E2EDA: Protein Domain Assembly Based on End-to-End Deep Learning.

With the development of deep learning, almost all single-domain proteins can be predicted at experimental resolution. However, the structure prediction of multi-domain proteins remains a challenge. Achieving end-to-end protein domain assembly and further improving the accuracy of the full-chain modeling by accurately predicting inter-domain orientation while improving the assembly efficiency will provide significant insights into structure-based drug discovery. In this work, we propose an End-to-End Domain Assembly method based on deep learning, named E2EDA. We first develop RMNet, an EfficientNetV2-based deep learning model that fuses multiple features using an attention mechanism to predict inter-domain rigid motion. Then, the predicted rigid motions are transformed into inter-domain spatial transformations to directly assemble the full-chain model. Finally, the scoring strategy RMscore is designed to select the best model from multiple assembled models. The experimental results show that the average TM-score of the model assembled by E2EDA on the benchmark set (282) is 0.827, which is better than those of other domain assembly methods SADA (0.792) and DEMO (0.730). Meanwhile, on our constructed multi-domain data set from AlphaFold DB, the model reassembled by E2EDA is 7.0% higher in TM-score compared to the full-chain model predicted by AlphaFold2, indicating that E2EDA can capture more accurate inter-domain orientations to improve the quality of the model predicted by AlphaFold2. Furthermore, compared to SADA and AlphaFold2, E2EDA reduced the average runtime on the benchmark by 64.7% and 19.2%, respectively, indicating that E2EDA can significantly improve assembly efficiency through an end-to-end approach. The online server is available at http://zhanglab-bioinf.com/E2EDA.