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491.
Discovering the mechanisms by which proteins aggregate into fibrils is an essential first step in understanding the molecular level processes underlying neurodegenerative diseases such as Alzheimer’s and Parkinson''s. The goal of this work is to provide insights into the structural changes that characterize the kinetic pathways by which amyloid-β peptides convert from monomers to oligomers to fibrils. By applying discontinuous molecular dynamics simulations to PRIME20, a force field designed to capture the chemical and physical aspects of protein aggregation, we have been able to trace out the entire aggregation process for a system containing 8 Aβ17–42 peptides. We uncovered two fibrillization mechanisms that govern the structural conversion of Aβ17–42 peptides from disordered oligomers into protofilaments. The first mechanism is monomeric conversion templated by a U-shape oligomeric nucleus into U-shape protofilament. The second mechanism involves a long-lived and on-pathway metastable oligomer with S-shape chains, having a C-terminal turn, en route to the final U-shape protofilament. Oligomers with this C-terminal turn have been regarded in recent experiments as a major contributing element to cell toxicity in Alzheimer’s disease. The internal structures of the U-shape protofilaments from our PRIME20/DMD simulation agree well with those from solid state NMR experiments. The approach presented here offers a simple molecular-level framework to describe protein aggregation in general and to visualize the kinetic evolution of a putative toxic element in Alzheimer’s disease in particular. 相似文献
492.
The goal of this work is to understand how the sequence of a protein affects the likelihood that it will form an amyloid fibril and the kinetics along the fibrillization pathway. The focus is on very short fragments of amyloid proteins since these play a role in the fibrillization of the parent protein and can form fibrils themselves. Discontinuous molecular dynamics simulations using the PRIME20 force field were performed of the aggregation of 48‐peptide systems containing SNQNNF ( PrP (170–175 )), SSTSAA (RNaseA(15–20)), MVGGVV (Aβ(35–40)), GGVVIA (Aβ(37–42)), and MVGGVVIA (Aβ(35–42)). In our simulations SNQQNF, SSTTSAA, and MVGGVV form large numbers of fibrillar structures spontaneously (as in experiment). GGVVIA forms β‐sheets that do not stack into fibrils (unlike experiment). The combination sequence MVGGVVIA forms less fibrils than MVGGVV, hindered by the presence of the hydrophobic residues at the C‐terminal. Analysis of the simulation kinetics and energetics reveals why MVGGVV forms fibrils and GGVVIA does not, and why adding I and A to MVGGVVIA reduces fibrillization and enhances amorphous aggregation into oligomeric structures. The latter helps explain why Aβ(1–42) assembles into more complex oligomers than Aβ(1–40), a consequence of which is that it is more strongly associated with Alzheimer's disease. Proteins 2014; 82:1469–1483. © 2014 Wiley Periodicals, Inc. 相似文献
493.
Yeon Ki Hong Dong Woo Lee Pyung Cheon Lee Won Hi Hong Ho Nam Chang 《Biotechnology letters》2001,23(12):983-988
Colloidal liquid aphrons (CLAs) are surfactant-stabilized solvent droplets which have recently been explored for predispersed solvent extraction (PDSE). We have compared the equilibrium distribution of lactic acid with solvent alone and with CLAs. In spite of the short contact time in the PDSE process with CLAs, there was little difference in equilibrium distribution with solvent alone. The toxicity of extractants and diluents on Lactobacillus rhamnosus was measured for in situ extraction. Long chain alcohols such as 1-octanol and 1-decanol were less toxic among diluents. CLAs reduced the toxicity of solvents on Lactobacillus rhamnosus. 相似文献