The amyloid beta (Aβ) fibrillar aggregate is the hallmark of Alzheimer's disease (AD). Disassembling preformed fibril or inhibiting Aβ aggregation is considered as a therapeutic strategy for AD. Increasing evidence shows that green tea extracts, epigallocatechin-3-gallate (EGCG, containing an extra gallic acid ester group compared to EGC) and epigallocatechin (EGC), can disassociate Aβ fibrils and attenuate Aβ toxicity. However, the underlying molecular mechanism is poorly understood. Herein, we performed microsecond all-atom molecular dynamics (MD) simulations to investigate the influences of EGCG/EGC on the newly cryo-EM resolved LS-shaped Aβ 42 protofibrils and their detailed interactions. MD simulations demonstrate that both EGCG and EGC can disrupt Aβ 42 protofibril and EGCG displays a higher disruptive capacity than EGC. EGCG alters the L-shape of Aβ 42 protofibril by breaking the hydrogen bond between H6 and E11 through π−π interactions with residues H14/Y10 and hydrogen-bonding interactions with E11, while EGC remodels the L-shape by inserting into the hydrophobic core formed by A2, F4, L34, and V36 and via aromatics interaction with H6/Y10. EGCG disrupts the salt bridges between the K28 side chain and A42 COO − through hydrogen-bonding interaction with A42 and cation−π interaction between its gallic acid ester group and K28, while EGC damages the salt bridges through hydrophobic interactions with V39 and I41 as well as with I32, M35, and V40 located in the C-terminal hydrophobic core. This study demonstrates the pivotal role of the gallic acid ester group of EGCG in disrupting Aβ 42 protofibril and provides atomic-level insights into the distinct mechanism by which EGCG and EGC disrupt Aβ protofibril, which could be useful for designing amyloid inhibitors.

Self-assembly is a process of key importance in natural systems and in nanotechnology. Peptides are attractive building blocks due to their relative facile synthesis, biocompatibility, and other unique properties. Diphenylalanine (FF) and its derivatives are known to form nanostructures of various architectures and interesting and varied characteristics. The larger triphenylalanine peptide (FFF) was found to self-assemble as efficiently as FF, forming related but distinct architectures of plate-like and spherical nanostructures. Here, to understand the effect of triaromatic systems on the self-assembly process, we examined carboxybenzyl-protected diphenylalanine (z-FF) as a minimal model for such an arrangement. We explored different self-assembly conditions by changing solvent compositions and peptide concentrations, generating a phase diagram for the assemblies. We discovered that z-FF can form a variety of structures, including nanowires, fibers, nanospheres, and nanotoroids, the latter were previously observed only in considerably larger or co-assembly systems. Secondary structure analysis revealed that all assemblies possessed a β-sheet conformation. Additionally, in solvent combinations with high water ratios, z-FF formed rigid and self-healing hydrogels. X-ray crystallography revealed a "wishbone" structure, in which z-FF dimers are linked by hydrogen bonds mediated by methanol molecules, with a 2-fold screw symmetry along the c-axis. All-atom molecular dynamics (MD) simulations revealed conformations similar to the crystal structure. Coarse-grained MD simulated the assembly of the peptide into either fibers or spheres in different solvent systems, consistent with the experimental results. This work thus expands the building block library for the fabrication of nanostructures by peptide self-assembly.

The aggregation of amyloid-β protein (Aβ) into fibrillary deposits is implicated in Alzheimer's disease (AD), and inhibiting Aβ aggregation and clearing Aβ fibrils are considered as promising strategies to treat...

Fibrillary aggregates of amyloid-β (Aβ) are the pathological hallmark of Alzheimer’s disease (AD). Clearing Aβ deposition or inhibiting Aβ aggregation is a promising approach to treat AD. Experimental studies reported that dopamine (DA), an important neurotransmitter, can inhibit Aβ aggregation and disrupt Aβ fibrils in a dose-dependent manner. However, the underlying molecular mechanisms still remain mostly elusive. Herein, we investigated the effect of DA on Aβ42 protofibrils at three different DA-to-Aβ molar ratios (1:1, 2:1, and 10:1) using all-atom molecular dynamics simulations. Our simulations demonstrate that protonated DA at a DA-to-Aβ ratio of 2:1 exhibits stronger Aβ protofibril disruptive capacity than that at a molar-ratio of 1:1 by mostly disrupting the F4-L34-V36 hydrophobic core. When the ratio of DA-to-Aβ increases to 10:1, DA has a high probability to bind to the outer surface of protofibril and has negligible effect on the protofibril structure. Interestingly, at the same DA-to-Aβ ratio (10:1), a mixture of protonated (DA+) and deprotonated (DA0) DA molecules significantly disrupts Aβ protofibrils by the binding of DA0 to the F4-L34-V36 hydrophobic core. Replica-exchange molecular dynamics simulations of Aβ42 dimer show that DA+ inhibits the formation of β-sheets, K28-A42/K28-D23 salt-bridges, and interpeptide hydrophobic interactions and results in disordered coil-rich Aβ dimers, which would inhibit the subsequent fibrillization of Aβ. Further analyses reveal that DA disrupts Aβ protofibril and prevents Aβ dimerization mostly through π–π stacking interactions with residues F4, H6, and H13, hydrogen bonding interactions with negatively charged residues D7, E11, E22 and D23, and cation−π interactions with residues R5. This study provides a complete picture of the molecular mechanisms of DA in disrupting Aβ protofibril and inhibiting Aβ aggregation, which could be helpful for the design of potent drug candidates for the treatment/intervention of AD.