Spectral decomposition of human BCL2 bonded to a PROTAC

Wietske J. Nauta; Christophe de Graaf; Yentl Meul; Kris Vissenberg; Sébastjen Schoenaers; Ana V. Cunha

doi:10.1063/5.0288378

Spectral decomposition of human BCL2 bonded to a PROTAC

Wietske J. Nauta
, Christophe de Graaf
, Yentl Meul
, Kris Vissenberg
, Sébastjen Schoenaers
, Ana V. Cunha

Advanced Computing for Chemistry and Mat

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

1 Scopus citations

Abstract

In this study, we have decomposed the linear infrared spectra and two-dimensional infrared spectroscopy of a VHL-recruiting Proteolysis-targeting chimera (PROTAC) complex with BCL-2 to understand the spectral signatures of this complex. Our findings show that both VHL and BCL-2 units have distinct spectral signatures that contribute to the total spectra in different regions. Furthermore, we observed that the interaction between VHL and BCL-2 within the PROTAC complex leads to unique spectral features, indicating a strong synergistic effect. Through detailed analysis, specific bands were identified that correspond to the vibrational modes of the individual components, as well as their interactive modes within the complex. This study provides valuable insight into the molecular interactions within the PROTAC complex, offering a deeper understanding of its structure and function. These insights could be pivotal in designing more efficient PROTACs for targeted protein degradation in therapeutic applications.

Original language	English
Article number	225101
Journal	Journal of Chemical Physics
Volume	163
Issue number	22
DOIs	https://doi.org/10.1063/5.0288378
State	Published - Dec 14 2025

Funding

This work was sponsored by NWO Exact and Natural Sciences for the use of supercomputer facilities (Contract No. NWO2022.004), and we thank S. Dolas (SURF, NL) for allowing us to perform calculations on the experimental AMD platform kleurplaat maintained and operated by the SURF Open Innovation Lab. Y.M., S.S., and K.V. were supported by a Ph.D. fellowship and Grant No. G013023N of the Research Foundation Flanders (FWO Vlaanderen), respectively. This manuscript has been authored by UT-Battelle, LLC, under Contract No. DE-AC05-00OR22725 with the U.S. Department of Energy (DOE). The U.S. government retains, and the publisher, by accepting the article for publication, acknowledges that the U.S. government retains, a nonexclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this manuscript, or allow others to do so, for U.S. government purposes. DOE will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan (https://www.energy.gov/doe-publicaccess-plan). This work was sponsored by NWO Exact and Natural Sciences for the use of supercomputer facilities (Contract No. NWO-2022.004), and we thank S. Dolas (SURF, NL) for allowing us to perform calculations on the experimental AMD platform kleurplaat maintained and operated by the SURF Open Innovation Lab. Y.M., S.S., and K.V. were supported by a Ph.D. fellowship and Grant No. G013023N of the Research Foundation Flanders (FWO Vlaanderen), respectively. This manuscript has been authored by UT-Battelle, LLC, under Contract No. DE-AC05-00OR22725 with the U.S. Department of Energy (DOE). The U.S. government retains, and the publisher, by accepting the article for publication, acknowledges that the U.S. government retains, a nonexclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this manuscript, or allow others to do so, for U.S. government purposes. DOE will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan ( https://www.energy.gov/doe-public-access-plan ).

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title = "Spectral decomposition of human BCL2 bonded to a PROTAC",

abstract = "In this study, we have decomposed the linear infrared spectra and two-dimensional infrared spectroscopy of a VHL-recruiting Proteolysis-targeting chimera (PROTAC) complex with BCL-2 to understand the spectral signatures of this complex. Our findings show that both VHL and BCL-2 units have distinct spectral signatures that contribute to the total spectra in different regions. Furthermore, we observed that the interaction between VHL and BCL-2 within the PROTAC complex leads to unique spectral features, indicating a strong synergistic effect. Through detailed analysis, specific bands were identified that correspond to the vibrational modes of the individual components, as well as their interactive modes within the complex. This study provides valuable insight into the molecular interactions within the PROTAC complex, offering a deeper understanding of its structure and function. These insights could be pivotal in designing more efficient PROTACs for targeted protein degradation in therapeutic applications.",

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AU - Nauta, Wietske J.

AU - de Graaf, Christophe

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AU - Cunha, Ana V.

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AB - In this study, we have decomposed the linear infrared spectra and two-dimensional infrared spectroscopy of a VHL-recruiting Proteolysis-targeting chimera (PROTAC) complex with BCL-2 to understand the spectral signatures of this complex. Our findings show that both VHL and BCL-2 units have distinct spectral signatures that contribute to the total spectra in different regions. Furthermore, we observed that the interaction between VHL and BCL-2 within the PROTAC complex leads to unique spectral features, indicating a strong synergistic effect. Through detailed analysis, specific bands were identified that correspond to the vibrational modes of the individual components, as well as their interactive modes within the complex. This study provides valuable insight into the molecular interactions within the PROTAC complex, offering a deeper understanding of its structure and function. These insights could be pivotal in designing more efficient PROTACs for targeted protein degradation in therapeutic applications.

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Spectral decomposition of human BCL2 bonded to a PROTAC

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