Spectral decomposition of human BCL2 bonded to a PROTAC
Wietske J Nauta1, Christophe de Graaf2, Yentl Meul3
1Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 3, 9747 AG Groningen, The Netherlands.
The Journal of Chemical Physics
|December 9, 2025
Summary
This study used infrared spectroscopy to analyze a VHL-recruiting Proteolysis-targeting chimera (PROTAC) complexed with BCL-2. Distinct spectral signatures reveal synergistic interactions crucial for designing targeted protein degradation therapies.
Area of Science:
- Molecular Spectroscopy
- Biochemistry
- Chemical Biology
Background:
- Proteolysis-targeting chimeras (PROTACs) are emerging therapeutics for targeted protein degradation.
- Understanding the molecular interactions within PROTAC complexes is key to optimizing their efficacy.
- VHL-recruiting PROTACs targeting BCL-2 are of significant therapeutic interest.
Purpose of the Study:
- To elucidate the spectral signatures of a VHL-recruiting PROTAC complexed with BCL-2 using vibrational spectroscopy.
- To identify distinct spectral contributions from VHL and BCL-2 components.
- To characterize the synergistic effects and molecular interactions within the PROTAC complex.
Main Methods:
- Linear infrared (IR) spectroscopy.
- Two-dimensional infrared (2D-IR) spectroscopy.
- Decomposition analysis of spectral data.
Main Results:
- VHL and BCL-2 units exhibit unique spectral signatures.
- The PROTAC complex formation results in distinct spectral features indicative of synergistic interactions.
- Specific vibrational modes corresponding to individual components and their interactions were identified.
Conclusions:
- Vibrational spectroscopy effectively characterizes molecular interactions in PROTAC complexes.
- The findings provide fundamental insights into the structure-function relationship of VHL-BCL-2 PROTACs.
- This knowledge can guide the rational design of enhanced PROTACs for therapeutic applications.
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