SHARMA, D.; GANGULY, A.; DEY, M.; GUPTA, A.; BADMALIA, M. D.

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