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SimHS-AFMfit-MD: An Integrative Approach for Inferring Alpha-Actinin Atomic Conformational Dynamics
Kien Xuan Ngo1,2, Takashi Sumikama1,3,4, Rémi Vuillemot5
1Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Nano Letters
|February 25, 2026
Summary
This study introduces SimHS-AFMfit-MD, a novel method combining high-speed atomic force microscopy (HS-AFM) and molecular dynamics (MD) simulations to visualize dynamic protein structures at atomic resolution.
Area of Science:
- Biophysics
- Structural Biology
- Computational Biology
Background:
- Flexible molecular systems like proteins present challenges for traditional structural biology techniques.
- Conformational heterogeneity hinders detailed atomic-level analysis.
Purpose of the Study:
- To develop an integrative framework for inferring dynamic protein conformations at atomic resolution.
- To visualize real-time protein dynamics bridging simulation and imaging.
Main Methods:
- Introduced SimHS-AFMfit-MD, integrating high-speed atomic force microscopy (HS-AFM) with molecular dynamics (MD) simulations.
- Employed AFMfit-based structural modeling, enhanced by nonlinear normal-mode analysis (AFMfit-NMA) and MD trajectory guidance (AFMfit-MD).
- Applied the method to alpha-actinin, an actin cross-linking protein.
Main Results:
- AFMfit-NMA improved structural fitting accuracy.
- AFMfit-MD significantly enhanced fitting performance, aligning with all-atom MD simulations.
- Generated atomic-scale conformational ensembles from thousands of HS-AFM images.
- Revealed Ca2+-dependent conformational transitions in alpha-actinin.
Conclusions:
- SimHS-AFMfit-MD enables atomic-scale visualization of protein dynamics.
- The hybrid approach effectively bridges computational and experimental methods.
- This framework advances the study of flexible molecular systems.
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