Quantum Mechanics-Based Ranking of Predicted Proteolysis Targeting Chimeras-Mediated Ternary Complexes.

Area of Science:

• Biochemistry
• Computational Chemistry
• Drug Discovery

Background:

• Targeted protein degradation is a key therapeutic strategy, with proteolysis-targeting chimeras (PROTACs) emerging as a promising modality.
• PROTACs are bivalent molecules designed to induce the degradation of specific target proteins, offering an alternative to traditional inhibition.

Purpose of the Study:

• To describe a combined computational protocol for modeling ternary complexes formed by PROTACs, target proteins, and E3 ligases.
• To enable accurate prediction and selection of optimal PROTAC-bound ternary complex conformations.

Main Methods:

• Utilized Rosetta for local protein-protein docking to model interactions between target proteins and E3 ligases.
• Sampled PROTAC conformational landscapes compatible with docking poses and employed clustering for representative selection.
• Integrated fragment molecular orbital and density functional tight-binding methods for rapid quantum mechanics-based energy calculations.
• Scored and selected optimal ternary poses based on computed energy values.

Main Results:

• Developed a computational workflow for modeling PROTAC-induced ternary complexes.
• Achieved good agreement between computed energy-based scoring and available crystallographic data.
• Demonstrated the utility of the protocol in selecting accurate ternary complex poses.

Conclusions:

• The presented computational protocol provides an effective method for modeling PROTAC-ternary complexes.
• This approach can aid in the rational design and optimization of PROTACs for targeted protein degradation.
• The findings support the advancement of PROTAC technology in drug discovery.