title: Beware of Cocktails: Chain-Length Bidispersity Triggers Explosive Self-Assembly of Poly-L-Glutamic Acid β2-Fibrils.
abstract: Chain-length polydispersity is among the least understood factors governing the fibrillation propensity of homopolypeptides. For monodisperse poly-L-glutamic acid (PLGA), the tendency to form fibrils depends of the main-chain length. Long-chained PLGA, so-called (Glu)200, fibrillates more readily than short (Glu)5 fragments. Here we show that conversion of α-helical (Glu)200 into amyloid-like β-fibrils is dramatically accelerated in the presence of intrinsically disordered (Glu)5. While separately self-assembled fibrils of (Glu)200 and (Glu)5 reveal distinct morphological and infrared characteristics, accelerated fibrillation in mixed (Glu)200 and (Glu)5 leads to aggregates similar to neat (Glu)200 fibrils, even in excess of (Glu)5. According to molecular dynamics simulations and circular dichroism measurements, local events of "misfolding transfer" from (Glu)5 to (Glu)200 may play a key role in the initial stages of conformational dynamics underlying the observed phenomenon. Our results highlight chain-length polydispersity as a potent, although so-far unrecognized factor profoundly affecting the fibrillation propensity of homopolypeptides.
authors.affiliation: Department of Chemistry, Biological and Chemical Research Centre, and ‡Institute of Theoretical Physics, Faculty of Physics, University of Warsaw , Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Hernik-Magoń
authors.affiliation: Department of Chemistry, Biological and Chemical Research Centre, and ‡Institute of Theoretical Physics, Faculty of Physics, University of Warsaw , Warsaw, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Puławski
authors.affiliation: Department of Chemistry, Biological and Chemical Research Centre, and ‡Institute of Theoretical Physics, Faculty of Physics, University of Warsaw , Warsaw, Poland.
authors.forename: Bartłomiej
authors.initials: B
authors.lastname: Fedorczyk
authors.affiliation: Department of Chemistry, Biological and Chemical Research Centre, and ‡Institute of Theoretical Physics, Faculty of Physics, University of Warsaw , Warsaw, Poland.
authors.forename: Dagmara
authors.initials: D
authors.lastname: Tymecka
authors.affiliation: Department of Chemistry, Biological and Chemical Research Centre, and ‡Institute of Theoretical Physics, Faculty of Physics, University of Warsaw , Warsaw, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Misicka
authors.affiliation: Department of Chemistry, Biological and Chemical Research Centre, and ‡Institute of Theoretical Physics, Faculty of Physics, University of Warsaw , Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Szymczak
authors.affiliation: Department of Chemistry, Biological and Chemical Research Centre, and ‡Institute of Theoretical Physics, Faculty of Physics, University of Warsaw , Warsaw, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Dzwolak
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D002942:Circular Dichroism; D018698:Glutamic Acid / Q000737:chemistry*; D018625:Microscopy, Atomic Force; D056004:Molecular Dynamics Simulation; D011099:Polyglutamic Acid / Q000737:chemistry*; D017510:Protein Folding
chemical_list: D000682:Amyloid; D011099:Polyglutamic Acid; D018698:Glutamic Acid