Aβ(16–22) Peptides Can Assemble into Ordered β‑Barrels and Bilayer β‑Sheets, while Substitution of Phenylalanine 19 by Tryptophan Increases the Population of Disordered Aggregates

A recent experimental study reported that termini-uncapped Aβ(16–22) (with sequence KLVFFAE) peptides self-assembled into nanofibrils at pH 2.0. The oligomerization of this uncapped peptide at atomic level in acidic pH condition remains to be determined, as computational studies mainly focus on the self-assembly of capped Aβ(16–22) peptides at neutral pH condition. In this study, using replica exchange molecular dynamics (REMD) simulations with explicit solvent, we investigated the octameric structures of the uncapped Aβ­(16–22) and its F19W variant at acidic pH condition. Our simulations reveal that the Aβ(16–22) octamers adopt various conformations, including closed β-barrels, bilayer β-sheets, and disordered aggregates. The closed β-barrel conformation is particularly interesting, as the cylindrical β-barrel has been reported recently as a cytotoxic species. Interpeptide contact probability analyses between all pairs of residues reveal that the hydrophobic and aromatic stacking interactions between F19 residues play an essential role in the formation of β-barrels and bilayer β-sheets. The importance of F19 and the steric effect on the structures of Aβ(16–22) octamers are further examined by REMD simulation of F19W mutant. This REMD run shows that substitution of F19 by W with a more bulky aromatic side chain significantly reduces the β-sheet content and in turn enhances the population of disordered aggregates, indicating that the steric effect significantly affect the self-assembly of low molecular weight Aβ(16–22) oligomers

Probing the Self-Assembly Mechanism of Diphenylalanine-Based Peptide Nanovesicles and Nanotubes

Nanostructures, particularly those from peptide self-assemblies, have attracted great attention lately due to their potential applications in nanotemplating and nanotechnology. Recent experimental studies reported that diphenylalanine-based peptides can self-assemble into highly ordered nanostructures such as nanovesicles and nanotubes. However, the molecular mechanism of the self-organization of such well-defined nanoarchitectures remains elusive. In this study, we investigate the assembly pathway of 600 diphenylalanine (FF) peptides at different peptide concentrations by performing extensive coarse-grained molecular dynamics (MD) simulations. Based on forty 0.6–1.8 μs trajectories at 310 K starting from random configurations, we find that FF dipeptides not only spontaneously assemble into spherical vesicles and nanotubes, consistent with previous experiments, but also form new ordered nanoarchitectures, namely, planar bilayers and a rich variety of other shapes of vesicle-like structures including toroid, ellipsoid, discoid, and pot-shaped vesicles. The assembly pathways are concentration-dependent. At low peptide concentrations, the self-assembly involves the fusion of small vesicles and bilayers, whereas at high concentrations, it occurs through the formation of a bilayer first, followed by the bending and closure of the bilayer. Energetic analysis suggests that the formation of different nanostructures is a result of the delicate balance between peptide–peptide and peptide–water interactions. Our all-atom MD simulation shows that FF nanostructures are stabilized by a combination of T-shaped aromatic stacking, interpeptide head-to-tail hydrogen-bonding, and peptide–water hydrogen-bonding interactions. This study provides, for the first time to our knowledge, the self-assembly mechanism and the molecular organization of FF dipeptide nanostructures

A Wind Load and Structural Parameters Estimation Approach for Building Structures

This paper was reviewed and accepted by the APCWE-IX Programme Committee for Presentation at the 9th Asia-Pacific Conference on Wind Engineering, University of Auckland, Auckland, New Zealand, held from 3-7 December 2017

Probing the Self-Assembly Mechanism of Diphenylalanine-Based Peptide Nanovesicles and Nanotubes

Nanostructures, particularly those from peptide self-assemblies, have attracted great attention lately due to their potential applications in nanotemplating and nanotechnology. Recent experimental studies reported that diphenylalanine-based peptides can self-assemble into highly ordered nanostructures such as nanovesicles and nanotubes. However, the molecular mechanism of the self-organization of such well-defined nanoarchitectures remains elusive. In this study, we investigate the assembly pathway of 600 diphenylalanine (FF) peptides at different peptide concentrations by performing extensive coarse-grained molecular dynamics (MD) simulations. Based on forty 0.6–1.8 μs trajectories at 310 K starting from random configurations, we find that FF dipeptides not only spontaneously assemble into spherical vesicles and nanotubes, consistent with previous experiments, but also form new ordered nanoarchitectures, namely, planar bilayers and a rich variety of other shapes of vesicle-like structures including toroid, ellipsoid, discoid, and pot-shaped vesicles. The assembly pathways are concentration-dependent. At low peptide concentrations, the self-assembly involves the fusion of small vesicles and bilayers, whereas at high concentrations, it occurs through the formation of a bilayer first, followed by the bending and closure of the bilayer. Energetic analysis suggests that the formation of different nanostructures is a result of the delicate balance between peptide–peptide and peptide–water interactions. Our all-atom MD simulation shows that FF nanostructures are stabilized by a combination of T-shaped aromatic stacking, interpeptide head-to-tail hydrogen-bonding, and peptide–water hydrogen-bonding interactions. This study provides, for the first time to our knowledge, the self-assembly mechanism and the molecular organization of FF dipeptide nanostructures

A Divergence-free Multi-scale Synthetic Eddy Method for LES Simulation of ABL

This paper was reviewed and accepted by the APCWE-IX Programme Committee for Presentation at the 9th Asia-Pacific Conference on Wind Engineering, University of Auckland, Auckland, New Zealand, held from 3-7 December 2017

Initial state and the simulation results of dimer1 system in two independent MD trajectories.

<p>(A): initial state. The final states (t = 200 ns) generated in dimer-R1 (B) and dimer-R2 (C); time evolution of the number of atomic contacts between two different regions (residues 1–19 and 20–37) of chain A and chain B (D) and the secondary structure profile of hIAPP in MD runs of dimer-R1 (E) and dimer-R2 (F). Snapshots (A)∼(C) are shown by using the same representations as those used in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038191#pone-0038191-g001" target="_blank">Fig. 1</a>.</p

Set up details of all MD simulations at 310 K.

<p>For each system, we describe the name of the system, the name of MD runs, the number of lipid and water molecules, the simulation time and the initial state of each MD run. To mimic the experimental neutral pH condition, the side-chains of Lys (Lys+), Arg (Arg+) and N-terminus (NH3+) are all charged. The C-terminus is amidated. Counterions (Na+) are added to neutralize the system.</p

Lipid Interaction and Membrane Perturbation of Human Islet Amyloid Polypeptide Monomer and Dimer by Molecular Dynamics Simulations

<div><p>The aggregation of human islet amyloid polypeptide (hIAPP or amylin) is associated with the pathogenesis of type 2 diabetes mellitus. Increasing evidence suggests that the interaction of hIAPP with β-cell membranes plays a crucial role in cytotoxicity. However, the hIAPP-lipid interaction and subsequent membrane perturbation is not well understood at atomic level. In this study, as a first step to gain insight into the mechanism of hIAPP-induced cytotoxicity, we have investigated the detailed interactions of hIAPP monomer and dimer with anionic palmitoyloleolyophosphatidylglycerol (POPG) bilayer using all-atom molecular dynamics (MD) simulations. Multiple MD simulations have been performed by employing the initial configurations where the N-terminal region of hIAPP is pre-inserted in POPG bilayer. Our simulations show that electrostatic interaction between hIAPP and POPG bilayer plays a major role in peptide-lipid interaction. In particular, the N-terminal positively-charged residues Lys1 and Arg11 make a dominant contribution to the interaction. During peptide-lipid interaction process, peptide dimerization occurs mostly through the C-terminal 20–37 region containing the amyloidogenic 20–29-residue segment. Membrane-bound hIAPP dimers display a pronounced ability of membrane perturbation than monomers. The higher bilayer perturbation propensity of hIAPP dimer likely results from the cooperativity of the peptide-peptide interaction (or peptide aggregation). This study provides insight into the hIAPP-membrane interaction and the molecular mechanism of membrane disruption by hIAPP oligomers.</p> </div

Conformational Distribution and α‑Helix to β‑Sheet Transition of Human Amylin Fragment Dimer

Experiments suggested that the fibrillation of the 11–25 fragment (hIAPP(11–25)) of human islet amyloid polypeptide (hIAPP or amylin) involves the formation of transient α-helical intermediates, followed by conversion to β-sheet-rich structure. However, atomic details of α-helical intermediates and the transition mechanism are mostly unknown. We investigated the structural properties of the monomer and dimer in atomistic detail by replica exchange molecular dynamics (REMD) simulations. Transient α-helical monomers and dimers were both observed in the REMD trajectories. Our calculated H^α chemical shifts based on the monomer REMD run are in agreement with the solution-state NMR experimental observations. Multiple 300 ns MD simulations at 310 K show that α-helix-to-β-sheet transition follows two mechanisms: the first involved direct transition of the random coil part of the helical conformation into antiparallel β-sheet, and in the second, the α-helical conformation unfolded and converted into antiparallel β-sheet. In both mechanisms, the α-helix-to-β-sheet transition occurred via random coil, and the transition was accompanied by an increase of interpeptide contacts. In addition, our REMD simulations revealed different temperature dependencies of helical and β-structures. Comparison with experimental data suggests that the propensity for hIAPP(11–25) to form α-helices and amyloid structures is concentration- and temperature-dependent

The z-displacement of phosphorus atom in the head group of POPG lipids in each system.

<p>The z-displacement of phosphorus atom is calculated for each leaflet. The data are average over the final 50 ns of each MD trajectory.</p