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VISUALIZING GAUSSIAN-CHAIN LIKE STRUCTURAL MODELS OF HUMAN α-SYNUCLEIN IN MONOMERIC PRE-FIBRILLAR STATE: SOLUTION SAXS DATA AND MODELING ANALYSIS
Open accessPreprint — published as 10.1016/j.ijbiomac.2024.138614 · Paper page
Abstract
Here, using small angle X-ray scattering (SAXS) data profile as reference, we attempted to visualize conformational ensemble accessible prefibrillar monomeric state of α-synuclein in solution. In agreement with previous reports, our analysis also confirmed that α-synuclein molecules adopted disordered shape profile under non-associating conditions. Chain-ensemble modeling protocol with dummy residues provided two weighted averaged clusters of semi-extended shapes. Further, Ensemble Optimization Method (EOM) computed mole fractions of semi-extended “twisted” conformations which might co-exist in solution. Since these were only C α traces of the models, ALPHAFOLD2 server was used to search for all-atom models. Comparison with experimental data showed all predicted models disagreed equally, as individuals. Finally, we employed molecular dynamics simulations and normal mode analysis-based search coupled with SAXS data to seek better agreeing models. Overall, our analysis concludes that a shifting equilibrium of curved models with low α-helical content best-represents non-associating monomeric α-synuclein.
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Metadata
- Authors
- Dey, M., Gupta, A., Badmalia, M. D., Ashish, & Sharma, D.
- Affiliations
- Institute of Microbial Technology (IN)
- Corresponding author
- Ashish
- Sharma, Deepak
- Venue
- International Journal of Biological Macromolecules
- Publisher
- openRxiv
- Published
- 2024-07-10
- Volume
- 288
- Pages
- 138614-138614
- ISSN
- 0141-8130 (ISSN-L)
- OpenAlex
- W4405316207
- Cited by
- 5
- References
- 1
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1
- FWCI
- 0.68
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- International Journal of Biological Macromolecules (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Council of Scientific and Industrial Research, India
- CSIR - Institute of Microbial Technology (50/2023)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- alpha-synuclein, conformational ensembles, Gaussian chain model, twisted conformation, solution structure, molecular dynamics, normal mode analysis, protein disorder
- MeSH terms
- Humans, Models, Molecular, Protein Conformation, Solutions, X-Ray Diffraction, alpha-Synuclein, Scattering, Small Angle, Molecular Dynamics Simulation
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