This title appears in the Scientific Report : 2020 

Symmetry-breaking transitions in the early steps of protein self-assembly
La Rosa, Carmelo
Condorelli, Marcello / Compagnini, Giuseppe / Lolicato, Fabio / Milardi, Danilo / Do, Trang Nhu / Karttunen, Mikko / Pannuzzo, Martina / Ramamoorthy, Ayyalusamy / Fraternali, Franca / Collu, Francesca / Rezaei, Human / Strodel, Birgit / Raudino, Antonio (Corresponding author)
Strukturbiochemie; IBI-7
European biophysics journal, 49 (2020) 2, S. 175 - 191
New York Springer 2020
10.1007/s00249-020-01424-1
Journal Article
Functional Macromolecules and Complexes
Published on 2020-03-02. Available in OpenAccess from 2021-03-02.
Restricted
Published on 2020-03-02. Available in OpenAccess from 2021-03-02.
Restricted
Please use the identifier: http://hdl.handle.net/2128/24709 in citations.
Please use the identifier: http://dx.doi.org/10.1007/s00249-020-01424-1 in citations.
Protein misfolding and subsequent self-association are complex, intertwined processes, resulting in development of a het-erogeneous population of aggregates closely related to many chronic pathological conditions including Type 2 Diabetes Mellitus and Alzheimer’s disease. To address this issue, here, we develop a theoretical model in the general framework of linear stability analysis. According to this model, self-assemblies of peptides with pronounced conformational flexibility may become, under particular conditions, unstable and spontaneously evolve toward an alternating array of partially ordered and disordered monomers. The predictions of the theory were verified by atomistic molecular dynamics (MD) simulations of islet amyloid polypeptide (IAPP) used as a paradigm of aggregation-prone polypeptides (proteins). Simulations of dimeric, tetrameric, and hexameric human-IAPP self-assemblies at physiological electrolyte concentration reveal an alternating dis-tribution of the smallest domains (of the order of the peptide mean length) formed by partially ordered (mainly β-strands) and disordered (turns and coil) arrays. Periodicity disappears upon weakening of the inter-peptide binding, a result in line with the predictions of the theory. To further probe the general validity of our hypothesis, we extended the simulations to other peptides, the Aβ(1–40) amyloid peptide, and the ovine prion peptide as well as to other proteins (SOD1 dimer) that do not belong to the broad class of intrinsically disordered proteins. In all cases, the oligomeric aggregates show an alternate distribution of partially ordered and disordered monomers. We also carried out Surface Enhanced Raman Scattering (SERS) measurements of hIAPP as an experimental validation of both the theory and in silico simulations