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Exploring Intra- and Inter-Regional Interactions in the IDP α-Synuclein Using smFRET and MD Simulations.
Gobert Heesink1, Mirjam J Marseille1, Mohammad A A Fakhree1
1Nanobiophysics, Faculty of Science and Technology, MESA + Institute for Nanotechnology and Technical Medical Centre, University of Twente, PO Box 217, 7500 AE Enschede, The Netherlands.
Biomacromolecules
|July 5, 2023
Summary
Intrinsically disordered proteins (IDPs) like alpha-synuclein exhibit complex dynamics. Combining single-molecule FRET and simulations reveals local interactions drive protein structure and deviations from polymer theory.
Area of Science:
- Biophysics
- Computational Biology
- Protein Dynamics
Background:
- Intrinsically disordered proteins (IDPs) are often modeled using polymer physics principles.
- Amino acid interactions can cause deviations from predicted polymer behavior and transient secondary structures in IDPs.
- Understanding these interactions is crucial for deciphering IDP function and dynamics.
Purpose of the Study:
- To investigate the amino acid-level interactions governing the dynamic intrinsically disordered protein alpha-synuclein (αS).
- To compare experimental findings with coarse-grained molecular dynamics (CG-MD) simulations for validation.
- To elucidate how local interactions influence αS conformation and deviate from global polymer scaling.
Main Methods:
- Single-molecule fluorescence resonance energy transfer (smFRET) experiments were performed on αS.
- Coarse-grained molecular dynamics (CG-MD) simulations were utilized to model αS behavior.
- Experimental and simulation data were analyzed for agreement and to identify key residue interactions.
Main Results:
- Excellent agreement was found between smFRET experiments and CG-MD simulations.
- αS behaves as if in a good solvent, exhibiting high chain dynamics with local interactions causing deviations from scaling.
- Observed conformational changes include C-terminal expansion, NAC region compaction (driven by hydrophobic and cation-π interactions), and altered N- and C-terminus distances.
Conclusions:
- Local interactions, including hydrophobic contacts, cation-π interactions, hydrogen bonds, electrostatic repulsion, and proline-induced stiffness, significantly impact αS structure.
- The C-terminal region expands due to electrostatic repulsion and prolines, while the NAC region compacts via specific residue interactions.
- The combination of smFRET and CG-MD simulations is a powerful approach for studying the detailed amino acid-level interactions in dynamic IDPs.
