Daniel Otzen

TY - JOUR

T1 - A Monte Carlo Study of the Early Steps of Functional Amyloid Formation

AU - Tian, Pengfei

AU - Lindorff-Larsen, Kresten

AU - Boomsma, Wouter

AU - Jensen, Mogens Høgh

AU - Otzen, Daniel Erik

PY - 2016/1/8

Y1 - 2016/1/8

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pone.0146096

DO - 10.1371/journal.pone.0146096

M3 - Journal article

C2 - 26745180

VL - 11

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 1

M1 - e0146096

ER -