural superposition. On the retrospective CASP16 QMODE3 benchmark dataset, DeepUMQA-Selection outperformed all participating methods and predictor-derived confidence metrics, as measured by mean Top-5 weighted penalty. The advantage was particularly pronounced for heteromeric targets, with a 13.9% improvement in model-selection performance relative to the best-performing CASP16 participating method. Furthermore, a confidence-assisted strategy enabled the framework to accommodate larger protein complexes while maintaining superior model-selection performance over competing methods, supporting its scalability. Runtime benchmarking showed that the proposed USR-based structural alignment achieved a substantial 317-fold speedup over US-align for candidate pools containing 1,000 models, demonstrating its computational efficiency for large-scale model selection. Our results demonstrate that DeepUMQA-Selection enables accurate and computationally efficient selection of high-quality protein complex models from large-scale candidate pools.