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Comparing Enhanced Sampling Methods in Exploring the Conformational Space of β-Catenin17-48
Laura I Gil Pineda1, Marcelo D Polêto1, Haley M Michel1
1Department of Biochemistry, Virginia Tech, Blacksburg, Virginia 24061, United States.
The Journal of Physical Chemistry. B
|June 24, 2026
Summary
Enhanced sampling methods like GaMD, METAD, and WESTPA explore diverse protein conformations. METAD and WESTPA revealed new states for intrinsically disordered proteins (IDPs) and their phosphorylation, unlike GaMD.
Area of Science:
- * Computational biophysics and structural biology.
- * Investigating protein dynamics and post-translational modifications.
Background:
- * Intrinsically disordered proteins (IDPs) are crucial for cellular processes but challenging to study due to their flexibility.
- * Phosphorylation, a key modification, alters IDP structure and function.
- * Enhanced sampling molecular dynamics methods can improve the exploration of IDP conformational landscapes.
Purpose of the Study:
- * To compare the effectiveness of Gaussian-accelerated molecular dynamics (GaMD), metadynamics (METAD), and weighted ensemble simulations (WESTPA) for sampling IDP conformations.
- * To evaluate the impact of phosphorylation on the conformational landscape of the β-catenin peptide.
- * To assess the suitability of different collective variables for capturing phosphorylation-induced changes.
Main Methods:
- * Conventional and enhanced sampling molecular dynamics simulations (GaMD, METAD, WESTPA) were performed on the β-catenin17-48 peptide.
- * Simulations were conducted for both nonphosphorylated and phosphorylated states.
- * Sampling was guided by collective variables including dihedral angles and end-to-end distance.
Main Results:
- * Different enhanced sampling methods sampled distinct conformational spaces, with GaMD showing overlap with unbiased simulations.
- * METAD and WESTPA accessed novel conformational regions not observed in conventional simulations.
- * Intermediate conformations between nonphosphorylated and phosphorylated states were identified, particularly with adaptive sampling.
- * The Ser33/Ser37 ϕ angle collective variable was more effective than end-to-end distance for detecting phosphorylation-dependent shifts.
Conclusions:
- * The choice of enhanced sampling method significantly impacts the exploration of intrinsically disordered protein conformational landscapes.
- * Collective variable selection is critical for accurately characterizing phosphorylation-induced conformational changes in IDPs.
- * METAD and WESTPA offer advantages over GaMD and conventional simulations for discovering functionally relevant IDP conformations.
