TY  - JOUR
AU  - La Rosa, Carmelo
AU  - Condorelli, Marcello
AU  - Compagnini, Giuseppe
AU  - Lolicato, Fabio
AU  - Milardi, Danilo
AU  - Do, Trang Nhu
AU  - Karttunen, Mikko
AU  - Pannuzzo, Martina
AU  - Ramamoorthy, Ayyalusamy
AU  - Fraternali, Franca
AU  - Collu, Francesca
AU  - Rezaei, Human
AU  - Strodel, Birgit
AU  - Raudino, Antonio
TI  - Symmetry-breaking transitions in the early steps of protein self-assembly
JO  - European biophysics journal
VL  - 49
IS  - 2
SN  - 1432-1017
CY  - New York
PB  - Springer
M1  - FZJ-2020-01550
SP  - 175 - 191
PY  - 2020
AB  - 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
LB  - PUB:(DE-HGF)16
C6  - pmid:32123956
UR  - <Go to ISI:>//WOS:000517713400001
DO  - DOI:10.1007/s00249-020-01424-1
UR  - https://juser.fz-juelich.de/record/874630
ER  -