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bioRxiv · 10.1101/2024.07.07.602212

VISUALIZING GAUSSIAN-CHAIN LIKE STRUCTURAL MODELS OF HUMAN alpha-SYNUCLEIN IN MONOMERIC PRE-FIBRILLAR STATE: SOLUTION SAXS DATA AND MODELING ANALYSIS

SHARMA, D.·GANGULY, A.·DEY, M.·GUPTA, A.·BADMALIA, M. D.
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Abstract

Here, using small angle X-ray scattering (SAXS) data profile as reference, we attempted to visualize conformational ensemble accessible prefibrillar monomeric state of -synuclein in solution. In agreement with previous reports, our analysis also confirmed that -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 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 -helical content best-represents non-associating monomeric -synuclein.

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SHARMA, D., GANGULY, A., DEY, M., GUPTA, A., BADMALIA, M. D.. 2024-07-10. VISUALIZING GAUSSIAN-CHAIN LIKE STRUCTURAL MODELS OF HUMAN alpha-SYNUCLEIN IN MONOMERIC PRE-FIBRILLAR STATE: SOLUTION SAXS DATA AND MODELING ANALYSIS. https://doi.org/10.1101/2024.07.07.602212

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