title: Effects of macromolecular crowding on amyloid beta (16-22) aggregation using coarse-grained simulations.
abstract: To examine the effect of crowding on protein aggregation, discontinuous molecular dynamics (DMD) simulations combined with an intermediate resolution protein model, PRIME20, were applied to a peptide/crowder system. The systems contained 192 Aβ(16-22) peptides and crowders of diameters 5, 20, and 40 Å, represented here by simple hard spheres, at crowder volume fractions of 0.00, 0.10, and 0.20. Results show that both crowder volume fraction and crowder diameter have a large impact on fibril and oligomer formation. The addition of crowders to a system of peptides increases the rate of oligomer formation, shifting from a slow ordered formation of oligomers in the absence of crowders, similar to nucleated polymerization, to a fast collapse of peptides and subsequent rearrangement characteristic of nucleated conformational conversion with a high maximum in the number of peptides in oligomers as the total crowder surface area increases. The rate of conversion from oligomers to fibrils also increases with increasing total crowder surface area, giving rise to an increased rate of fibril growth. In all cases, larger volume fractions and smaller crowders provide the greatest aggregation enhancement effects. We also show that the size of the crowders influences the formation of specific oligomer sizes. In our simulations, the 40 Å crowders enhance the number of dimers relative to the numbers of trimers, hexamers, pentamers, and hexamers, while the 5 Å crowders enhance the number of hexamers relative to the numbers of dimers, trimers, tetramers, and pentamers. These results are in qualitative agreement with previous experimental and theoretical work.
authors.affiliation: Center for Proteome Biophysics, Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST) , Daegu 711-873, Korea.
authors.forename: David C
authors.initials: DC
authors.lastname: Latshaw
authors.forename: Mookyung
authors.initials: M
authors.lastname: Cheon
authors.forename: Carol K
authors.initials: CK
authors.lastname: Hall
mesh_terms: D000682:Amyloid / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D055503:Protein Multimerization
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C417223:amyloid beta-protein (16-22)