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1. Molecular insights into the surface-catalyzed secondary nucleation of amyloid-β ₄₀ (Aβ ₄₀ ) by the peptide fragment Aβ _16–22

   https://doi.org/10.1126/sciadv.aav8216  

   Bunce, Samuel J.; Wang, Yiming; Stewart, Katie L.; Ashcroft, Alison E.; Radford, Sheena E.; Hall, Carol K.; Wilson, Andrew J. (June 2019, Science Advances)

   Understanding the structural mechanism by which proteins and peptides aggregate is crucial, given the role of fibrillar aggregates in debilitating amyloid diseases and bioinspired materials. Yet, this is a major challenge as the assembly involves multiple heterogeneous and transient intermediates. Here, we analyze the co-aggregation of Aβ 40 and Aβ 16–22 , two widely studied peptide fragments of Aβ 42 implicated in Alzheimer’s disease. We demonstrate that Aβ 16–22 increases the aggregation rate of Aβ 40 through a surface-catalyzed secondary nucleation mechanism. Discontinuous molecular dynamics simulations allowed aggregation to be tracked from the initial random coil monomer to the catalysis of nucleation on the fibril surface. Together, the results provide insight into how dynamic interactions between Aβ 40 monomers/oligomers on the surface of preformed Aβ 16–22 fibrils nucleate Aβ 40 amyloid assembly. This new understanding may facilitate development of surfaces designed to enhance or suppress secondary nucleation and hence to control the rates and products of fibril assembly. 

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2. Thermodynamic phase diagram of amyloid-β (16–22) peptide

   https://doi.org/10.1073/pnas.1819592116  

   Wang, Yiming; Bunce, Samuel J.; Radford, Sheena E.; Wilson, Andrew J.; Auer, Stefan; Hall, Carol K. (February 2019, Proceedings of the National Academy of Sciences)

   The aggregation of monomeric amyloid β protein (Aβ) peptide into oligomers and amyloid fibrils in the mammalian brain is associated with Alzheimer’s disease. Insight into the thermodynamic stability of the Aβ peptide in different polymeric states is fundamental to defining and predicting the aggregation process. Experimental determination of Aβ thermodynamic behavior is challenging due to the transient nature of Aβ oligomers and the low peptide solubility. Furthermore, quantitative calculation of a thermodynamic phase diagram for a specific peptide requires extremely long computational times. Here, using a coarse-grained protein model, molecular dynamics (MD) simulations are performed to determine an equilibrium concentration and temperature phase diagram for the amyloidogenic peptide fragment Aβ_16–22. Our results reveal that the only thermodynamically stable phases are the solution phase and the macroscopic fibrillar phase, and that there also exists a hierarchy of metastable phases. The boundary line between the solution phase and fibril phase is found by calculating the temperature-dependent solubility of a macroscopic Aβ_16–22fibril consisting of an infinite number of β-sheet layers. This in silico determination of an equilibrium (solubility) phase diagram for a real amyloid-forming peptide, Aβ_16–22, over the temperature range of 277–330 K agrees well with fibrillation experiments and transmission electron microscopy (TEM) measurements of the fibril morphologies formed. This in silico approach of predicting peptide solubility is also potentially useful for optimizing biopharmaceutical production and manufacturing nanofiber scaffolds for tissue engineering. 

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3. Influence of central sidechain on self-assembly of glycine-x-glycine peptides

   https://doi.org/10.1039/d2sm01082h  

   Thursch, Lavenia J.; Lima, Thamires A.; O’Neill, Nichole; Ferreira, Fabio F.; Schweitzer-Stenner, Reinhard; Alvarez, Nicolas J. (January 2023, Soft Matter)

   Low molecular weight gelators (LMWGs) are the subject of intense research for a range of biomedical and engineering applications. Peptides are a special class of LMWG, which offer infinite sequence possibilities and, therefore, engineered properties. This work examines the propensity of the GxG peptide family, where x denotes a guest residue, to self-assemble into fibril networks via changes in pH and ethanol concentration. These triggers for gelation are motivated by recent work on GHG and GAG, which unexpectedly self-assemble into centimeter long fibril networks with unique rheological properties. The propensity of GxG peptides to self-assemble, and the physical and chemical properties of the self-assembled structures are characterized by microscopy, spectroscopy, rheology, and X-ray diffraction. Interestingly, we show that the number, length, size, and morphology of the crystalline self-assembled aggregates depend significantly on the x-residue chemistry and the solution conditions, i.e. pH, temperature, peptide concentration, etc. The different x-residues allow us to probe the importance of different peptide interactions, e.g. π–π stacking, hydrogen bonding, and hydrophobicity, on the formation of fibrils. We conclude that fibril formation requires π–π stacking interactions in pure water, while hydrogen bonding can form fibrils in the presence of ethanol–water solutions. These results validate and support theoretical arguments on the propensity for self-assembly and leads to a better understanding of the relationship between peptide chemistry and fibril self-assembly. Overall, GxG peptides constitute a unique family of peptides, whose characterization will aid in advancing our understanding of self-assembly driving forces for fibril formation in peptide systems. 

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4. Multivariate effects of pH, salt, and Zn2+ ions on Aβ40 fibrillation

   https://doi.org/10.1038/s42004-022-00786-1  

   Wang, Hongzhi; Wu, Jinming; Sternke-Hoffmann, Rebecca; Zheng, Wenwei; Mörman, Cecilia; Luo, Jinghui (December 2022, Communications Chemistry)

   Abstract Amyloid-β (Aβ) peptide aggregation plays a central role in the progress of Alzheimer’s disease (AD), of which Aβ-deposited extracellular amyloid plaques are a major hallmark. The brain micro-environmental variation in AD patients, like local acidification, increased ionic strength, or changed metal ion levels, cooperatively modulates the aggregation of the Aβ peptides. Here, we investigate the multivariate effects of varied pH, ionic strength and Zn 2+ on Aβ 40 fibrillation kinetics. Our results reveal that Aβ fibrillation kinetics are strongly affected by pH and ionic strength suggesting the importance of electrostatic interactions in regulating Aβ 40 fibrillation. More interestingly, the presence of Zn 2+ ions can further alter or even reserve the role of pH and ionic strength on the amyloid fibril kinetics, suggesting the importance of amino acids like Histidine that can interact with Zn 2+ ions. Both pH and ionic strength regulate the secondary nucleation processes, however regardless of pH and Zn 2+ ions, ionic strength can also modulate the morphology of Aβ 40 aggregates. These multivariate effects in bulk solution provide insights into the correlation of pH-, ionic strength- or Zn 2+ ions changes with amyloid deposits in AD brain and will deepen our understanding of the molecular pathology in the local brain microenvironment. 

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5. Repurposing Antimicrobial Protegrin-1 as a Dual-Function Amyloid Inhibitor via Cross-seeding

   https://doi.org/10.1021/acschemneuro.3c00293  

   Tang, Yijing; Zhang, Dong; Zheng, Jie (September 2023, ACS Chemical Neuroscience)

   Amyloids and antimicrobial peptides have traditionally been recognized as distinct families with separate biological functions and targets. However, certain amyloids and antimicrobial peptides share structural and functional characteristics that contribute to the development of neurodegenerative diseases. Specifically, the aggregation of amyloid-β (Aβ) and microbial infections are interconnected pathological factors in Alzheimer’s disease (AD). In this study, we propose and demonstrate a novel repurposing strategy for an antimicrobial peptide of protegrin-1 (PG-1), which exhibits the ability to simultaneously prevent Aβ aggregation and microbial infection both in vitro and in vivo. Through a comprehensive analysis using protein, cell, and worm assays, we uncover multiple functions of PG-1 against Aβ, including the following: (i) complete inhibition of Aβ aggregation at a low molar ratio of PG-1/Aβ = 0.25:1, (ii) disassembly of the preformed Aβ fibrils into amorphous aggregates, (iii) reduction of Aβ-induced cytotoxicity in SH-SY5Y cells and transgenic GMC101 nematodes, and (iv) preservation of original antimicrobial activity against P.A., E.coli., S.A., and S.E. strains in the presence of Aβ. Mechanistically, the dual anti-amyloid and anti-bacterial functions of PG-1 primarily arise from its strong binding to distinct Aβ seeds (KD = 1.24–1.90 μM) through conformationally similar β-sheet associations. This work introduces a promising strategy to repurpose antimicrobial peptides as amyloid inhibitors, effectively targeting multiple pathological pathways in AD. 

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