Benchmarking Methods for PROTAC Ternary Complex Structure Prediction.

Area of Science:

• Computational chemistry and structural biology
• Drug discovery and molecular design

Background:

• Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce target protein degradation via ubiquitination.
• Accurate structural models of PROTAC ternary complexes are crucial for rational drug design and optimization.
• In the absence of experimental structures, computational methods are employed to predict these ternary complexes.

Purpose of the Study:

• To systematically benchmark the performance of three commonly used computational tools (PRosettaC, MOE, and ICM) for predicting PROTAC ternary complex structures.
• To evaluate the accuracy and reliability of these tools in generating models that reflect experimentally observed structures.
• To assess the conformational flexibility of PROTAC ternary complexes using molecular dynamics simulations.

Main Methods:

• Systematic benchmarking of PRosettaC, MOE, and ICM using a defined dataset.
• Generation of multiple ternary complex structures for each PROTAC.
• Molecular dynamics (MD) simulations to explore conformational landscapes.

Main Results:

• The evaluated computational tools generated diverse ternary complex structures, with some aligning with experimental data and others deviating significantly.
• Molecular dynamics simulations indicated that PROTAC complexes can exist in multiple configurational states.
• The study questions the sole reliance on experimentally observed structures as a definitive reference for computational predictions.

Conclusions:

• Current computational tools for PROTAC ternary complex modeling offer valuable insights but face challenges in accuracy and conformational representation.
• PROTAC complex structures may be more dynamic than typically represented by single experimental snapshots.
• Future computational efforts should integrate structural and biophysical data, and the provided benchmarking dataset can aid in evaluating new tools.