PDNAPred: Interpretable prediction of protein-DNA binding sites based on pre-trained protein language models.

Protein-DNA interactions play critical roles in various biological processes and are essential for drug discovery. However, traditional experimental methods are labor-intensive and unable to keep pace with the increasing volume of protein sequences, leading to a substantial number of proteins lacking DNA-binding annotations. Therefore, developing an efficient computational method to identify protein-DNA binding sites is crucial. Unfortunately, most existing computational methods rely on manually selected features or protein structure information, making these methods inapplicable to large-scale prediction tasks. In this study, we introduced PDNAPred, a sequence-based method that combines two pre-trained protein language models with a designed CNN-GRU network to identify DNA-binding sites. Additionally, to tackle the issue of imbalanced dataset samples, we employed focal loss. Our comprehensive experiments demonstrated that PDNAPred significantly improved the accuracy of DNA-binding site prediction, outperforming existing state-of-the-art sequence-based methods. Remarkably, PDNAPred also achieved results comparable to advanced structure-based methods. The designed CNN-GRU network enhances its capability to detect DNA-binding sites accurately. Furthermore, we validated the versatility of PDNAPred by training it on RNA-binding site datasets, showing its potential as a general framework for amino acid binding site prediction. Finally, we conducted model interpretability analysis to elucidate the reasons behind PDNAPred's outstanding performance.