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Construction of PROTAC-Mediated Ternary Complex Structure Distribution Profiles Using Extensive Conformational

Genki Kudo1, Takumi Hirao2,3, Ryuhei Harada4

  • 1Physics Department, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.

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|June 23, 2025
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Summary

Proteolysis-targeting chimeras (PROTACs) are molecules that degrade target proteins. Linker length significantly impacts PROTACs' conformational dynamics and degradation efficiency, guiding rational drug design.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules.
  • PROTACs recruit E3 ubiquitin ligases to target proteins for ubiquitination and degradation.
  • The structural dynamics of PROTAC-mediated ternary complex formation and degradation efficiency are not fully understood.

Purpose of the Study:

  • To investigate the impact of linker length on PROTAC conformational dynamics.
  • To elucidate the relationship between PROTAC structure and degradation activity.
  • To provide mechanistic insights for rational PROTAC design.

Main Methods:

  • Employed parallel cascade selection molecular dynamics (PaCS-MD) and outlier flooding (OFLOOD) for extensive conformational searching.
  • Utilized Markov state models to analyze conformational landscapes.
  • Studied PROTACs with varying linker lengths.

Main Results:

  • All PROTACs explored shared a common low free-energy state.
  • Significant differences in structural distribution profiles were observed based on linker length.
  • Linker-dependent conformational profiles were found to modulate degradation activity and cooperativity.

Conclusions:

  • PROTAC linker length critically influences conformational dynamics.
  • Understanding these dynamics is key to optimizing PROTAC-mediated protein degradation.
  • This study offers valuable insights for the rational design of more effective PROTACs.