Snapshots for the 5^th run.

<p>The time evolution of the structure for the 5^th run at T* = 0.20 in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004258#pcbi.1004258.g001" target="_blank">Fig 1C and 1D</a>. Snapshots are taken at (A) t* = 5, (B) 1244, (C) 2608, (D) 3656, (E) 4233, (F) 5442, (G) 6086, (H) 10454, (I) 11063. See <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004258#pcbi.1004258.s018" target="_blank">S1 Video</a>. The β-strand contents measured by the STRIDE program are (A) 0%, (B) 12%, (C) 26%, (D) 50%, (E) 48%, (F) 66%, (G) 64%, (H) 74%, (I) 75%. The α-helix content is insignificant in these structures and the remaining portions are coil and turns.</p

β–strand content and solvent accessible area.

<p>Probability that each residue is in β-strand conformation. Data are averaged over three time windows (A) t* = 2153~6727, (B) 19648~24266 and (C) 38120~42736. (D) Solvent accessible area for each residue. Data are averaged over time window (t* = 38120~42736).</p

Structural Conversion of Aβ_17–42 Peptides from Disordered Oligomers to U-Shape Protofilaments via Multiple Kinetic Pathways

<div><p>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.</p></div

Time evolution of the interaction energy.

<p>The total interaction energy in units of ɛ_HB for (A) 1st, 2nd, 3rd, (B) 4th, 5th, 6th, (C) 7th, 8th, 9th, 10th trajectories. The 3rd (green), 5th (red), 10th (blue) trajectories show lower energies than the others. (D) P_max (max population) within each Δt* = 5000 interval which is defined in text.</p

Salt-bridge and hydrophobic interactions for the 10^th run.

<p>(A) Structure at 568 billion collision (t*≈52,000) for the 10^th run. (B)(C) Fibril axis view with ribbon diagram or with side-chain spheres. (D)~(K) Fibril axis views for each chain showing side-chain spheres; F19(purple), D23(red), K28(cyan), I32(green) and L34(pink sphere). Figs (D)~(H) have salt-bridge pairs (D23-K28) and hydrophobic interactions between I32, L34 and F19; the rest do not.</p