2. Academic Validation
  3. Construction of PROTAC-Mediated Ternary Complex Structure Distribution Profiles Using Extensive Conformational Search

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

  • J Chem Inf Model. 2025 Jul 14;65(13):6939-6948. doi: 10.1021/acs.jcim.5c00102.
Genki Kudo 1,  Takumi Hirao 2 3,  Ryuhei Harada 4,  Yasuteru Shigeta 4,  Takatsugu Hirokawa 3 5,  Ryunosuke Yoshino 3 5
Affiliations

Affiliations

  • 1 Physics Department, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
  • 2 Doctoral Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
  • 3 Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
  • 4 Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
  • 5 Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
PMID: 40550492 DOI: 10.1021/acs.jcim.5c00102
Abstract

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional small molecules that recruit E3 ubiquitin ligases to a target protein and induce its ubiquitination by forming a ternary complex. However, the structural dynamics underlying the complex formation and degradation efficiency remain unclear. In this study, we attempted an extensive conformational search using the parallel cascade selection molecular dynamics (PaCS-MD) and outlier flooding (OFLOOD) method for PROTACs differing in linker length. Markov state models revealed that while all PROTACs share a common low free-energy state, their structural distribution profiles differ significantly. These results suggest that linker-dependent conformational distribution profiles modulate degradation activity and cooperativity, offering mechanistic insights into rational PROTAC design.

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