Decoding The Conformational Plasticity Of Ternary Complexes For Protacs' Differential Activity Based On Long Term MD Simulation And QM Based Studies

By Ashis Nandy, Kiran Boppana, Samiron Phukan, Simon Haydar Integrated Drug Discovery, Aragen Lifesciences Ltd., 125 & 126 IDA Mallapur, Hyderabad, India

Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) has emerged as a powerful therapeutic modality for addressing previously “undruggable” targets. The mechanism of PROTAC-induced degradation relies on the formation of a productive ternary complex, the stability and activity of which are strongly influenced by its inherent plasticity.

In this work, we employed long-term molecular dynamics (MD) simulations (500 ns) to investigate how ternary complex flexibility contributes to differential activity. Specifically, we analyzed two representative complexes — FAK–VHL and BTK–CRBN — to elucidate the structural and dynamic factors underlying their behavior. In addition, quantum mechanical (QM) calculations were performed to further probe the differential stability of these PROTAC-mediated ternary complexes.

Together, these studies provide deeper mechanistic insights into how ternary complex plasticity governs PROTAC activity, thereby informing the design of next-generation degraders for therapeutic applications.