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.
Alzheimer's disease is associated with the abnormal self-assembly of the amyloid-β (Aβ) peptide into toxic β-rich aggregates. Experimental studies have shown that hydrophobic nanoparticles retard Aβ fibrillation by slowing down the nucleation process; however, the effects of nanoparticles on Aβ oligomeric structures remain elusive. In this study, we investigate the conformations of Aβ(16-22) octamers in the absence and presence of a single-walled carbon nanotube (SWCNT) by performing extensive all-atom replica exchange molecular-dynamics simulations in explicit solvent. Our simulations starting from eight random chains demonstrate that the addition of SWCNT into Aβ(16-22) solution prevents β-sheet formation. Simulation starting from a prefibrillar β-sheet octamer shows that SWCNT destabilizes the β-sheet structure. A detailed analysis of the Aβ(16-22)/SWCNT/water interactions reveals that both the inhibition of β-sheet formation and the destabilization of prefibrillar β-sheets by SWCNT result from the same physical forces: hydrophobic and π-stacking interactions (with the latter playing a more important role). By analyzing the stacking patterns between the Phe aromatic rings and the SWCNT carbon rings, we find that short ring-centroid distances mostly favor parallel orientation, whereas large distances allow all other orientations to be populated. Overall, our computational study provides evidence that SWCNT is likely to inhibit Aβ(16-22) and full-length Aβ fibrillation.
Recent studies suggest that both soluble oligomers and insoluble fibrils have toxic effects in cell cultures, raising the interest in determining the first steps of the assembly process. We have determined the aggregation mechanisms of Abeta(16-22) dimer using the activation-relaxation technique and an approximate free energy model. Consistent with the NMR solid-state analysis, the dimer is predicted to prefer an antiparallel beta sheet structure with the expected registry of intermolecular hydrogen bonds. The simulations, however, locate three other antiparallel minima with nonnative beta sheet registries and one parallel beta sheet structure, slightly destabilized with respect to the ground state. This result is significant because it can explain the observed dependency of beta sheet registry on pH conditions. We also find that assembly of Abeta(16-22) into dimers follows multiple routes, but alpha-helical intermediates are not obligatory. This indicates that destabilization of alpha-helical intermediates is unlikely to abolish oligomerization of Abeta peptides.
The free energy landscape for folding of the Alzheimer's amyloid-beta(25-35) peptide is explored using replica exchange molecular dynamics in both pure water and in HFIP/water cosolvent. This amphiphilic peptide is a natural by-product of the Alzheimer's amyloid-beta(1-40) peptide and retains the toxicity of its full-length counterpart as well as the ability to aggregate into beta-sheet-rich fibrils. Our simulations reveal that the peptide preferentially populates a helical structure in apolar organic solvent, while in pure water, the peptide adopts collapsed coil conformations and to a lesser extent beta-hairpin conformations. The beta-hairpin is characterized by a type II' beta-turn involving residues G29 and A30 and two short beta-strands involving residues N27, K28, I31, and I32. The hairpin is stabilized by backbone hydrogen-bonding interactions between residues K28 and I31; S26 and G33; and by side-chain-to-side-chain interactions between N27 and I32. Implications regarding the mechanism of aggregation of this peptide into fibrils and the role of the environment in modulating secondary structure are discussed.
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