Controlling Amyloid Fibril Properties Via Ionic Liquids: The Representative Case of Ethylammonium Nitrate and Tetramethylguanidinium Acetate on the Amyloidogenesis of Lysozyme

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This article references 58 other publications.

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   A review. COVID-19 vaccines were developed with an unprecedented pace since the beginning of the pandemic. Several of them have reached market authorization and mass prodn., leading to their global application on a large scale. This enormous progress was achieved with fundamentally different vaccine technologies used in parallel. mRNA, adenoviral vector as well as inactivated whole-virus vaccines are now in widespread use, and a subunit vaccine is in a final stage of authorization. They all rely on the native viral spike protein (S) of SARS-CoV-2 for inducing potently neutralizing antibodies, but the presentation of this key antigen to the immune system differs substantially between the different categories of vaccines. In this article, we review the relevance of structural modifications of S in different vaccines and the different modes of antigen expression after vaccination with genetic adenovirus-vector and mRNA vaccines. Distinguishing characteristics and unknown features are highlighted in the context of protective antibody responses and reactogenicity of vaccines.

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   Dobson, Christopher M.

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   A review. Here, the author summarizes the current understanding of the underlying and universal mechanism by which newly synthesized proteins achieve their biol. functional states. Protein mols., however, all have a finite tendency either to misfold, or to fail to maintain their correctly folded states, under some circumstances. The author describes some of the consequences of such behavior, particularly in the context of the aggregation events that are frequently assocd. with aberrant folding. The authors focuses in particular on the emerging links between protein aggregation and the increasingly prevalent forms of debilitating disease with which it is now known to be assocd.

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   The activities of amyloids from a structural perspective

   Riek Roland; Eisenberg David S; Eisenberg David S

   Nature (2016), 539 (7628), 227-235 ISSN:.

   The aggregation of proteins into structures known as amyloids is observed in many neurodegenerative diseases, including Alzheimer's disease. Amyloids are composed of pairs of tightly interacting, many stranded and repetitive intermolecular β-sheets, which form the cross-β-sheet structure. This structure enables amyloids to grow by recruitment of the same protein and its repetition can transform a weak biological activity into a potent one through cooperativity and avidity. Amyloids therefore have the potential to self-replicate and can adapt to the environment, yielding cell-to-cell transmissibility, prion infectivity and toxicity.

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   Jiménez, J. L.; Nettleton, E. J.; Bouchard, M.; Robinson, C. V.; Dobson, C. M.; Saibil, H. R. The Protofilament Structure of Insulin Amyloid Fibrils. Proc. Natl. Acad. Sci. U.S. A. 2002, 99 (14), 9196– 9201,  DOI: 10.1073/pnas.142459399

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   The protofilament structure of insulin amyloid fibrils

   Jimenez, Jose L.; Nettleton, Ewan J.; Bouchard, Mario; Robinson, Carol V.; Dobson, Christopher M.; Saibil, Helen R.

   Proceedings of the National Academy of Sciences of the United States of America (2002), 99 (14), 9196-9201CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

   Under soln. conditions where the native state is destabilized, the largely helical polypeptide hormone insulin readily aggregates to form amyloid fibrils with a characteristic cross-β structure. However, there is a lack of information relating the 4.8 Å β-strand repeat to the higher order assembly of amyloid fibrils. We have used cryo-electron microscopy (EM), combining single particle anal. and helical reconstruction, to characterize these fibrils and to study the three-dimensional (3D) arrangement of their component protofilaments. Low-resoln. 3D structures of fibrils contg. 2, 4, and 6 protofilaments reveal a characteristic, compact shape of the insulin protofilament. Considerations of protofilament packing indicate that the cross-β ribbon is composed of relatively flat β-sheets rather than being the highly twisted, β-coil structure previously suggested by anal. of globular protein folds. Comparison of the various fibril structures suggests that very small, local changes in β-sheet twist are important in establishing the long-range coiling of the protofilaments into fibrils of diverse morphol.

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   Nature Reviews Molecular Cell Biology (2014), 15 (6), 384-396CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)

   A review. The phenomenon of protein aggregation and amyloid formation has become the subject of rapidly increasing research activities across a wide range of scientific disciplines. Such activities have been stimulated by the assocn. of amyloid deposition with a range of debilitating medical disorders, from Alzheimer's disease to type II diabetes, many of which are major threats to human health and welfare in the modern world. It has become clear, however, that the ability to form the amyloid state is more general than previously imagined, and that its study can provide unique insights into the nature of the functional forms of peptides and proteins, as well as understanding the means by which protein homeostasis can be maintained and protein metastasis avoided.

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   Chiti, F.; Dobson, C. M. Protein Misfolding, Functional Amyloid, and Human Disease. Annu. Rev. Biochem. 2006, 75 (1), 333– 366,  DOI: 10.1146/annurev.biochem.75.101304.123901

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   Chiti, Fabrizio; Dobson, Christopher M.

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   A review. Peptides or proteins convert under some conditions from their sol. forms into highly ordered fibrillar aggregates. Such transitions can give rise to pathol. conditions ranging from neurodegenerative disorders to systemic amyloidoses. In this review, we identify the diseases known to be assocd. with formation of fibrillar aggregates and the specific peptides and proteins involved in each case. We describe, in addn., that living organisms can take advantage of the inherent ability of proteins to form such structures to generate novel and diverse biol. functions. We review recent advances toward the elucidation of the structures of amyloid fibrils and the mechanisms of their formation at a mol. level. Finally, we discuss the relative importance of the common main-chain and side-chain interactions in detg. the propensities of proteins to aggregate and describe some of the evidence that the oligomeric fibril precursors are the primary origins of pathol. behavior.

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   Reymann, A. C.; Boujemaa-Paterski, R.; Martiel, J.-L.; Guérin, C.; Cao, W.; Chin, H. F.; De La Cruz, E. M.; Théry, M.; Blanchoin, L. Actin Network Architecture Can Determine Myosin Motor Activity. Science 2012, 336 (6086), 1310– 1314,  DOI: 10.1126/science.1221708

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   Science (Washington, DC, United States) (2012), 336 (6086), 1310-1314CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

   The organization of actin filaments into higher-ordered structures governs eukaryotic cell shape and movement. Global actin network size and architecture are maintained in a dynamic steady state through regulated assembly and disassembly. Here, we used exptl. defined actin structures in vitro to investigate how the activity of myosin motors depends on network architecture. Direct visualization of filaments revealed myosin-induced actin network deformation. During this reorganization, myosins selectively contracted and disassembled antiparallel actin structures, while parallel actin bundles remained unaffected. The local distribution of nucleation sites and the resulting orientation of actin filaments appeared to regulate the scalability of the contraction process. This "orientation selection" mechanism for selective contraction and disassembly suggests how the dynamics of the cellular actin cytoskeleton can be spatially controlled by actomyosin contractility.

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    Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade

    Chiti, Fabrizio; Dobson, Christopher M.

    Annual Review of Biochemistry (2017), 86 (), 27-68CODEN: ARBOAW; ISSN:0066-4154. (Annual Reviews)

    Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is assocd. with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a no. of systemic amyloidoses. In this review, we describe this field of science with particular ref. to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are assocd., as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addn., we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors and of the mechanisms by which they are formed and proliferate to generate cellular dysfunction. We show evidence that a complex proteostasis network actively combats protein aggregation and that such an efficient system can fail in some circumstances and give rise to disease. Finally, we anticipate the development of novel therapeutic strategies with which to prevent or treat these highly debilitating and currently incurable conditions.

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    Koo, Edward H.; Lansbury, Peter T., Jr.; Kelly, Jeffery W.

    Proceedings of the National Academy of Sciences of the United States of America (1999), 96 (18), 9989-9990CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    A review, with 21 refs., focuses on biophys. studies of protein aggregation in Alzheimer's disease (AD) and familial amyloid polyneuropathy (FAP), where mechanistic models connecting pathol. and genetic data to clin. disease are beginning to emerge. These 2 examples illustrate 2 ends of the biophys. spectrum: in one (AD), a flexible peptide is poised to form fibrils, whereas in the other (FAP), a stable globular tetramer must dissoc. and partially unfold before forming a new stable fibril structure.

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    Hauser, C. A. E.; Maurer-Stroh, S.; Martins, I. C. Amyloid-Based Nanosensors and Nanodevices. Chem. Soc. Rev. 2014, 43 (15), 5326– 5345,  DOI: 10.1039/C4CS00082J

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    Amyloid-based nanosensors and nanodevices

    Hauser, Charlotte A. E.; Maurer-Stroh, Sebastian; Martins, Ivo C.

    Chemical Society Reviews (2014), 43 (15), 5326-5345CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

    A review. Self-assembling amyloid-like peptides and proteins give rise to promising biomaterials with potential applications in many fields. Amyloid structures are formed by the process of mol. recognition and self-assembly, wherein a peptide or protein monomer spontaneously self-assocs. into dimers and oligomers and subsequently into supramol. aggregates, finally resulting in condensed fibrils. Mature amyloid fibrils possess a quasi-cryst. structure featuring a characteristic fiber diffraction pattern and have well-defined properties, in contrast to many amorphous protein aggregates that arise when proteins misfold. Core sequences of four to seven amino acids have been identified within natural amyloid proteins. They are capable to form amyloid fibers and fibrils and have been used as amyloid model structures, simplifying the investigations on amyloid structures due to their small size. Recent studies have highlighted the use of self-assembled amyloid-based fibers as nanomaterials. Here, we discuss the latest advances and the major challenges in developing amyloids for future applications in nanotechnol. and nanomedicine, with the focus on development of sensors to study protein-ligand interactions.

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    Li, C.; Adamcik, J.; Mezzenga, R. Biodegradable Nanocomposites of Amyloid Fibrils and Graphene with Shape-Memory and Enzyme-Sensing Properties. Nat. Nanotechnol. 2012, 7 (7), 421– 427,  DOI: 10.1038/nnano.2012.62

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    Biodegradable nanocomposites of amyloid fibrils and graphene with shape-memory and enzyme-sensing properties

    Li, Chaoxu; Adamcik, Jozef; Mezzenga, Raffaele

    Nature Nanotechnology (2012), 7 (7), 421-427CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)

    Graphene has exceptional mech. and electronic properties, but its hydrophobic nature is a disadvantage in biol. related applications. Amyloid fibrils are naturally occurring protein aggregates that are stable in soln. or under highly hydrated conditions, have well-organized supramol. structures and outstanding strength. Here, we show that graphene and amyloid fibrils can be combined to create a new class of biodegradable composite materials with adaptable properties. This new composite material is inexpensive, highly conductive and can be degraded by enzymes. Furthermore, it can reversibly change shape in response to variations in humidity, and can be used in the design of biosensors for quantifying the activity of enzymes. The properties of the composite can be fine-tuned by changing the graphene-to-amyloid ratio.

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    Cherny, I.; Gazit, E. Amyloids: Not Only Pathological Agents but Also Ordered Nanomaterials. Angew. Chem., Int. Ed. Engl. 2008, 47 (22), 4062– 4069,  DOI: 10.1002/anie.200703133

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    Amyloids: not only pathological agents but also ordered nanomaterials

    Cherny Izhack; Gazit Ehud

    Angewandte Chemie (International ed. in English) (2008), 47 (22), 4062-9 ISSN:.

    Amyloid fibers constitute one of the most abundant and important naturally occurring self-associated assemblies. A variety of protein and peptide molecules with various amino acid sequences form these highly stable and well-organized assemblies under diverse conditions. These assemblies display phase states ranging from liquid crystals to rigid nanotubes. The potential applications of these supramolecular assemblies exceed those of synthetic polymers since the building blocks may introduce biological function in addition to mechanical properties. Here we review the structural characteristics of amyloidal supramolecular assemblies, their potential use as either natural or de novo designed sequences, and the range of applications that have been demonstrated so far.

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    Jacob, R. S.; Ghosh, D.; Singh, P. K.; Basu, S. K.; Jha, N. N. Self Healing Hydrogels Composed of Amyloid Nano Fibrils for Cell Culture and Stem Cell Differentiation. Biomaterials 2015, 54, 97– 105,  DOI: 10.1016/j.biomaterials.2015.03.002

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    Self healing hydrogels composed of amyloid nano fibrils for cell culture and stem cell differentiation

    Jacob, Reeba S.; Ghosh, Dhiman; Singh, Pradeep K.; Basu, Santanu K.; Jha, Narendra Nath; Das, Subhadeep; Sukul, Pradip K.; Patil, Sachin; Sathaye, Sadhana; Kumar, Ashutosh; Chowdhury, Arindam; Malik, Sudip; Sen, Shamik; Maji, Samir K.

    Biomaterials (2015), 54 (), 97-105CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

    Amyloids are highly ordered protein/peptide aggregates assocd. with human diseases as well as various native biol. functions. Given the diverse range of physiochem. properties of amyloids, we hypothesized that higher order amyloid self-assembly could be used for fabricating novel hydrogels for biomaterial applications. For proof of concept, we designed a series of peptides based on the high aggregation prone C-terminus of Aβ42, which is assocd. with Alzheimer's disease. These Fmoc protected peptides self assemble to β sheet rich nanofibrils, forming hydrogels that are thermoreversible, non-toxic and thixotropic. Mechanistic studies indicate that while hydrophobic, π-π interactions and hydrogen bonding drive amyloid network formation to form supramol. gel structure, the exposed hydrophobic surface of amyloid fibrils may render thixotropicity to these gels. We have demonstrated the utility of these hydrogels in supporting cell attachment and spreading across a diverse range of cell types. Finally, by tuning the stiffness of these gels through modulation of peptide concn. and salt concn. these hydrogels could be used as scaffolds that can drive differentiation of mesenchymal stem cells. Taken together, our results indicate that small size, ease of custom synthesis, thixotropic nature makes these amyloid-based hydrogels ideally suited for biomaterial/nanotechnol. applications.

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    Kollmer, M.; Close, W.; Funk, L.; Rasmussen, J.; Bsoul, A.; Schierhorn, A.; Schmidt, M.; Sigurdson, C. J.; Jucker, M.; Fändrich, M. Cryo-EM Structure and Polymorphism of Aβ Amyloid Fibrils Purified from Alzheimer’s Brain Tissue. Nat. Commun. 2019, 10 (1), 47– 60,  DOI: 10.1038/s41467-019-12683-8

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    Close, W.; Neumann, M.; Schmidt, A.; Hora, M.; Annamalai, K.; Schmidt, M.; Reif, B.; Schmidt, V.; Grigorieff, N.; Fändrich, M. Physical Basis of Amyloid Fibril Polymorphism. Nat. Commun. 2018, 9 (1), 699,  DOI: 10.1038/s41467-018-03164-5

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    19

    Physical basis of amyloid fibril polymorphism

    Close William; Schmidt Andreas; Annamalai Karthikeyan; Schmidt Matthias; Fandrich Marcus; Neumann Matthias; Schmidt Volker; Hora Manuel; Reif Bernd; Hora Manuel; Reif Bernd; Grigorieff Nikolaus

    Nature communications (2018), 9 (1), 699 ISSN:.

    Polymorphism is a key feature of amyloid fibril structures but it remains challenging to explain these variations for a particular sample. Here, we report electron cryomicroscopy-based reconstructions from different fibril morphologies formed by a peptide fragment from an amyloidogenic immunoglobulin light chain. The observed fibril morphologies vary in the number and cross-sectional arrangement of a structurally conserved building block. A comparison with the theoretically possible constellations reveals the experimentally observed spectrum of fibril morphologies to be governed by opposing sets of forces that primarily arise from the β-sheet twist, as well as peptide-peptide interactions within the fibril cross-section. Our results provide a framework for rationalizing and predicting the structure and polymorphism of cross-β fibrils, and suggest that a small number of physical parameters control the observed fibril architectures.

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    Adamcik, J.; Mezzenga, R. Amyloid Polymorphism in the Protein Folding and Aggregation Energy Landscape. Angew. Chem., Int. Ed. 2018, 57 (28), 8370– 8382,  DOI: 10.1002/anie.201713416

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    Amyloid polymorphism in the protein folding and aggregation energy landscape

    Adamcik, Jozef; Mezzenga, Raffaele

    Angewandte Chemie, International Edition (2018), 57 (28), 8370-8382CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

    A review. Protein folding involves a large no. of steps and conformations in which the folding protein samples different thermodn. states characterized by local min. Kinetically trapped on- or off-pathway intermediates are metastable folding intermediates towards the lowest abs. energy min., which have been postulated to be the natively folded state where intramol. interactions dominate, and the amyloid state where intermol. interactions dominate. However, this view largely neglects the rich polymorphism found within amyloid species. We review the protein folding energy landscape in view of recent findings identifying specific transition routes among different amyloid polymorphs. Obsd. transitions such as twisted ribbon→crystal or helical ribbon→nanotube, and forbidden transitions such helical ribbon .dnreslt. crystal, are discussed and positioned within the protein folding and aggregation energy landscape. Finally, amyloid crystals are identified as the ground state of the protein folding and aggregation energy landscape.

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    Wei, G.; Su, Z.; Reynolds, N. P.; Arosio, P.; Hamley, I. W.; Gazit, E.; Mezzenga, R. Self-Assembling Peptide and Protein Amyloids: From Structure to Tailored Function in Nanotechnology. Chem. Soc. Rev. 2017, 46 (15), 4661– 4708,  DOI: 10.1039/C6CS00542J

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    Self-assembling peptide and protein amyloids: from structure to tailored function in nanotechnology

    Wei, Gang; Su, Zhiqiang; Reynolds, Nicholas P.; Arosio, Paolo; Hamley, Ian W.; Gazit, Ehud; Mezzenga, Raffaele

    Chemical Society Reviews (2017), 46 (15), 4661-4708CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

    Self-assembled peptide and protein amyloid nanostructures have traditionally been considered only as pathol. aggregates implicated in human neurodegenerative diseases. In more recent times, these nanostructures have found interesting applications as advanced materials in biomedicine, tissue engineering, renewable energy, environmental science, nanotechnol. and material science, to name only a few fields. In all these applications, the final function depends on: (i) the specific mechanisms of protein aggregation, (ii) the hierarchical structure of the protein and peptide amyloids from the atomistic to mesoscopic length scales and (iii) the phys. properties of the amyloids in the context of their surrounding environment (biol. or artificial). In this review, we will discuss recent progress made in the field of functional and artificial amyloids and highlight connections between protein/peptide folding, unfolding and aggregation mechanisms, with the resulting amyloid structure and functionality. We also highlight current advances in the design and synthesis of amyloid-based biol. and functional materials and identify new potential fields in which amyloid-based structures promise new breakthroughs.

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    Dahlgren, K. N.; Manelli, A. M.; Stine, W. B.; Baker, L. K.; Krafft, G. A.; LaDu, M. J. Oligomeric and Fibrillar Species of Amyloid-Beta Peptides Differentially Affect Neuronal Viability. J. Biol. Chem. 2002, 277 (35), 32046– 32053,  DOI: 10.1074/jbc.M201750200

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    22

    Oligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability

    Dahlgren, Karie N.; Manelli, Arlene M.; Stine, W. Blaine, Jr.; Baker, Lorinda K.; Krafft, Grant A.; LaDu, Mary Jo

    Journal of Biological Chemistry (2002), 277 (35), 32046-32053CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    Genetic evidence predicts a causative role for amyloid-β (Aβ) in Alzheimer's disease. Recent debate has focused on whether fibrils (amyloid) or sol. oligomers of Aβ are the active species that contribute to neurodegeneration and dementia. We developed two aggregation protocols for the consistent prodn. of stable oligomeric or fibrillar prepns. of Aβ-(1-42). Here we report that oligomers inhibit neuronal viability 10-fold more than fibrils and ∼40-fold more than unaggregated peptide, with oligomeric Aβ-(1-42)-induced inhibition significant at 10 nM. Under Aβ-(1-42) oligomer- and fibril-forming conditions, Aβ-(1-40) remains predominantly as unassembled monomer and had significantly less effect on neuronal viability than prepns. of Aβ-(1-42). We applied the aggregation protocols developed for wild type Aβ-(1-42) to Aβ-(1-42) with the Dutch (E22Q) or Arctic (E22G) mutations. Oligomeric prepns. of the mutations exhibited extensive protofibril and fibril formation, resp., but were not consistently different from wild type Aβ-(1-42) in terms of inhibition of neuronal viability. However, fibrillar prepns. of the mutants appeared larger and induced significantly more inhibition of neuronal viability than wild type Aβ-(1-42) fibril prepns. These data demonstrate that protocols developed to produce oligomeric and fibrillar Aβ-(1-42) are useful in distinguishing the structural and functional differences between Aβ-(1-42) and Aβ-(1-40) and genetic mutations of Aβ-(1-42).

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23. 23

    Kayed, R.; Head, E.; Thompson, J. L.; McIntire, T. M.; Milton, S. C.; Cotman, C. W.; Glabe, C. G. Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis. Science 2003, 300 (5618), 486– 489,  DOI: 10.1126/science.1079469

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    23

    Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis

    Kayed, Rakez; Head, Elizabeth; Thompson, Jennifer L.; McIntire, Theresa M.; Milton, Saskia C.; Cotman, Carl W.; Glabe, Charles G.

    Science (Washington, DC, United States) (2003), 300 (5618), 486-489CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

    Sol. oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Aβ peptide in Alzheimer's disease (AD). Here the authors show that all of the sol. oligomers tested display a common conformation-dependent structure that is unique to sol. oligomers regardless of sequence. The in vitro toxicity of sol. oligomers is inhibited by oligomer-specific antibody. Sol. oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of sol. amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.

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24. 24

    Sacchettini, J. C.; Kelly, J. W. Therapeutic Strategies for Human Amyloid Diseases. Nat. Rev. Drug Discovery 2002, 1 (4), 267– 275,  DOI: 10.1038/nrd769

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    24

    Therapeutic strategies for human amyloid diseases

    Sacchettini, James C.; Kelly, Jeffery W.

    Nature Reviews Drug Discovery (2002), 1 (4), 267-275CODEN: NRDDAG ISSN:. (Nature Publishing Group)

    A review. Amyloid diseases are a large group of a much larger family of misfolding diseases. This group includes pathologies as diverse as Alzheimer's disease, Ig-light-chain disease, reactive amyloid disease and the familial amyloid polyneuropathies. These diseases are generally incurable at present, although some drugs are known to transiently slow the progression of Alzheimer's disease. As we increase our understanding of the causative mechanisms of these disorders, the likelihood of success for a given therapeutic strategy will become clearer. This review will look at small-mol. and macromol. approaches for intervention in amyloid diseases other than Alzheimer's disease, although select examples from Alzheimer's disease will be discussed.

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25. 25

    Das, S.; Jacob, R. S.; Patel, K.; Singh, N.; Maji, S. K. Amyloid Fibrils: Versatile Biomaterials for Cell Adhesion and Tissue Engineering Applications. Biomacromolecules 2018, 19 (6), 1826– 1839,  DOI: 10.1021/acs.biomac.8b00279

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    25

    Amyloid fibrils: Versatile biomaterials for cell adhesion and tissue engineering applications

    Das, Subhadeep; Jacob, Reeba S.; Patel, Komal; Singh, Namrata; Maji, Samir K.

    Biomacromolecules (2018), 19 (6), 1826-1839CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

    A review. Extracellular matrixes (ECM) play an enormous role in any living system, controlling various factors and eventually fates of cells. ECM regulates cell fate by providing const. exogenous signals altering intracellular signal transduction for diverse pathways including proliferation, migration, differentiation, and apoptosis. Biomaterial scaffolds are designed to mimic the natural extracellular matrix such that the cells could recapitulate natural events alike their natural niche. Therefore, the success of tissue engineering is largely dependent on how one can engineer the natural matrix properties at nanoscale precision. In this aspect, several recent studies have suggested that, as long as amyloid fibrils are not toxic, they can be utilized for cell adhesion and tissue engineering applications due to its ECM mimetic surface topog. and ability to mediate active cell adhesion via focal adhesions. Although historically assocd. with human diseases, amyloids have presently emerged as one of the excellent biomaterials evolved in nature. In this review, we focus on the recent advances of amyloid-based biomaterials for cell adhesion and tissue engineering applications.

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26. 26

    Thirumalai, D.; Reddy, G.; Straub, J. E. Role of Water in Protein Aggregation and Amyloid Polymorphism. Acc. Chem. Res. 2012, 45 (1), 83– 92,  DOI: 10.1021/ar2000869

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    26

    Role of Water in Protein Aggregation and Amyloid Polymorphism

    Thirumalai, D.; Reddy, Govardhan; Straub, John E.

    Accounts of Chemical Research (2012), 45 (1), 83-92CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)

    A review. A variety of neurodegenerative diseases are assocd. with amyloid plaques, which begin as sol. protein oligomers but develop into amyloid fibrils. Our incomplete understanding of this process underscores the need to decipher the principles governing protein aggregation. Mechanisms of in vivo amyloid formation involve a no. of coconspirators and complex interactions with membranes. Nevertheless, understanding the biophys. basis of simpler in vitro amyloid formation is considered important for discovering ligands that preferentially bind regions harboring amyloidogenic tendencies. The detn. of the fibril structure of many peptides has set the stage for probing the dynamics of oligomer formation and amyloid growth through computer simulations. Most exptl. and simulation studies, however, have been interpreted largely from the perspective of proteins: the role of solvent has been relatively overlooked in oligomer formation and assembly to protofilaments and amyloid fibrils. In this Account, we provide a perspective on how interactions with water affect folding landscapes of amyloid beta (Aβ) monomers, oligomer formation in the Aβ16-22 fragment, and protofilament formation in a peptide from yeast prion Sup35. Explicit mol. dynamics simulations illustrate how water controls the self-assembly of higher order structures, providing a structural basis for understanding the kinetics of oligomer and fibril growth. Simulations show that monomers of Aβ peptides sample a no. of compact conformations. The formation of aggregation-prone structures (N*) with a salt bridge, strikingly similar to the structure in the fibril, requires overcoming a high desolvation barrier. In general, sequences for which N* structures are not significantly populated are unlikely to aggregate. Oligomers and fibrils generally form in two steps. First, water is expelled from the region between peptides rich in hydrophobic residues (for example, Aβ16-22), resulting in disordered oligomers. Then the peptides align along a preferred axis to form ordered structures with anti-parallel β-strand arrangement. The rate-limiting step in the ordered assembly is the rearrangement of the peptides within a confining vol. The mechanism of protofilament formation in a polar peptide fragment from the yeast prion, in which the two sheets are packed against each other and create a dry interface, illustrates that water dramatically slows self-assembly. As the sheets approach each other, two perfectly ordered one-dimensional water wires form. They are stabilized by hydrogen bonds to the amide groups of the polar side chains, resulting in the formation of long-lived metastable structures. Release of trapped water from the pore creates a helically twisted protofilament with a dry interface. Similarly, the driving force for addn. of a solvated monomer to a preformed fibril is water release; the entropy gain and favorable interpeptide hydrogen bond formation compensate for entropy loss in the peptides. We conclude by offering evidence that a two-step model, similar to that postulated for protein crystn., must also hold for higher order amyloid structure formation starting from N*. Distinct water-laden polymorphic structures result from multiple N* structures. Water plays multifarious roles in all of these protein aggregations. In predominantly hydrophobic sequences, water accelerates fibril formation. In contrast, water-stabilized metastable intermediates dramatically slow fibril growth rates in hydrophilic sequences.

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27. 27

    Chatani, E.; Inoue, R.; Imamura, H.; Sugiyama, M.; Kato, M.; Yamamoto, M.; Nishida, K.; Kanaya, T. Early Aggregation Preceding the Nucleation of Insulin Amyloid Fibrils as Monitored by Small Angle X-Ray Scattering. Sci. Rep. 2015, 5 (1), 15485,  DOI: 10.1038/srep15485

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    27

    Early aggregation preceding the nucleation of insulin amyloid fibrils as monitored by small angle X-ray scattering

    Chatani, Eri; Inoue, Rintaro; Imamura, Hiroshi; Sugiyama, Masaaki; Kato, Minoru; Yamamoto, Masahide; Nishida, Koji; Kanaya, Toshiji

    Scientific Reports (2015), 5 (), 15485CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)

    The nucleation event of amyloid fibrils is one of the most crucial processes that dictate the timing and rate of the pathol. of diseases; however, information regarding how protein mols. assoc. to produce fibril nuclei is currently limited. In order to explore this issue in more detail, we performed time-resolved small angle X-ray scattering (SAXS) measurements on insulin fibrillation, in combination with addnl. multidirectional analyses of thioflavin T fluorescence, FTIR spectroscopy, light scattering, and light transmittance, during the fibrillation process of bovine insulin. SAXS monitoring revealed that insulin mols. assocd. into rod-like prefibrillar aggregates in the very early stage of the reaction. After the formation of these early aggregates, they appeared to further coalesce mutually to form larger clusters, and the SAXS profiles subsequently showed the further time evolution of conformational development towards mature amyloid fibrils. Distinct types of structural units in terms of shape in a nano-scale order, cross-β content, and thioflavin T fluorescence intensity were obsd. in a manner that was dependent on the fibrillation pathways. These results suggest the presence of diverse substructures that characterize various fibrillation pathways, and eventually, manifest polymorphisms in mature amyloid fibrils.

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28. 28

    Welton, T. Room-Temperature Ionic Liquids. Solvents for Synthesis and Catalysis. Chem. Rev. 1999, 99 (8), 2071– 2084,  DOI: 10.1021/cr980032t

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    28

    Room-Temperature Ionic Liquids. Solvents for Synthesis and Catalysis

    Welton, Thomas

    Chemical Reviews (Washington, D. C.) (1999), 99 (8), 2071-2083CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)

    A review with 124 refs. covering org. reactions in alkylhalo- and haloaluminate ionic liqs.

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    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXkt1artrw%253D&md5=e17d4c2a7f45438755b34161e86f24e6
29. 29

    Benedetto, A.; Ballone, P. Room Temperature Ionic Liquids Meet Biomolecules: A Microscopic View of Structure and Dynamics. ACS Sustain. Chem. Eng. 2016, 4 (2), 392– 412,  DOI: 10.1021/acssuschemeng.5b01385

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    There is no corresponding record for this reference.
30. 30

    Kumari, P.; Pillai, V. V. S.; Benedetto, A. Mechanisms of Action of Ionic Liquids on Living Cells: The State of the Art. Biophys. Rev. 2020, 12 (5), 1187– 1215,  DOI: 10.1007/s12551-020-00754-w

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    30

    Mechanisms of action of ionic liquids on living cells: the state of the art

    Kumari, Pallavi; Pillai, Visakh V. S.; Benedetto, Antonio

    Biophysical Reviews (2020), 12 (5), 1187-1215CODEN: BRIECG; ISSN:1867-2450. (Springer)

    Abstr.: Ionic liqs. (ILs) are a relatively new class of org. electrolytes composed of an org. cation and either an org. or inorg. anion, whose melting temp. falls around room-temp. In the last 20 years, the toxicity of ILs towards cells and micro-organisms has been heavily investigated with the main aim to assess the risks assocd. with their potential use in (industrial) applications, and to develop strategies to design greener ILs. Toxicity, however, is synonym with affinity, and this has stimulated, in turn, a series of biophys. and chem.-phys. investigations as well as few biochem. studies focused on the mechanisms of action (MoAs) of ILs, key step in the development of applications in bio-nanomedicine and bio-nanotechnol. The overall picture that emerges is quite intriguing and shows that ILs interact with cells in a variety of different mechanisms, including alteration of lipid distribution and cell membrane viscoelasticity, disruption of cell and nuclear membranes, mitochondrial permeabilization and dysfunction, cytoplasmatic proteins/enzyme functions, alteration of signaling pathways, and DNA fragmentation. Together with our earlier review work on the biophysics and chem.-physics of IL-cell membrane interactions (Biophys. Rev. 9:309, 2017), we hope that the present review, focused instead on the biochem. aspects, will stimulate a series of new investigations and discoveries in the still new and interdisciplinary field of "ILs, biomols., and cells.

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31. 31

    Benedetto, A.; Galla, H.-J. Editorial of the “Ionic Liquids and Biomolecules” Special Issue. Biophys. Rev. 2018, 10 (3), 687– 690,  DOI: 10.1007/s12551-018-0426-3

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    31

    Editorial of the "ionic liquids and biomolecules" special issue

    Benedetto Antonio; Benedetto Antonio; Benedetto Antonio; Benedetto Antonio; Galla Hans-Joachim

    Biophysical reviews (2018), 10 (3), 687-690 ISSN:1867-2450.

    There is no expanded citation for this reference.

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32. 32

    Egorova, K. S.; Gordeev, E. G.; Ananikov, V. P. Biological Activity of Ionic Liquids and Their Application in Pharmaceutics and Medicine. Chem. Rev. 2017, 117 (10), 7132– 7189,  DOI: 10.1021/acs.chemrev.6b00562

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    32

    Biological Activity of Ionic Liquids and Their Application in Pharmaceutics and Medicine

    Egorova, Ksenia S.; Gordeev, Evgeniy G.; Ananikov, Valentine P.

    Chemical Reviews (Washington, DC, United States) (2017), 117 (10), 7132-7189CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)

    A review. Ionic liqs. are remarkable chem. compds., which find applications in many areas of modern science. Due to their highly tunable nature and exceptional properties, ionic liqs. have become essential players in the fields of synthesis and catalysis, extn., electrochem., analytics, biotechnol., etc. Apart from phys. and chem. features of ionic liqs., their high biol. activity has been attracting significant attention of biochemists, ecologists and medical scientists. This review is dedicated to biol. activities of ionic liqs., with a special emphasize on their potential employment in pharmaceutics and medicine. The accumulated data on the biol. activity of ionic liqs., including their antimicrobial and cytotoxic properties, is discussed in view of possible applications in drug synthesis and drug delivery systems. Dedicated attention is given to a novel active pharmaceutical ingredient-ionic liq. (API-IL) concept, which suggests using traditional drugs in the form of ionic liq. species. The main aim of the review is to attract a broad audience of chem., biol. and medical scientists to study advantages of ionic liq. pharmaceutics. In overall, the discussed data highlights the importance of the research direction defined as "Ioliomics" - studies of ions in liqs. in modern chem., biol. and medicine.

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33. 33

    Benedetto, A.; Ballone, P. Room-Temperature Ionic Liquids and Biomembranes: Setting the Stage for Applications in Pharmacology, Biomedicine, and Bionanotechnology. Langmuir 2018, 34 (33), 9579– 9597,  DOI: 10.1021/acs.langmuir.7b04361

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    33

    Room-Temperature Ionic Liquids and Biomembranes: Setting the Stage for Applications in Pharmacology, Biomedicine, and Bionanotechnology

    Benedetto, Antonio; Ballone, Pietro

    Langmuir (2018), 34 (33), 9579-9597CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)

    A review on the current researches and future prospects on the remarkable affinity of room-temp. ionic liqs. (RTILs) for biomembranes, causing a variety of observable biol. effects, and its applications in various related fields such as pharmacol., biomedicine, and bionanotechnol.

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34. 34

    Banerjee, A.; Ibsen, K.; Brown, T.; Chen, R.; Agatemor, C.; Mitragotri, S. Ionic Liquids for Oral Insulin Delivery. Proc. Natl. Acad. Sci. U.S. A. 2018, 115 (28), 7296– 7301,  DOI: 10.1073/pnas.1722338115

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    34

    Ionic liquids for oral insulin delivery

    Banerjee, Amrita; Ibsen, Kelly; Brown, Tyler; Chen, Renwei; Agatemor, Christian; Mitragotri, Samir

    Proceedings of the National Academy of Sciences of the United States of America (2018), 115 (28), 7296-7301CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    With the rise in diabetes mellitus cases worldwide and lack of patient adherence to glycemia management using injectable insulin, there is an urgent need for the development of efficient oral insulin formulations. However, the gastrointestinal tract presents a formidable barrier to oral delivery of biologics. Here we report the development of a highly effective oral insulin formulation using choline and geranate (CAGE) ionic liq. CAGE significantly enhanced paracellular transport of insulin, while protecting it from enzymic degrdn. and by interacting with the mucus layer resulting in its thinning. In vivo, insulin-CAGE demonstrated exceptional pharmacokinetic and pharmacodynamic outcome after jejunal administration in rats. Low insulin doses (3-10 U/kg) brought about a significant decrease in blood glucose levels, which were sustained for longer periods (up to 12 h), unlike s.c. injected insulin. When 10 U/kg insulin-CAGE was orally delivered in enterically coated capsules using an oral gavage, a sustained decrease in blood glucose of up to 45% was obsd. The formulation exhibited high biocompatibility and was stable for 2 mo at room temp. and for at least 4 mo under refrigeration. Taken together, the results indicate that CAGE is a promising oral delivery vehicle and should be further explored for oral delivery of insulin and other biologics that are currently marketed as injectables.

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35. 35

    Kumari, P.; Pillai, V. V. S.; Rodriguez, B. J.; Prencipe, M.; Benedetto, A. Sub-Toxic Concentrations of Ionic Liquids Enhance Cell Migration by Reducing the Elasticity of the Cellular Lipid Membrane. J. Phys. Chem. Lett. 2020, 11 (17), 7327– 7333,  DOI: 10.1021/acs.jpclett.0c02149

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    35

    Sub-toxic concentrations of ionic liquids enhance cell migration by reducing the elasticity of the cellular lipid membrane

    Kumari, Pallavi; Pillai, Visakh V. S.; Rodriguez, Brian J.; Prencipe, Maria; Benedetto, Antonio

    Journal of Physical Chemistry Letters (2020), 11 (17), 7327-7333CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)

    Cell migration is a universal and crucial mechanism for life. It is required in a series of physiol. processes, in wound repair and immune response and is involved in several pathol. conditions, including cancer and virus dissemination. Among the several biochem. and biophys. routes, changing cell membrane elasticity holds the promise to be a universal strategy to alter cell mobility. Due to their affinity with cell membranes, ionic liqs. (ILs) may play an important role. This work focuses on the effect of subtoxic amts. of imidazolium-ILs on the migration of the model cancer cell line MDA-MB-231. Here we show that ILs are able to enhance cell mobility by reducing the elasticity of the cellular lipid membrane, and that both mobility and elasticity can be tuned by IL-concn. and IL-cation chain length. This biochem.-phys. mechanism is potentially valid for all mammalian cells, and its impact in bionanomedicine and bionanotechnol. is discussed.

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36. 36

    Attri, P.; Jha, I.; Choi, E. H.; Venkatesu, P. Variation in the Structural Changes of Myoglobin in the Presence of Several Protic Ionic Liquid. Int. J. Biol. Macromol. 2014, 69, 114– 123,  DOI: 10.1016/j.ijbiomac.2014.05.032

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    36

    Variation in the structural changes of myoglobin in the presence of several protic ionic liquid

    Attri, Pankaj; Jha, Indrani; Choi, Eun Ha; Venkatesu, Pannuru

    International Journal of Biological Macromolecules (2014), 69 (), 114-123CODEN: IJBMDR; ISSN:0141-8130. (Elsevier B.V.)

    Protein stability in ionic soln. depends on the delicate balance between protein-ion and ion-ion interactions. To address the ion specific effects on the protein, we have examd. the stability of myoglobin (Mb) in the presence of buffer and ammonium-based ionic liqs. (ILs) (50%, vol./vol.). Here, fluorescence and CD (CD) spectroscopy expts. are used to study the influence of ILs on structure and stability of Mb. Our exptl. results reveal that more viscous ILs (sulfate or phosphate ions) are stabilizers and therefore more biocompatible for Mb structure. Surprisingly, the less viscous ILs such as acetate anion based ILs are destabilizers for the native structure of Mb. Our results explicitly elucidate that anion variation has significant influence on Mb stability efficiency than cation variation. This study provides insight into anion effects on protein stability and explains that the intrasolvent interactions can be leveraged to enhance the stability.

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    Pillai, V. V. S.; Benedetto, A. Ionic Liquids in Protein Amyloidogenesis: A Brief Screenshot of the State-of-the-Art. Biophys. Rev. 2018, 10 (3), 847– 852,  DOI: 10.1007/s12551-018-0425-4

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    37

    Ionic liquids in protein amyloidogenesis: a brief screenshot of the state-of-the-art

    Pillai, Visakh V. S.; Benedetto, Antonio

    Biophysical Reviews (2018), 10 (3), 847-852CODEN: BRIECG; ISSN:1867-2450. (Springer)

    Ionic liqs. (ILs) are a vast class of org. non-aq. electrolytes whose interaction with biomols. is receiving great attention for potential applications in bio-nano-technol. Recently, it has been shown that ILs can affect protein amyloidogenesis. Whereas some ILs favor the aggregation of proteins into amyloids, others inhibit their formation. Moreover, ILs can dissolve mature fibrils and restore the protein biochem. function. In this letter, we present a brief state-of-the-art summary of this emerging field that holds the promise of important developments both in basic science and in applications from bio-medicine to material science, and bio-nano-technol. The huge variety of ILs offers a vast playground for future studies and potential applications.

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38. 38

    Takekiyo, T.; Yamaguchi, E.; Abe, H.; Yoshimura, Y. Suppression Effect on the Formation of Insulin Amyloid by the Use of Ionic Liquids. ACS Sustain. Chem. Eng. 2016, 4 (2), 422– 428,  DOI: 10.1021/acssuschemeng.5b00936

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    Takekiyo, T.; Yamada, N.; Nakazawa, C. T.; Amo, T.; Asano, A.; Yoshimura, Y. Formation of A-synuclein Aggregates in Aqueous Ethylammonium Nitrate Solutions. Biopolymers 2020, 111 (6), e23352,  DOI: 10.1002/bip.23352

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    39

    Formation of α-synuclein aggregates in aqueous ethylammonium nitrate solutions

    Takekiyo, Takahiro; Yamada, Natsuki; Nakazawa, Chikako T.; Amo, Taku; Asano, Atsushi; Yoshimura, Yukihiro

    Biopolymers (2020), 111 (6), e23352CODEN: BIPMAA; ISSN:0006-3525. (John Wiley & Sons, Inc.)

    The effect of adding ethylammonium nitrate (EAN), which is an ionic liq. (IL), on the aggregate formation of α-synuclein (α-Syn) in aq. soln. has been investigated. FTIR and Raman spectroscopy were used to investigate changes in the secondary structure of α-Syn and in the states of water mols. and EAN. The results presented here show that the addn. of EAN to α-Syn causes the formation of an intermol. β-sheet structure in the following manner: native disordered state → polyproline II (PPII)-helix → intermol. β-sheet (α-Syn amyloid-like aggregates: α-SynA). Although cations and anions of EAN play roles in masking the charged side chains and PPII-helix-forming ability involved in the formation of α-SynA, water mols. are not directly related to its formation. We conclude that EAN-induced α-Syn amyloid-like aggregates form at hydrophobic assocns. in the middle of the mols. after masking the charged side chains at the N- and C-terminals of α-Syn.

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    Takekiyo, T.; Yamada, N.; Amo, T.; Yoshimura, Y. Aggregation Selectivity of Amyloid β1–11 Peptide in Aqueous Ionic Liquid Solutions. Peptide Sci. 2020, 112 (2), e24138,  DOI: 10.1002/pep2.24138

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    40

    Aggregation selectivity of amyloid β1-11 peptide in aqueous ionic liquid solutions

    Takekiyo, Takahiro; Yamada, Natsuki; Amo, Taku; Yoshimura, Yukihiro

    Peptide Science (Hoboken, NJ, United States) (2020), 112 (2), e24138CODEN: PSHNAR; ISSN:2475-8817. (John Wiley & Sons, Inc.)

    Understanding the aggregation selectivity of peptide fragments of full-length proteins in aq. solns. with ionic liqs. (ILs) could facilitate the elucidation of the relationship between the IL-protein interactions and structural behavior of intrinsically disordered proteins (IDPs) such as amyloid β protein following the addn. of ILs. In the present study, we investigate structural changes in peptide fragment 1-11 (Aβ1-11) of amyloid β protein in aq. solns. with two ILs including 1-butyl-3-methylimidazolium thiocyanate ([bmim][SCN]) and ethylammonium nitrate (EAN) using optical spectroscopy. The addn. of [bmim][SCN], which exhibits strong protein denaturant ability, induced the formation of an intermol. β-sheet structure (aggregation), while the addn. of EAN, which has a weaker denaturant ability compared with [bmim][SCN], did not cause aggregation. Since the role of cations is related to the ability to mask the charged residues of Aβ1-11, the aggregation selectivity of Aβ1-11 depends on the anionic species and anions with high denaturation ability enhanced aggregation. Our results demonstrated that the structural change in peptide fragment in aq. IL solns. could be used to evaluate the relationship between the IL-protein interactions and aggregation selectivity in IDPs in aq. IL solns.

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41. 41

    Singh, G.; Kaur, M.; Singh, M.; Kaur, H.; Kang, T. S. Spontaneous Fibrillation of Bovine Serum Albumin at Physiological Temperatures Promoted by Hydrolysis-Prone Ionic Liquids. Langmuir 2021, 37 (34), 10319– 10329,  DOI: 10.1021/acs.langmuir.1c01350

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    41

    Spontaneous Fibrillation of Bovine Serum Albumin at Physiological Temperatures Promoted by Hydrolysis-Prone Ionic Liquids

    Singh, Gagandeep; Kaur, Manvir; Singh, Manpreet; Kaur, Harmandeep; Kang, Tejwant Singh

    Langmuir (2021), 37 (34), 10319-10329CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)

    This study highlights the role of time-dependent hydrolysis of ionic liq. anion, [BF4]-, of ionic liq. (IL), 1-ethyl-3-methylimidazolium tetrafluoroborate, [C2mim][BF4], which results in ever-changing pH conditions. Such pH changes along with the ionic interactions bring conformational changes in bovine serum albumin (BSA), giving amyloid fibers at 37° without external control of pH or addn. of electrolyte. The fibrillation of BSA occurs spontaneously with the addn. of IL; however, the highest growth rate was obsd. in aq. soln. of 10% IL (vol./vol. %) among studied systems. Thioflavin T (ThT) fluorescence emission was employed to monitor the growth and development of β-sheet content in amyloid fibrils. The structural alterations in BSA also were studied using intrinsic fluorescence measurements. CD measurements confirmed the formation of amyloid fibrils. TEM was explored to establish the morphologies of BSA fibrils at different intervals of time, whereas at. force microscopy (AFM) established the helically twisted nature of grown amyloid fibrils. The docking studies were used to understand the insertion of IL ions in different domains of BSA, which along with decreased pH cause the unfolding and growth of BSA into amyloid fibrils. It is expected that the results obtained from this study would help to understand the impact of IL contg. [BF4]- anion on protein stability and aggregation along with providing a new platform to control the formation of amyloid fibrils and other biomaterials driven via ionic interactions and alterations in pH.

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42. 42

    Gobbo, D.; Cavalli, A.; Ballone, P.; Benedetto, A. Computational Analysis of the Effect of [Tea][Ms] and [Tea][H₂ PO₄] Ionic Liquids on the Structure and Stability of Aβ(17–42) Amyloid Fibrils. Phys. Chem. Chem. Phys. 2021, 23 (11), 6695– 6709,  DOI: 10.1039/D0CP06434C

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    42

    Computational analysis of the effect of [Tea][Ms] and [Tea][H2PO4] ionic liquids on the structure and stability of Aβ(17-42) amyloid fibrils

    Gobbo, D.; Cavalli, A.; Ballone, P.; Benedetto, A.

    Physical Chemistry Chemical Physics (2021), 23 (11), 6695-6709CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)

    Exptl. studies have reported the possibility of affecting the growth/dissoln. of amyloid fibers by the addn. of org. salts of the room-temp. ionic-liq. family, raising the tantalizing prospect of controlling these processes under physiol. conditions. The effect of [Tea][Ms] and [Tea][H2PO4] at various concns. on the structure and stability of a simple model of Aβ42 fibrils has been investigated by computational means. Free energy computations show that both [Tea][Ms] and [Tea][H2PO4] decrease the stability of fibrils with respect to isolated peptides in soln., and the effect is significantly stronger for [Tea][Ms]. The secondary structure of fibrils is not much affected, but single peptides in soln. show a marked decrease in their β-strand character and an increase in α-propensity, again esp. for [Tea][Ms]. These observations, consistent with the exptl. picture, can be traced to two primary effects, i.e., the difference in the ionicity of the [Tea][Ms] and [Tea][H2PO4] water solns. and the remarkable affinity of peptides for [Ms]- anions, due to the multiplicity of H-bonds.

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43. 43

    Fedunova, D.; Antosova, A.; Marek, J.; Vanik, V.; Demjen, E.; Bednarikova, Z.; Gazova, Z. Effect of 1-Ethyl-3-Methylimidazolium Tetrafluoroborate and Acetate Ionic Liquids on Stability and Amyloid Aggregation of Lysozyme. Int. J. Mol. Sci. 2022, 23 (2), 783,  DOI: 10.3390/ijms23020783

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    43

    Effect of 1-Ethyl-3-methylimidazolium Tetrafluoroborate and Acetate Ionic Liquids on Stability and Amyloid Aggregation of Lysozyme

    Fedunova, Diana; Antosova, Andrea; Marek, Jozef; Vanik, Vladimir; Demjen, Erna; Bednarikova, Zuzana; Gazova, Zuzana

    International Journal of Molecular Sciences (2022), 23 (2), 783CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)

    Amyloid fibrils draw attention as potential novel biomaterials due to their high stability, strength, elasticity or resistance against degrdn. Therefore, the controlled and fast fibrillization process is of great interest, which raises the demand for effective tools capable of regulating amyloid fibrillization. Ionic liqs. (ILs) were identified as effective modulators of amyloid aggregation. The present work is focused on the study of the effect of 1-ethyl-3-Me imidazolium-based ILs with kosmotropic anion acetate (EMIM-ac) and chaotropic cation tetrafluoroborate (EMIM-BF4) on the kinetics of lysozyme amyloid aggregation and morphol. of formed fibrils using fluorescence and CD spectroscopy, differential scanning calorimetry, AFM with statistical image anal. and docking calcns. We have found that both ILs decrease the thermal stability of lysozyme and significantly accelerate amyloid fibrillization in a dose-dependent manner at concns. of 0.5%, 1% and 5% (vol./vol.) in conditions and time-frames when no fibrils are formed in ILs-free solvent. The effect of EMIM-BF4 is more prominent than EMIM-ac due to the different specific interactions of the anionic part with the protein surface. Although both ILs induced formation of amyloid fibrils with typical needle-like morphol., a higher variability of fibril morphol. consisting of a different no. of intertwining protofilaments was identified for EMIM-BF4.

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44. 44

    Bharmoria, P.; Mondal, D.; Pereira, M. M.; Neves, M. C.; Almeida, M. R. Instantaneous Fibrillation of Egg White Proteome with Ionic Liquid and Macromolecular Crowding. Commun. Mater. 2020, 1 (1), 34,  DOI: 10.1038/s43246-020-0035-0

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45. 45

    Kumari, M.; Sharma, S.; Deep, S. Tetrabutylammonium Based Ionic Liquids (ILs) Inhibit the Amyloid Aggregation of Superoxide Dismutase 1 (SOD1). J. Mol. Liq. 2022, 353, 118761,  DOI: 10.1016/j.molliq.2022.118761

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    45

    Tetrabutylammonium based ionic liquids (ILs) inhibit the amyloid aggregation of superoxide dismutase 1 (SOD1)

    Kumari, Meena; Sharma, Shilpa; Deep, Shashank

    Journal of Molecular Liquids (2022), 353 (), 118761CODEN: JMLIDT; ISSN:0167-7322. (Elsevier B.V.)

    Aggregation of a protein is assocd. with several biol. and industrial processes: some wanted and some unwanted. An understanding of the mechanism of modulation of aggregation is, thus, required for designing strategies for the prevention/enhancement of amyloids. Misfolding and aggregation of human Cu-Zn superoxide dismutase (SOD1) into amyloid aggregates is a hallmark of a fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS). Therefore, targeting SOD1 protein could be a good choice for understanding the mechanism of SOD1 pathol. in ALS. Here, we study the inhibitory effect of ammonium and choline based ionic liqs. (ILs) (tetrabutylammonium methanesulfonate (TBAMS), tetrabutylammonium chloride (TBACl) and choline chloride (CholCl) on amyloid aggregation of SOD1 and explore how ILs modulate the formation of amyloid aggregates. We demonstrate that aq. solns. of TBAMS and TBACl effectively inhibit SOD1 fibrillation, and their inhibitory effect increased with increasing the concn. Conversely, CholCl has been found to act as an amyloid inhibitor at lower concns. by acting at the elongation step and as an amyloid promoter at higher concns. Our exptl. results showed that TBAMS and TBACl induce the formation of compact structures with reduced hydrophobicity. Theor. anal. revealed that ILs stabilize Zn binding loop and electrostatic loop which play an important role in the structure and function of SOD1. These findings provide important insights about using IL as an anti-amyloidal agent for other amyloidogenic proteins and help to design effective modulators for protein aggregation.

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46. 46

    Byrne, N.; Angell, C. A. Formation and Dissolution of Hen Egg White Lysozyme Amyloid Fibrils in Protic Ionic Liquids. Chem. Commun. 2009, (9), 1046– 1048,  DOI: 10.1039/b817590j

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    46

    Formation and dissolution of hen egg white lysozyme amyloid fibrils in protic ionic liquids

    Byrne, Nolene; Angell, C. Austen

    Chemical Communications (Cambridge, United Kingdom) (2009), (9), 1046-1048CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)

    The formation of amyloid fibrils from non-disease-related proteins demonstrates that any protein can adopt this "rogue" form; we show that it is possible to use protic ionic liqs. to fibrilize hen egg white lysozyme, and then subsequently to dissolve the fibrils with up to 72% restoration of enzymic activity.

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47. 47

    Kalhor, H. R.; Kamizi, M.; Akbari, J.; Heydari, A. Inhibition of Amyloid Formation by Ionic Liquids: Ionic Liquids Affecting Intermediate Oligomers. Biomacromolecules 2009, 10 (9), 2468– 2475,  DOI: 10.1021/bm900428q

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    47

    Inhibition of Amyloid Formation by Ionic Liquids: Ionic Liquids Affecting Intermediate Oligomers

    Kalhor, Hamid Reza; Kamizi, Mostafa; Akbari, Jafar; Heydari, Akbar

    Biomacromolecules (2009), 10 (9), 2468-2475CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

    In searching for alternative ways to reduce or inhibit amyloid formation, we have studied this process using hen egg white lysozyme (HEWL) in the presence of a low concn. of protic ionic liqs. The ionic liqs. were synthesized in a combinatorial fashion maintaining the cationic part (tetramethylguanidinium) with alteration of the anionic component of each compd. tested. It was obsd. that one of these compds. (tetramethylguanidinium acetate) inhibited amyloid formation of HEWL in vitro by nearly 50%. Examn. under transmission electron microscopy confirmed the fibril inhibition, and fibrils were obsd. to be morphol. thinner. To investigate the mechanism of inhibition, intrinsic fluorescence, ANS binding, and CD analyses were performed. These analyses indicated that the native structure of HEWL was maintained in the presence of the ionic liq. Performing native PAGE and nondenaturing agarose electrophoresis, it became evident that some of the intermediate oligomers were not converted to protofibrils and that the oligomers were trapped in more stable conformations. Addnl., it was obsd. that this inhibitory effect was related to the ionic liq. itself and not the solvated ions. It also became evident that the carboxyl functional group was important in the inhibition. The size of the anions and kosmotropicity did not play significant roles in the fibril inhibition.

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48. 48

    Gosal, W. S.; Morten, I. J.; Hewitt, E. W.; Smith, D. A.; Thomson, N. H.; Radford, S. E. Competing Pathways Determine Fibril Morphology in the Self-Assembly of Beta2-Microglobulin into Amyloid. J. Mol. Biol. 2005, 351 (4), 850– 864,  DOI: 10.1016/j.jmb.2005.06.040

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    48

    Competing Pathways Determine Fibril Morphology in the Self-assembly of β2-Microglobulin into Amyloid

    Gosal, Walraj S.; Morten, Isobel J.; Hewitt, Eric W.; Smith, D. Alastair; Thomson, Neil H.; Radford, Sheena E.

    Journal of Molecular Biology (2005), 351 (4), 850-864CODEN: JMOBAK; ISSN:0022-2836. (Elsevier B.V.)

    Despite its importance in biol. phenomena, a comprehensive understanding of the mechanism of amyloid formation remains elusive. Here, we use at. force microscopy to map the formation of β2-microglobulin amyloid fibrils with distinct morphologies and persistence lengths, when protein concn., pH and ionic strength are varied. Using the resulting state-diagrams, we demonstrate the existence of two distinct competitive pathways of assembly, which define an energy landscape that rationalises the sensitivity of fibril morphol. on the soln. conditions. Importantly, we show that semi-flexible (worm-like) fibrils, which form rapidly during assembly, are kinetically trapped species, formed via a non-nucleated pathway that is explicitly distinct from that leading to the formation of the relatively rigid long-straight fibrils classically assocd. with amyloid. These semi-flexible fibrils also share an antibody epitope common to other protein oligomers that are known to be toxic species linked to human disease. The results demonstrate the heterogeneity of amyloid assembly, and have important implications for our understanding of the importance of oligomeric states in amyloid disease, the origins of prion strains, and the development of therapeutic strategies.

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49. 49

    Nitani, A.; Muta, H.; Adachi, M.; So, M.; Sasahara, K. Heparin-Dependent Aggregation of Hen Egg White Lysozyme Reveals Two Distinct Mechanisms of Amyloid Fibrillation. J. Biol. Chem. 2017, 292 (52), 21219– 21230,  DOI: 10.1074/jbc.M117.813097

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    49

    Heparin-dependent aggregation of hen egg white lysozyme reveals two distinct mechanisms of amyloid fibrillation

    Nitani, Ayame; Muta, Hiroya; Adachi, Masayuki; So, Masatomo; Sasahara, Kenji; Sakurai, Kazumasa; Chatani, Eri; Naoe, Kazumitsu; Ogi, Hirotsugu; Hall, Damien; Goto, Yuji

    Journal of Biological Chemistry (2017), 292 (52), 21219-21230CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    Heparin, a biopolymer possessing high neg. charge d., is known to accelerate amyloid fibrillation by various proteins. Using hen egg white lysozyme, we studied the effects of heparin on protein aggregation at low pH, raised temp., and applied ultrasonic irradn., conditions under which amyloid fibrillation was promoted. Heparin exhibited complex bimodal concn.-dependent effects, either accelerating or inhibiting fibrillation at pH 2.0 and 60 °C. At concns. lower than 20 μg/mL, heparin accelerated fibrillation through transient formation of hetero-oligomeric aggregates. Between 0.1 and 10 mg/mL, heparin rapidly induced amorphous heteroaggregation with little to no accompanying fibril formation. Above 10 mg/mL, heparin again induced fibrillation after a long lag time preceded by oligomeric aggregate formation. Compared with studies performed using monovalent and divalent anions, the results suggest two distinct mechanisms of heparin-induced fibrillation. At low heparin concns., initial hen egg white lysozyme cluster formation and subsequent fibrillation is promoted by counter ion binding and screening of repulsive charges. At high heparin concns., fibrillation is caused by a combination of salting out and macromol. crowding effects probably independent of protein net charge. Both fibrillation mechanisms compete against amorphous aggregation, producing a complex heparin concn.-dependent phase diagram. Moreover, the results suggest an active role for amorphous oligomeric aggregates in triggering fibrillation, whereby breakdown of supersatn. takes place through heterogeneous nucleation of amyloid on amorphous aggregates.

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50. 50

    Hill, S. E.; Miti, T.; Richmond, T.; Muschol, M. Spatial Extent of Charge Repulsion Regulates Assembly Pathways for Lysozyme Amyloid Fibrils. PLoS One 2011, 6 (4), e18171,  DOI: 10.1371/journal.pone.0018171

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    50

    Spatial extent of charge repulsion regulates assembly pathways for lysozyme amyloid fibrils

    Hill, Shannon E.; Miti, Tatiana; Richmond, Tyson; Muschol, Martin

    PLoS One (2011), 6 (4), e18171CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

    Formation of large protein fibrils with a characteristic cross β-sheet architecture is the key indicator for a wide variety of systemic and neurodegenerative amyloid diseases. Recent expts. have strongly implicated oligomeric intermediates, transiently formed during fibril assembly, as crit. contributors to cellular toxicity in amyloid diseases. At the same time, amyloid fibril assembly can proceed along different assembly pathways that might or might not involve such oligomeric intermediates. Elucidating the mechanisms that det. whether fibril formation proceeds along non-oligomeric or oligomeric pathways, therefore, is important not just for understanding amyloid fibril assembly at the mol. level but also for developing new targets for intervening with fibril formation. We have investigated fibril formation by hen egg white lysozyme, an enzyme for which human variants underlie non-neuropathic amyloidosis. Using a combination of static and dynamic light scattering, at. force microscopy and CD, we find that amyloidogenic lysozyme monomers switch between three different assembly pathways: from monomeric to oligomeric fibril assembly and, eventually, disordered pptn. as the ionic strength of the soln. increases. Fibril assembly only occurred under conditions of net repulsion among the amyloidogenic monomers while net attraction caused pptn. The transition from monomeric to oligomeric fibril assembly, in turn, occurred as salt-mediated charge screening reduced repulsion among individual charged residues on the same monomer. We suggest a model of amyloid fibril formation in which repulsive charge interactions are a prerequisite for ordered fibril assembly. Furthermore, the spatial extent of non-specific charge screening selects between monomeric and oligomeric assembly pathways by affecting which subset of denatured states can form suitable intermol. bonds and by altering the energetic and entropic requirements for the initial intermediates emerging along the monomeric vs. oligomeric assembly path.

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    Yoshiike, Y.; Akagi, T.; Takashima, A. Surface Structure of Amyloid-Beta Fibrils Contributes to Cytotoxicity. Biochemistry 2007, 46 (34), 9805– 9812,  DOI: 10.1021/bi700455c

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    51

    Surface Structure of Amyloid-β Fibrils Contributes to Cytotoxicity

    Yoshiike, Yuji; Akagi, Takumi; Takashima, Akihiko

    Biochemistry (2007), 46 (34), 9805-9812CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

    Amyloid β (Aβ) toxicity has been hypothesized to initiate the pathogenesis of Alzheimer's disease (AD). The characteristic fibrillar morphol. of Aβ-aggregates, that constitute the main components of senile plaque, has long been considered to account for the neurotoxicity. But recent reports argue against a primary role for mature fibrils in AD pathogenesis because of the lack of a robust correlation between the severity of neurol. impairment and the extent of amyloid deposition. Toxicity from the sol. prefibrillar intermediate entity of aggregates often called oligomer has recently proposed a plausible explanation for this inconsistency. An alternative explanation is based on the observation that certain amyloid fibril morphologies are more toxic than others, indicating that not all amyloid fibrils are equally toxic. Here, we report that it is not only the β-sheeted fibrillar structure but also the surface physicochem. compn. that affects the toxicity of Aβ fibrils. For the first time, colloidal gold was used to visualize by electron microscopy pos.-charge clusters on Aβ fibrils. Chem. modifications as well as point-mutated Aβ synthesis techniques were applied to change the surface structures of Aβ and to show how local structure affects surface properties that are responsible for electrostatic and hydrophobic interactions with cells. We also report that covering the surface of Aβ fibers with myelin basic protein, which has surface properties contrary to those of Aβ, suppresses Aβ toxicity. On the basis of these results, we propose that the surface structure of Aβ fibrils plays an important role in Aβ toxicity.

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    Makky, A.; Bousset, L.; Polesel-Maris, J.; Melki, R. Nanomechanical Properties of Distinct Fibrillar Polymorphs of the Protein α-Synuclein. Sci. Rep. 2016, 6 (1), 37970,  DOI: 10.1038/srep37970

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    52

    Nanomechanical properties of distinct fibrillar polymorphs of the protein α-synuclein

    Makky, Ali; Bousset, Luc; Polesel-Maris, Jerome; Melki, Ronald

    Scientific Reports (2016), 6 (), 37970CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)

    Alpha-synuclein (α-Syn) is a small presynaptic protein of 140 amino acids. Its pathol. intracellular aggregation within the central nervous system yields protein fibrillar inclusions named Lewy bodies that are the hallmarks of Parkinson's disease (PD). In soln., pure α-Syn adopts an intrinsically disordered structure and assembles into fibrils that exhibit considerable morphol. heterogeneity depending on their assembly conditions. We recently established tightly controlled exptl. conditions allowing the assembly of α-Syn into highly homogeneous and pure polymorphs. The latter exhibited differences in their shape, their structure but also in their functional properties. We have conducted an AFM study at high resoln. and performed a statistical anal. of fibrillar α-Syn shape and thermal fluctuations to calc. the persistence length to further assess the nanomech. properties of α-Syn polymorphs. Herein, we demonstrated quant. that distinct polymorphs made of the same protein (wild-type α-Syn) show significant differences in their morphol. (height, width and periodicity) and phys. properties (persistence length, bending rigidity and axial Young's modulus).

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53. 53

    Lee, G.; Lee, W.; Lee, H.; Woo Lee, S.; Sung Yoon, D.; Eom, K.; Kwon, T. Mapping the Surface Charge Distribution of Amyloid Fibril. Appl. Phys. Lett. 2012, 101 (4), 043703,  DOI: 10.1063/1.4739494

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    53

    Mapping the surface charge distribution of amyloid fibril

    Lee, Gyudo; Lee, Wonseok; Lee, Hyungbeen; Woo Lee, Sang; Sung Yoon, Dae; Eom, Kilho; Kwon, Taeyun

    Applied Physics Letters (2012), 101 (4), 043703/1-043703/4CODEN: APPLAB; ISSN:0003-6951. (American Institute of Physics)

    It is of high importance to measure and map the surface charge distribution of amyloids, since electrostatic interaction between amyloidogenic proteins and biomols. plays a vital role in amyloidogenesis. In this work, we have measured and mapped the surface charge distributions of amyloids (i.e., β-lactoglobulin fibril) using Kelvin probe force microscopy. It is shown that the surface charge distribution is highly dependent on the conformation of amyloids (e.g., the helical pitch of amyloid fibrils) as well as the pH of a solvent. (c) 2012 American Institute of Physics.

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54. 54

    Gupta, A. N.; Neupane, K.; Rezajooei, N.; Cortez, L. M.; Sim, V. L.; Woodside, M. T. Pharmacological Chaperone Reshapes the Energy Landscape for Folding and Aggregation of the Prion Protein. Nat. Commun. 2016, 7 (1), 12058,  DOI: 10.1038/ncomms12058

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    Pharmacological chaperone reshapes the energy landscape for folding and aggregation of the prion protein

    Gupta, Amar Nath; Neupane, Krishna; Rezajooei, Negar; Cortez, Leonardo M.; Sim, Valerie L.; Woodside, Michael T.

    Nature Communications (2016), 7 (), 12058CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)

    The development of small-mol. pharmacol. chaperones as therapeutics for protein misfolding diseases has proven challenging, partly because their mechanism of action remains unclear. Here we study Fe-TMPyP, a tetrapyrrole that binds to the prion protein PrP and inhibits misfolding, examg. its effects on PrP folding at the single-mol. level with force spectroscopy. Single PrP mols. are unfolded with and without Fe-TMPyP present using optical tweezers. Ligand binding to the native structure increases the unfolding force significantly and alters the transition state for unfolding, making it more brittle and raising the barrier height. Fe-TMPyP also binds the unfolded state, delaying native refolding. Furthermore, Fe-TMPyP binding blocks the formation of a stable misfolded dimer by interfering with intermol. interactions, acting in a similar manner to some mol. chaperones. The ligand thus promotes native folding by stabilizing the native state while also suppressing interactions driving aggregation.

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55. 55

    Benedetto, A. STFC ISIS Neutron and Muon Source, 2014.  DOI: 10.5286/ISIS.E.49916443 .

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56. 56

    Benedetto, A. Low-Temperature Decoupling of Water and Protein Dynamics Measured by Neutron Scattering. J. Phys. Chem. Lett. 2017, 8 (19), 4883– 4886,  DOI: 10.1021/acs.jpclett.7b02273

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    Low-temperature decoupling of water and protein dynamics measured by neutron scattering

    Benedetto, Antonio

    Journal of Physical Chemistry Letters (2017), 8 (19), 4883-4886CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)

    Water plays a major role in biosystems, greatly contributing to det. their structure, stability, and function. It is well known, for instance, that proteins require a min. amt. of water to be fully functional. Despite many years of intensive research, however, the detailed nature of protein-hydration water interactions is still partly unknown. The widely accepted "protein dynamical transition" scenario is based on perfect coupling between the dynamics of proteins and that of their hydration water, which has never been probed in depth exptl. Here, the author presents high-resoln. elastic neutron scattering measurements of the atomistic dynamics of lysozyme in water. The results showed for the first time that the dynamics of proteins and of their hydration water are actually decoupled at low temps. This important result challenges the "protein dynamical transition" scenario and requires a new model to link protein dynamics to the dynamics of its hydration water.

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    Gardner, J. S.; Ehlers, G.; Faraone, A.; García Sakai, V. High-Resolution Neutron Spectroscopy Using Backscattering and Neutron Spin-Echo Spectrometers in Soft and Hard Condensed Matter. Nat. Rev. Phys. 2020, 2 (2), 103– 116,  DOI: 10.1038/s42254-019-0128-1

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58. 58

    Benedetto, A. STFC ISIS Neutron and Muon Source, 2014. DOI: 10.5286/ISIS.E.42583628 .

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