Single-sequence protein structure prediction using supervised transformer protein language models

Significant progress has been made in protein structure prediction in recent years. However, it remains challenging for AlphaFold2 and other deep learning-based methods to predict protein structure with single-sequence input. Here we introduce trRosettaX-Single, an automated algorithm for single-sequence protein structure prediction. It incorporates the sequence embedding from a supervised transformer protein language model into a multi-scale network enhanced by knowledge distillation to predict inter-residue two-dimensional geometry, which is then used to reconstruct three-dimensional structures via energy minimization. Benchmark tests show that trRosettaX-Single outperforms AlphaFold2 and RoseTTAFold on orphan proteins and works well on human-designed proteins (with an average template modeling score (TM-score) of 0.79). An experimental test shows that the full trRosettaX-Single pipeline is two times faster than AlphaFold2, using much fewer computing resources (<10%). On 2,000 designed proteins from network hallucination, trRosettaX-Single generates structure models with high confidence. As a demonstration, trRosettaX-Single is applied to missense mutation analysis. These data suggest that trRosettaX-Single may find potential applications in protein design and related studies.