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Updated: Jun 8, 2025

Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes
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Non-Markovian Dynamic Models Identify Non-Canonical KRAS-VHL Encounter Complex Conformations for Novel PROTAC Design.

Yunrui Qiu1,2, Rafal P Wiewiora3, Jesus A Izaguirre4

  • 1Department of Chemistry, Theoretical Chemistry Institute, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.

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Summary

A new computational protocol predicts protein-protein interactions for designing Proteolysis Targeting Chimeras (PROTACs). This method aids in developing novel linkers to stabilize ternary complexes and enhance targeted protein degradation for cancer therapies.

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Area of Science:

  • Biochemistry and Structural Biology
  • Computational Chemistry and Drug Design
  • Oncology and Molecular Therapeutics

Background:

  • Targeted protein degradation (TPD) is a promising therapeutic strategy, with Proteolysis Targeting Chimeras (PROTACs) showing significant clinical potential.
  • PROTACs function by hijacking the cell's ubiquitin-proteasome system to degrade specific proteins of interest (POIs).
  • Designing effective PROTACs requires optimizing the linker to stabilize the ternary complex between the POI and the E3 ligase.

Purpose of the Study:

  • To develop a physics-based computational protocol for predicting noncanonical and metastable protein-protein interaction (PPI) interfaces between E3 ligases and POIs.
  • To aid in the rational design of linkers for PROTACs that stabilize the ternary complex and enhance targeted protein degradation.
  • To explore inherent PPIs between an oncogene homologue and the von Hippel-Lindau E3 ligase.

Main Methods:

  • Utilized a non-Markovian dynamic model based on the Integrative Generalized Master Equation (IGME) method.
  • Performed all-atom molecular dynamics simulations (∼1.5 ms) of linker-less encounter complexes.
  • Systematically explored and identified metastable states representing different PPI interfaces.

Main Results:

  • The computational protocol predicted six distinct metastable states with unique PPI interfaces.
  • Three promising metastable states were selected based on thermodynamic/kinetic stability and accessibility for linker design.
  • One predicted PPI interface closely matched a recently determined cocrystal structure from an effective PROTAC.

Conclusions:

  • The developed physics-based protocol can predict metastable POI-E3 ligase interfaces crucial for PROTAC design.
  • This approach facilitates the rational design of linkers to stabilize ternary complexes and improve degradation efficiency.
  • The protocol holds significant potential for advancing the development of novel PROTAC-based therapeutics.