GeoPep: A Geometry-Aware Masked Language Model for Protein-Peptide Binding Site Prediction.

Multimodal approaches that integrate protein structure and sequence have achieved remarkable success in protein-protein interface prediction. However, extending these methods to protein-peptide interactions remains challenging due to the inherent conformational flexibility of peptides and the limited availability of structural data that hinders direct training of structure-aware models. To address these limitations, we introduce GeoPep, a novel framework for peptide binding site prediction that leverages transfer learning from ESM3, a multimodal protein foundation model. GeoPep fine-tunes ESM3's rich prelearned representations from protein-protein binding to address the limited availability of protein-peptide binding data. The fine-tuned model is further integrated with a Kolmogorov-Arnold Network (KAN)-based architecture for complex nonlinear approximation. Furthermore, the model is trained using distance-based loss functions that exploit 3D structural information to enhance binding site prediction. Comprehensive evaluations demonstrate that GeoPep significantly outperforms existing methods in protein-peptide binding site prediction by effectively capturing sparse and heterogeneous binding patterns.