title: A Monte Carlo Study of the Early Steps of Functional Amyloid Formation.
abstract: In addition to their well-known roles in neurodegenerative diseases and amyloidoses, amyloid structures also assume important functional roles in the cell. Although functional amyloid shares many physiochemical properties with its pathogenic counterpart, it is evolutionarily optimized to avoid cytotoxicity. This makes it an interesting study case for aggregation phenomenon in general. One of the most well-known examples of a functional amyloid, E. coli curli, is an essential component in the formation of bacterial biofilm, and is primarily formed by aggregates of the protein CsgA. Previous studies have shown that the minor sequence variations observed in the five different subrepeats (R1-R5), which comprise the CsgA primary sequence, have a substantial influence on their individual aggregation propensities. Using a recently described diffusion-optimized enhanced sampling approach for Monte Carlo simulations, we here investigate the equilibrium properties of the monomeric and dimeric states of these subrepeats, to probe whether structural properties observed in these early stage oligomers are decisive for the characteristics of the resulting aggregate. We show that the dimerization propensities of these peptides have strong correlations with their propensity for amyloid formation, and provide structural insights into the inter- and intramolecular contacts that appear to be essential in this process.
authors.affiliation: Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100, Copenhagen, Denmark.|Linderstrøm-Lang Centre for Protein Science and Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200, Copenhagen N, Denmark.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Tian
authors.affiliation: Linderstrøm-Lang Centre for Protein Science and Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200, Copenhagen N, Denmark.
authors.forename: Kresten
authors.initials: K
authors.lastname: Lindorff-Larsen
authors.affiliation: Linderstrøm-Lang Centre for Protein Science and Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200, Copenhagen N, Denmark.
authors.forename: Wouter
authors.initials: W
authors.lastname: Boomsma
authors.affiliation: Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100, Copenhagen, Denmark.
authors.forename: Mogens Høgh
authors.initials: MH
authors.lastname: Jensen
authors.affiliation: Interdisciplinary Nanoscience Center (iNANO), Centre for Insoluble Protein Structures (inSPIN), Department of Molecular Biology, Aarhus University, Gustav Wieds Vej 10, 8000, Aarhus C, Denmark.
authors.forename: Daniel Erik
authors.initials: DE
authors.lastname: Otzen
mesh_terms: D000595:Amino Acid Sequence; D058227:Amyloidogenic Proteins / Q000737:chemistry*; D018441:Biofilms / Q000254:growth & development*; D003198:Computer Simulation; D004926:Escherichia coli / Q000737:chemistry* / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry*; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D066329:Protein Aggregates / Q000502:physiology; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D013329:Structure-Activity Relationship
chemical_list: D058227:Amyloidogenic Proteins; D029968:Escherichia coli Proteins; D066329:Protein Aggregates; C489688:csgA protein, E coli