Generalizing the Gaussian Network Model: Spanning-Tree Thermodynamics Shows Entropy-Driven KRAS Activation
Fatma Senguler Ciftci1, Burak Erman1
1Department of Chemical and Biological Engineering, Koç University, Istanbul, Turkey.
Proteins
|June 8, 2026
Summary
This study reveals how KRAS protein switches between active and inactive states. It uses a new statistical model to show that the active state gains flexibility through entropy, driven by network changes in Switch I.
Area of Science:
- Biophysics
- Computational Biology
- Structural Biology
Background:
- The GTPase KRAS protein switches between active (GTP-bound) and inactive (GDP-bound) states, a critical process in oncogenic signaling.
- Traditional binary models incompletely characterize the residue-contact organization underlying this conformational switch.
Purpose of the Study:
- To develop a generalized statistical-mechanical model for analyzing KRAS conformational switching.
- To investigate the thermodynamic and topological basis of KRAS allostery and its functional versatility.
Main Methods:
- Generalized the Gaussian Network Model (GNM) using spanning-tree partition functions and the weighted Kirchhoff Laplacian.
- Employed the Matrix-Tree Theorem for network analysis.
- Computed thermodynamic properties (free energy, mean contact energy, heat capacity, entropy) across an effective temperature sweep.
Main Results:
- The generalized GNM framework enables continuous Boltzmann-weighted ensemble analysis.
- KRAS activation involves an entropy-enthalpy compensation mechanism, with the active state having higher conformational entropy.
- Switch I (residues 25-40) was identified as the key allosteric site for nucleotide-driven network reorganization.
Conclusions:
- The study provides a thermodynamically grounded perspective on KRAS allostery.
- Network architecture enables KRAS functional versatility through entropy-driven conformational flexibility.
- The developed model offers a powerful tool for probing topological landscapes in protein dynamics.
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