Pocket-PROTACs: an interpretable pocket-aware deep learning framework for predicting PROTAC-induced protein degradation.

Abstract

Proteolysis-targeting chimeras (PROTACs) enable targeted protein degradation by recruiting an E3 ubiquitin ligase to a protein of interest (POI) and forming a ternary complex. Despite their therapeutic promise, rational PROTAC design remains challenging, as degradation efficacy depends on subtle and highly structure-dependent interactions among the POI, the E3 ligase, and the bifunctional molecule. We propose Pocket-PROTACs, a pocket-aware attention-based framework for predicting PROTAC-induced protein degradation from a triplet of POI, E3 ligase, and PROTAC. Pocket-PROTACs encodes protein sequences using a pre-trained protein language model and represents PROTACs with a geometry-aware graph neural network over an ensemble of three-dimensional conformers. Both POI-PROTAC and E3 ligase-PROTAC interactions are explicitly modeled through a residue-atom cross-attention mechanism that captures fine-grained interaction patterns. To improve model interpretability, we introduce a pocket-aware module that incorporates structural context to guide residue-level relevance estimation, enabling multi-level attribution analysis. Experiments on two benchmark datasets show that Pocket-PROTACs consistently outperforms fingerprint-based baselines and recent deep learning methods. The learned relevance maps highlight localized interaction patterns on both the POI and the E3 ligase that are qualitatively consistent with known pocket-level features. A case study on kelch domain containing 2 (KLHDC2)-engaging bromodomain and extra-terminal domain (BET) PROTACs further demonstrates that our model accurately predicts degradation behavior and provides biologically meaningful, attention-based interpretations, offering practical support for PROTAC design and experimental investigation. Source code and datasets are available at https://github.com/Adochew/Pocket-PROTACs.