Interplay of PROTAC Complex Dynamics for Undruggable Targets: Insights into Ternary Complex Behavior and Linker Design.

Protein degraders, such as bifunctional proteolysis-targeting chimeras (PROTACs), selectively eliminate target proteins by leveraging the natural protein degradation machinery. PROTACs bridge the target protein with an E3 ligase, which induces ubiquitination and degradation. Investigating ternary complex structures elucidates the molecular mechanisms of their formation and degradation. This study examines the binding dynamics of E3 ligases (VHL, CRBN, and cIAP) with proteins of interest, focusing on dynamics, cooperativity, selectivity, linker length, and PROTAC conformations. The influence of interface residues and linker lengths on specific conformations for target proteins and E3 ligases is highlighted. Utilizing molecular dynamics and steered molecular dynamics simulations, the study provides comprehensive parameters on the behavior and stability of diverse ternary complexes. These insights are crucial for designing PROTACs targeting disease-causing proteins and advancing the development of degradable ternary complexes for therapeutic applications.