Symmetry-breaking transitions in the early steps of protein self-assembly

Carmelo La Rosa; Marcello Condorelli; Giuseppe Compagnini; Fabio Lolicato; Danilo Milardi; Trang Nhu Do; Mikko Karttunen; Martina Pannuzzo; Ayyalusamy Ramamoorthy; Franca Fraternali; Francesca Collu; Human Rezaei; Birgit Strodel; Antonio Raudino

doi:10.1007/s00249-020-01424-1

Symmetry-breaking transitions in the early steps of protein self-assembly

Carmelo La Rosa, Marcello Condorelli, Giuseppe Compagnini, Fabio Lolicato, Danilo Milardi, Trang Nhu Do, Mikko Karttunen, Martina Pannuzzo, Ayyalusamy Ramamoorthy, Franca Fraternali, Francesca Collu, Human Rezaei, Birgit Strodel, Antonio Raudino^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

28 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	175-191
Number of pages	17
Journal	European Biophysics Journal
Volume	49
Issue number	2
DOIs	https://doi.org/10.1007/s00249-020-01424-1
Publication status	Published - 1 Mar 2020

Keywords

Analytical model
Intrinsically disordered proteins
Molecular dynamics
Oligomers
Symmetry-breaking

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s00249-020-01424-1

Cite this

@article{227776b773f343b19710cf523658517e,

title = "Symmetry-breaking transitions in the early steps of protein self-assembly",

abstract = "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{\textquoteright}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.",

keywords = "Analytical model, Intrinsically disordered proteins, Molecular dynamics, Oligomers, Symmetry-breaking",

author = "{La Rosa}, Carmelo and Marcello Condorelli and Giuseppe Compagnini and Fabio Lolicato and Danilo Milardi and Do, {Trang Nhu} and Mikko Karttunen and Martina Pannuzzo and Ayyalusamy Ramamoorthy and Franca Fraternali and Francesca Collu and Human Rezaei and Birgit Strodel and Antonio Raudino",

year = "2020",

month = mar,

day = "1",

doi = "10.1007/s00249-020-01424-1",

language = "English",

volume = "49",

pages = "175--191",

journal = "European Biophysics Journal",

issn = "0175-7571",

publisher = "Springer Verlag",

number = "2",

}

TY - JOUR

T1 - Symmetry-breaking transitions in the early steps of protein self-assembly

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

PY - 2020/3/1

Y1 - 2020/3/1

N2 - 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.

AB - 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.

KW - Analytical model

KW - Intrinsically disordered proteins

KW - Molecular dynamics

KW - Oligomers

KW - Symmetry-breaking

UR - http://www.scopus.com/inward/record.url?scp=85081614249&partnerID=8YFLogxK

U2 - 10.1007/s00249-020-01424-1

DO - 10.1007/s00249-020-01424-1

M3 - Article

C2 - 32123956

AN - SCOPUS:85081614249

SN - 0175-7571

VL - 49

SP - 175

EP - 191

JO - European Biophysics Journal

JF - European Biophysics Journal

IS - 2

ER -

Symmetry-breaking transitions in the early steps of protein self-assembly

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this