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Updated: Aug 7, 2025
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Comparing the Affinity of GTPase-binding Proteins using Competition Assays
Published on: October 8, 2015
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Classification of GTP-dependent K-Ras4B active and inactive conformational states
Brajesh Narayan1, Christina Kiel2, Nicolae-Viorel Buchete1
1School of Physics, University College Dublin, Belfield, Dublin 4, Ireland.
The Journal of Chemical Physics
|March 8, 2023
Summary
Understanding oncogenic protein K-Ras4B
Area of Science:
- Molecular biology
- Computational chemistry
- Cancer research
Background:
- Reliably classifying active/inactive protein conformations is crucial for cancer studies.
- K-Ras4B oncogenic protein dynamics are key to its activity.
- Existing methods struggle with accurate conformational classification.
Purpose of the Study:
- To investigate GTP-bound K-Ras4B conformational dynamics.
- To develop improved methods for assessing protein activation propensities.
- To understand mutation effects on K-Ras4B activity and binding.
Main Methods:
- Long-time atomistic molecular dynamics (MD) simulations.
- Free energy landscape analysis.
- Development of novel reaction coordinates.
- Hybrid MD-docking modeling.
Main Results:
- Identified a complex network of K-Ras4B equilibrium states.
- Introduced a new reaction coordinate accounting for sidechain orientation (e.g., D38).
- Explained how mutation D33E alters activation propensities.
- Revealed modulation of salt bridges at the K-Ras4B-RAF1 interface.
Conclusions:
- A new reaction coordinate is essential for accurate K-Ras4B conformational analysis.
- Residue interactions at the K-Ras4B-RAF1 interface critically influence activation.
- The hybrid MD-docking approach facilitates in silico drug design for cancer.
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