title: Contribution of Electrostatics in the Fibril Stability of a Model Ionic-Complementary Peptide.
abstract: In this work we quantified the role of electrostatic interactions in the self-assembly of a model amphiphilic peptide (RADA 16-I) into fibrillar structures by a combination of size exclusion chromatography and molecular simulations. For the peptide under investigation, it is found that a net charge of +0.75 represents the ideal condition to promote the formation of regular amyloid fibrils. Lower net charges favor the formation of amorphous precipitates, while larger net charges destabilize the fibrillar aggregates and promote a reversible dissociation of monomers from the ends of the fibrils. By quantifying the dependence of the equilibrium constant of this reversible reaction on the pH value and the peptide net charge, we show that electrostatic interactions contribute largely to the free energy of fibril formation. The addition of both salt and a charged destabilizer (guanidinium hydrochloride) at moderate concentration (0.3-1 M) shifts the monomer-fibril equilibrium toward the fibrillar state. Whereas the first effect can be explained by charge screening of electrostatic repulsion only, the promotion of fibril formation in the presence of guanidinium hydrochloride is also attributed to modifications of the peptide conformation. The results of this work indicate that the global peptide net charge is a key property that correlates well with the fibril stability, although the peptide conformation and the surface charge distribution also contribute to the aggregation propensity.
authors.affiliation: Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich , 8093 Zurich, Switzerland.
authors.forename: Marta
authors.initials: M
authors.lastname: Owczarz
authors.affiliation: Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich , 8093 Zurich, Switzerland.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Casalini
authors.affiliation: Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich , 8093 Zurich, Switzerland.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Motta
authors.affiliation: Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich , 8093 Zurich, Switzerland.
authors.forename: Massimo
authors.initials: M
authors.lastname: Morbidelli
authors.affiliation: Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich , 8093 Zurich, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure; D002850:Chromatography, Gel; D019791:Guanidine / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D066329:Protein Aggregates; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012996:Solutions; D055672:Static Electricity
chemical_list: D000682:Amyloid; D010455:Peptides; D066329:Protein Aggregates; C546681:RADA16-I; D012996:Solutions; D019791:Guanidine