Exploring PROTAC Cooperativity with Coarse-Grained Alchemical Methods.

Area of Science:

• Biochemistry
• Computational Chemistry
• Drug Discovery

Background:

• Proteolysis targeting chimeras (PROTACs) are an emerging drug modality.
• PROTACs function by inducing proximity between a target protein and an E3 ligase for targeted protein degradation.
• Understanding the biophysical drivers of PROTAC-E3 and PROTAC-target interactions is crucial for optimizing drug efficacy.

Purpose of the Study:

• To develop a computational framework for modeling cooperativity in PROTAC-E3 and PROTAC-target binding.
• To elucidate the physical and chemical drivers of non-native protein-protein interactions (PPIs) induced by PROTACs.
• To investigate the influence of PROTAC structure, specifically linker length, on binding cooperativity.

Main Methods:

• Development of a coarse-grained (CG) computational approach to model interactions within target-PROTAC-E3 complexes.
• Application of alchemical free energy calculations for thermodynamic estimations.
• Qualitative characterization of cooperativity dependence on linker length, protein charge, and shape.

Main Results:

• The CG model successfully captures fundamental principles of cooperativity, including the impact of configurational entropy on optimal PROTAC linker lengths.
• The study qualitatively characterizes how PROTAC linker length, protein charge, and shape influence binding cooperativity.
• The computational framework enables converged thermodynamic estimations despite unconventional scales of perturbation.

Conclusions:

• The developed CG model provides insights into the physical basis of PROTAC cooperativity.
• Optimizing PROTAC linker length is critical for maximizing protein degradation efficiency.
• Further development of the CG model holds potential for computational screening and optimization of PROTAC-based therapeutics.