Construction of PROTAC-Mediated Ternary Complex Structure Distribution Profiles Using Extensive Conformational Search
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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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Cites
Markov state models of biomolecular conformational dynamics
Chodera, J. D., & Noé, F. (2014) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2014.04.002 · Cited by 776 · see citing works
Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?
Churcher, I. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01272 · Cited by 491 · see citing works
Current strategies for the design of PROTAC linkers: a critical review
Troup, R. I., Fallan, C., & Baud, M. G. J. (2020) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2020.00018 · Cited by 424 · see citing works
PRosettaC: Rosetta Based Modeling of PROTAC Mediated Ternary Complexes
Zaidman, D., Prilusky, J., & London, N. (2020) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.0c00589 · Cited by 224 · see citing works
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- Authors
- Kudo, G., Hirao, T., Harada, R., Shigeta, Y., Hirokawa, T., & Yoshino, R.
- Affiliations
- University of Tsukuba (JP)
- Corresponding author
- Yoshino, Ryunosuke
- Venue
- Journal of Chemical Information and Modeling
- Publisher
- American Chemical Society (ACS)
- Published
- 2025-06-23
- Volume
- 65
- Issue
- 13
- Pages
- 6939-6948
- ISSN
- 1549-9596 (ISSN-L)
- 1549-960X
- PMC
- PMC12264966
- OpenAlex
- W4411545881
- Cited by
- 18
- References
- 4
- Citations by year
- 2026: 14 · 2025: 4
- FWCI
- 5.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Chemical Information and Modeling (publishedVersion, cc-by-nc-nd)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (JPMXP1020230120)
- Japan Agency for Medical Research and Development (JP24ama121029j0003)
- Japan Society for the Promotion of Science (JP23H02427, JP23H04879, JP23K16987, JP23K18033)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- PROTACs, ternary complex, E3 ubiquitin ligase, protein degradation, linker length, conformational search, Markov state models, PROTAC design
- MeSH terms
- Markov Chains, Protein Conformation, Ubiquitin-Protein Ligases, Small Molecule Libraries, Ubiquitination, Molecular Dynamics Simulation, Proteolysis
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