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Updated: Jun 25, 2026
09:17
Structure-Based Simulation and Sampling of Transcription Factor Protein Movements along DNA from Atomic-Scale Stepping to Coarse-Grained Diffusion
Published on: March 1, 2022
Mapping the conformational transition in Src activation by cumulating the information from multiple molecular
Sichun Yang1, Nilesh K Banavali, Benoît Roux
1Department of Biochemistry and Molecular Biology, University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
Summary
Src-family kinases, like Hck, regulate cell growth by switching between inactive and active states. Computational analysis reveals intermediate conformations during activation, crucial for understanding kinase function.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Biology
Background:
- Src-family kinases are critical allosteric enzymes regulating cell growth and proliferation.
- These enzymes transition between inactive and active states via significant conformational changes.
- Understanding these dynamic transitions is key to deciphering kinase regulation.
Purpose of the Study:
- To computationally characterize the conformational transition pathway between inactive and active states of the Hck kinase domain.
- To identify and structurally characterize intermediate states during kinase activation.
- To build a free-energy landscape of the activation process.
Main Methods:
- Utilized 78 all-atom molecular dynamics trajectories with explicit solvent.
- Assembled a connectivity map of conformational transitions.
- Constructed a coarse free-energy landscape based on collective motions.
Main Results:
- Identified two intermediate conformational states during Hck activation.
- Characterized structural features of these intermediates, including partially open A-loop and specific alphaC helix orientations.
- Revealed that full activation requires concerted movements of the A-loop, N-lobe/C-lobe alignment, and alphaC helix rotation.
Conclusions:
- The study provides a dynamic model for full-length kinase activation.
- Intermediate states with partially open A-loops are permitted before full activation.
- These findings offer a framework for understanding kinase conformational dynamics and activation mechanisms.
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