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Femtosecond Hydration Map of Intrinsically Disordered alpha-Synuclein

TitleFemtosecond Hydration Map of Intrinsically Disordered alpha-Synuclein
Publication TypeJournal Article
Year of Publication2018
AuthorsArya, S, Singh, AK, Bhasne, K, Dogra, P, Datta, A, Das, P, Mukhopadhyay, S
JournalBiophysical Journal
Date Published06
Type of ArticleArticle
ISBN Number0006-3495
Accession NumberWOS:000434787900008
Keywordsaggregation, alzheimers, biomolecular force-fields, Biophysics, diffusion, ensembles, mechanism, mobility, molecular-dynamics simulations, protein disorder, water models

s disease. We took advantage of nonoccurrence of cysteine in the sequence and incorporated a number of cysteine residues at the N-terminal segment, the central amyloidogenic nonamyloid-beta component (NAC) domain, and the C-terminal end of alpha-synuclein. We then labeled these cysteine variants using environment-sensitive thiol-active fluorophore and monitored the solvation dynamics using femtosecond time-resolved fluorescence. The site-specific femtosecond time-resolved experiments allowed us to construct the hydration map of alpha-synuclein. Our results show the presence of three dynamically distinct types of water: bulk, hydration, and confined water. The amyloidogenic NAC domain contains dynamically restrained water molecules that are strikingly different from the water molecules present in the other two domains. Atomistic molecular dynamics simulations revealed longer residence times for water molecules near the NAC domain and supported our experimental observations. Additionally, our simulations allowed us to decipher the molecular origin of the dynamical heterogeneity of water in alpha-synuclein. These simulations captured the quasi-bound water molecules within the NAC domain originating from a complex interplay between the local chain compaction and the sequence composition. Our findings from this synergistic experimental simulation approach suggest longer trapping of interfacial water molecules near the amyloidogenic hotspot that triggers the pathological conversion into amyloids via chain sequestration, chain desolvation, and entropic liberation of ordered water molecules.

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