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Comparing PAS domain-coupled intrinsic dynamics in bHLH-PAS domain transcription factor complexes
Karthik Sudarsanam1, Ashutosh Srivastava1, Sandhya P Tiwari2
1Department of Biological Sciences and Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar, Gujarat, India.
Biophysical Journal
|November 2, 2025
Summary
Basic helix-loop-helix Per-Arnt-Sim (bHLH-PAS) transcription factors
Area of Science:
- Molecular Biology
- Biophysics
- Structural Biology
Background:
- Basic helix-loop-helix Per-Arnt-Sim (bHLH-PAS) transcription factors regulate vital cellular processes.
- PAS domains, while structurally conserved, exhibit distinct interaction interfaces in different TF complexes.
- The impact of these interface differences on PAS domain dynamics is not well understood.
Purpose of the Study:
- To comparatively analyze PAS domain dynamics across various bHLH-PAS TF complexes.
- To investigate how intrinsic dynamics are influenced by both internal architecture and partner protein interactions.
- To explore the functional diversification of bHLH-PAS TFs through their dynamic properties.
Main Methods:
- All-atom elastic network model (ENM)-based normal mode analysis.
- Molecular dynamics simulations.
- Domain-domain coupled motions analysis using a projection-based approach.
Main Results:
- Self-coupled motions in PAS domains are more conserved than sequence or structure alone.
- Directly coupled motions reflect context-specific partner protein influences.
- Hierarchical clustering revealed distinct dynamic groupings for CLOCK:BMAL1-type and HIF:ARNT-type complexes, not evident from sequence/structure.
- PAS-B domains are generally less flexible than PAS-A domains.
- High directly coupled flexibility in PAS-B domains suggests coupled dynamics at interaction interfaces.
Conclusions:
- PAS domain dynamics are shaped by intrinsic architecture and complex-specific interactions.
- ENMs and coupled motions analysis effectively capture biologically relevant dynamics, even for AlphaFold3-modeled structures.
- Distinct dynamic profiles contribute to the functional diversification of bHLH-PAS transcription factors.
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