Symmetry-breaking transitions in the early steps of protein self-assembly(199 views) La Rosa C, Condorelli M, Compagnini G, Lolicato F, Milardi D, Do TN, Karttunen M, Pannuzzo M, Ramamoorthy A, Fraternali F, Collu F, Rezaei H, Strodel B, Raudino A
Keywords: Colloids Chemistry, Computer Simulation, Electrolytes, Humans, Islet Amyloid Polypeptide Chemistry, Kinetics, Models, Theoretical, Molecular Dynamics Simulation, Peptides Chemistry, Protein Denaturation, Protein Folding, Protein Multimerization, Protein Structure, Secondary, Reproducibility Of Results, Solvents, Spectrum Analysis, Raman, Thermodynamics, Analytical Model, Intrinsically Disordered Proteins, Oligomers, Symmetry-Breaking,
Affiliations: *** IBB - CNR ***
Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125, Catania, Italy.
Department of Physics, University of Helsinki, P.O. Box 64, 00014, Helsinki, Finland.
Heidelberg University Biochemistry Center, Heidelberg, Germany.
Unità Organizzativa e di Supporto di Catania, CNR, Istituto di Biostrutture e Bioimmagini, Via P. Gaifami 18, 95126, Catania, Italy.
Istituto Italiano di Tecnologia (IIT), Via Morego 30, 16163, Genoa, Italy.
Randall Division of Cell and Molecular Biophysics, Guy's Campus, New Hunt's House King's College London, London, SE1 1UL, UK.
Virologie et Immunologie Moléculaires, Institut National de la Recherche Agronomique, 78352, Jouy-en-Josas, France.
Institute of Complex Systems, Structural Biochemistry (ICS-6), ForschungszentrumJülich, 52425, Jülich, Germany.
References: Not available.
Symmetry-breaking transitions in the early steps of protein self-assembly
Protein misfolding and subsequent self-association are complex, intertwined processes, resulting in development of a heterogeneous 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 distribution 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.
Symmetry-breaking transitions in the early steps of protein self-assembly