Frustration in the protein-protein interface plays a central role in the cooperativity of PROTAC ternary complexes

Ning Ma; Supriyo Bhattacharya; Sanychen Muk; Zuzana Jandova; Philipp S. Schmalhorst; Soumadwip Ghosh; Keith Le; Emelyne Diers; Nicole Trainor; William Farnaby; Michael J. Roy; Christiane Kofink; Peter Greb; Harald Weinstabl; Alessio Ciulli; Gerd Bader; Kyra Sankar; Andreas Bergner; Nagarajan Vaidehi

doi:10.1038/s41467-025-63713-7

Frustration in the protein-protein interface plays a central role in the cooperativity of PROTAC ternary complexes

Ning Ma
, Supriyo Bhattacharya
, Sanychen Muk
, Zuzana Jandova
, Philipp S. Schmalhorst
, Soumadwip Ghosh
, Keith Le
, Emelyne Diers
, Nicole Trainor
, William Farnaby
, Michael J. Roy
, Christiane Kofink
, Peter Greb
, Harald Weinstabl
, Alessio Ciulli
, Gerd Bader
, Kyra Sankar
, Andreas Bergner (Lead / Corresponding author)
, Nagarajan Vaidehi

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

73 Downloads (Pure)

Abstract

Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) offers a promising strategy to eliminate previously undruggable proteins. PROTACs are bifunctional molecules that link a target protein with an E3 ubiquitin ligase, enabling the formation of a ternary complex that promotes ubiquitination and subsequent proteasomal degradation. Although many ternary complex structures are available, understanding how structural features relate to PROTAC function remains challenging due to the dynamic nature of these complexes. Here we show that the interface between the target protein SMARCA2 and the E3 ligase VHL is conformationally flexible and stabilized by interactions involving disordered loops. Using molecular dynamics simulations and X-ray crystallography of SMARCA2–VHL complexes bound to five different PROTACs, we find that interfacial residues often adopt energetically suboptimal, or ‘frustrated,’ configurations. We further show that the degree of frustration correlates with experimentally measured cooperativity for a set of 11 PROTACs. These findings suggest that quantifying interface frustration provides a rational, structure-based approach to guiding PROTAC design.

Original language	English
Article number	8595
Journal	Nature Communications
Volume	16
Issue number	1
Early online date	29 Sept 2025
DOIs	https://doi.org/10.1038/s41467-025-63713-7
Publication status	Published - Dec 2025

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General
General Physics and Astronomy

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Cite this

Ma, N., Bhattacharya, S., Muk, S., Jandova, Z., Schmalhorst, P. S., Ghosh, S., Le, K., Diers, E., Trainor, N., Farnaby, W., Roy, M. J., Kofink, C., Greb, P., Weinstabl, H., Ciulli, A., Bader, G., Sankar, K., Bergner, A., & Vaidehi, N. (2025). Frustration in the protein-protein interface plays a central role in the cooperativity of PROTAC ternary complexes. Nature Communications, 16(1), Article 8595. https://doi.org/10.1038/s41467-025-63713-7

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abstract = "Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) offers a promising strategy to eliminate previously undruggable proteins. PROTACs are bifunctional molecules that link a target protein with an E3 ubiquitin ligase, enabling the formation of a ternary complex that promotes ubiquitination and subsequent proteasomal degradation. Although many ternary complex structures are available, understanding how structural features relate to PROTAC function remains challenging due to the dynamic nature of these complexes. Here we show that the interface between the target protein SMARCA2 and the E3 ligase VHL is conformationally flexible and stabilized by interactions involving disordered loops. Using molecular dynamics simulations and X-ray crystallography of SMARCA2{\textendash}VHL complexes bound to five different PROTACs, we find that interfacial residues often adopt energetically suboptimal, or {\textquoteleft}frustrated,{\textquoteright} configurations. We further show that the degree of frustration correlates with experimentally measured cooperativity for a set of 11 PROTACs. These findings suggest that quantifying interface frustration provides a rational, structure-based approach to guiding PROTAC design.",

author = "Ning Ma and Supriyo Bhattacharya and Sanychen Muk and Zuzana Jandova and Schmalhorst, \{Philipp S.\} and Soumadwip Ghosh and Keith Le and Emelyne Diers and Nicole Trainor and William Farnaby and Roy, \{Michael J.\} and Christiane Kofink and Peter Greb and Harald Weinstabl and Alessio Ciulli and Gerd Bader and Kyra Sankar and Andreas Bergner and Nagarajan Vaidehi",

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doi = "10.1038/s41467-025-63713-7",

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Ma, N, Bhattacharya, S, Muk, S, Jandova, Z, Schmalhorst, PS, Ghosh, S, Le, K, Diers, E, Trainor, N, Farnaby, W, Roy, MJ, Kofink, C, Greb, P, Weinstabl, H, Ciulli, A, Bader, G, Sankar, K, Bergner, A & Vaidehi, N 2025, 'Frustration in the protein-protein interface plays a central role in the cooperativity of PROTAC ternary complexes', Nature Communications, vol. 16, no. 1, 8595. https://doi.org/10.1038/s41467-025-63713-7

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AU - Ma, Ning

AU - Bhattacharya, Supriyo

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AU - Schmalhorst, Philipp S.

AU - Ghosh, Soumadwip

AU - Le, Keith

AU - Diers, Emelyne

AU - Trainor, Nicole

AU - Farnaby, William

AU - Roy, Michael J.

AU - Kofink, Christiane

AU - Greb, Peter

AU - Weinstabl, Harald

AU - Ciulli, Alessio

AU - Bader, Gerd

AU - Sankar, Kyra

AU - Bergner, Andreas

AU - Vaidehi, Nagarajan

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N2 - Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) offers a promising strategy to eliminate previously undruggable proteins. PROTACs are bifunctional molecules that link a target protein with an E3 ubiquitin ligase, enabling the formation of a ternary complex that promotes ubiquitination and subsequent proteasomal degradation. Although many ternary complex structures are available, understanding how structural features relate to PROTAC function remains challenging due to the dynamic nature of these complexes. Here we show that the interface between the target protein SMARCA2 and the E3 ligase VHL is conformationally flexible and stabilized by interactions involving disordered loops. Using molecular dynamics simulations and X-ray crystallography of SMARCA2–VHL complexes bound to five different PROTACs, we find that interfacial residues often adopt energetically suboptimal, or ‘frustrated,’ configurations. We further show that the degree of frustration correlates with experimentally measured cooperativity for a set of 11 PROTACs. These findings suggest that quantifying interface frustration provides a rational, structure-based approach to guiding PROTAC design.

AB - Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) offers a promising strategy to eliminate previously undruggable proteins. PROTACs are bifunctional molecules that link a target protein with an E3 ubiquitin ligase, enabling the formation of a ternary complex that promotes ubiquitination and subsequent proteasomal degradation. Although many ternary complex structures are available, understanding how structural features relate to PROTAC function remains challenging due to the dynamic nature of these complexes. Here we show that the interface between the target protein SMARCA2 and the E3 ligase VHL is conformationally flexible and stabilized by interactions involving disordered loops. Using molecular dynamics simulations and X-ray crystallography of SMARCA2–VHL complexes bound to five different PROTACs, we find that interfacial residues often adopt energetically suboptimal, or ‘frustrated,’ configurations. We further show that the degree of frustration correlates with experimentally measured cooperativity for a set of 11 PROTACs. These findings suggest that quantifying interface frustration provides a rational, structure-based approach to guiding PROTAC design.

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Frustration in the protein-protein interface plays a central role in the cooperativity of PROTAC ternary complexes

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A Translational Engine for Biomedical Discoveries (Strategic Grant)

State-of-the-Art Facilities for Structural Biology at the University of Dundee

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Frustration in the protein-protein interface plays a central role in the cooperativity of PROTAC ternary complexes

Abstract

ASJC Scopus subject areas

Access to Document

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A Translational Engine for Biomedical Discoveries (Strategic Grant)

State-of-the-Art Facilities for Structural Biology at the University of Dundee

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