TY - JOUR
T1 - Exploring Intra- and Inter-Regional Interactions in the IDP α-Synuclein Using smFRET and MD Simulations
AU - Heesink, Gobert
AU - Marseille, Mirjam J.
AU - Fakhree, Mohammad A.A.
AU - Driver, Mark D.
AU - van Leijenhorst-Groener, Kirsten A.
AU - Onck, Patrick R.
AU - Blum, Christian
AU - Claessens, Mireille M.A.E.
N1 - Funding Information:
The authors are grateful to the Dutch Parkinson’s disease foundation “Stichting Parkinson Fonds” for financial support. This publication is part of the project Manipulating the protein aggregation energy landscape (with project number OCNW.KLEIN.300) of the research program Open Competition Domain Science that is financed by the Dutch Research Council (NWO). They thank the oLife COFUND project for funding MDD. The COFUND project oLife has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 847675. They thank the Center for Information Technology of the University of Groningen for their support and for providing access to the Peregrine high-performance computing cluster.
Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.
PY - 2023/8/14
Y1 - 2023/8/14
N2 - Theoretical concepts from polymer physics are often used to describe intrinsically disordered proteins (IDPs). However, amino acid interactions within and between regions of the protein can lead to deviations from typical polymer scaling behavior and even to short-lived secondary structures. To investigate the key interactions in the dynamic IDP α-synuclein (αS) at the amino acid level, we conducted single-molecule fluorescence resonance energy transfer (smFRET) experiments and coarse-grained molecular dynamics (CG-MD) simulations. We find excellent agreement between experiments and simulations. Our results show that a physiological salt solution is a good solvent for αS and that the protein is highly dynamic throughout its entire chain, with local intra- and inter-regional interactions leading to deviations from global scaling. Specifically, we observe expansion in the C-terminal region, compaction in the NAC region, and a slightly smaller distance between the C- and N-termini than expected. Our simulations indicate that the compaction in the NAC region results from hydrophobic aliphatic contacts, mostly between valine and alanine residues, and cation−π interactions between lysine and tyrosine. In addition, hydrogen bonds also seem to contribute to the compaction of the NAC region. The expansion of the C-terminal region is due to intraregional electrostatic repulsion and increased chain stiffness from several prolines. Overall, our study demonstrates the effectiveness of combining smFRET experiments with CG-MD simulations to investigate the key interactions in highly dynamic IDPs at the amino acid level.
AB - Theoretical concepts from polymer physics are often used to describe intrinsically disordered proteins (IDPs). However, amino acid interactions within and between regions of the protein can lead to deviations from typical polymer scaling behavior and even to short-lived secondary structures. To investigate the key interactions in the dynamic IDP α-synuclein (αS) at the amino acid level, we conducted single-molecule fluorescence resonance energy transfer (smFRET) experiments and coarse-grained molecular dynamics (CG-MD) simulations. We find excellent agreement between experiments and simulations. Our results show that a physiological salt solution is a good solvent for αS and that the protein is highly dynamic throughout its entire chain, with local intra- and inter-regional interactions leading to deviations from global scaling. Specifically, we observe expansion in the C-terminal region, compaction in the NAC region, and a slightly smaller distance between the C- and N-termini than expected. Our simulations indicate that the compaction in the NAC region results from hydrophobic aliphatic contacts, mostly between valine and alanine residues, and cation−π interactions between lysine and tyrosine. In addition, hydrogen bonds also seem to contribute to the compaction of the NAC region. The expansion of the C-terminal region is due to intraregional electrostatic repulsion and increased chain stiffness from several prolines. Overall, our study demonstrates the effectiveness of combining smFRET experiments with CG-MD simulations to investigate the key interactions in highly dynamic IDPs at the amino acid level.
KW - UT-Hybrid-D
UR - http://www.scopus.com/inward/record.url?scp=85164800992&partnerID=8YFLogxK
U2 - 10.1021/acs.biomac.3c00404
DO - 10.1021/acs.biomac.3c00404
M3 - Article
C2 - 37407505
AN - SCOPUS:85164800992
SN - 1525-7797
VL - 24
SP - 3680
EP - 3688
JO - Biomacromolecules
JF - Biomacromolecules
IS - 8
ER -