PRosettaC

PRosettaC predicts ternary protein–PROTAC–E3 ligase complex structures to provide structural models for rational design and optimization of PROTAC molecules.

Key Features:

• Ternary Complex Prediction: Predicts the structure of ternary complexes with high accuracy, often achieving atomic-level precision.
• Benchmarking Success: Benchmarked against ten known ternary complex crystal structures, successfully predicting six to atomic accuracy within one of the top three clusters.
• Input Requirements: Requires two protein structures (the target protein and E3 ligase) with their respective ligands and the PROTAC chemical structure provided in SMILES format.
• Output Models: Outputs detailed models of the predicted ternary complex including modeled protein chains and PROTAC binding moieties.

Scientific Applications:

• Rational Design: Provides structural models of ternary complexes to inform rational design strategies for new PROTACs.
• Optimization: Aids refinement of existing PROTAC molecules to enhance efficacy and specificity.
• Time and Resource Efficiency: Offers predictive insights into complex formation that can reduce time and resources required for experimental synthesis.
• CRBN/BTK Modeling: Applied to model a CRBN/BTK complex, aligning with experimental results across various PROTACs.

Methodology:

Alternates sampling the conformational space of protein–protein interactions and the PROTAC molecule (dual-space exploration) to generate near-native predictions modeling both protein chains and PROTAC binding moieties.