Modulation of amyloid fibrillation of bovine β-lactoglobulin by selective methionine oxidation

Deposition of oxidation-modified proteins during normal aging and oxidative stress are directly associated with systemic amyloidoses. Methionine (Met) is believed to be one of the most readily oxidisable amino acid residues of protein. Bovine beta-lactoglobulin (β-lg), a model globular whey protein, has been presented as a subsequent paradigm for studies on protein aggregation and amyloid formation. Herein, we investigated the effect of t-butyl hydroperoxide (tBHP)-induced oxidation on structure, compactness and fibrillation propensity of β-lg at physiological pH. Notably, whey protein modification, specifically Met residues, plays an important role in the dairy industry during milk processing and lowering nutritional value and ultimately affecting their technological properties. Several bio-physical studies revealed enhanced structural flexibility and aggregation propensity of oxidised β-lg in a temperature dependent manner. A molecular docking study is used to predict possible interactions with tBHP and infers selective oxidation of methionine residues at 7, 24 and 107 positions. From our studies, it can be corroborated that specific orientations of Met residues directs the formation of a partially unfolded state susceptible to fibrillation with possible different cytotoxic effects. Our studies have greater implications in deciphering the underlying mechanism of different whey proteins encountering oxidative stress. Our findings are also important to elucidate the understanding of oxidation induced amyloid fibrillation of protein which may constitute a new route to pave the way for a modulatory role of oxidatively stressed proteins in neurological disorders.

This work reports selective methionine oxidation of β-lactoglobulin by tBHP reduces its thermal stability and enhances fibrillation propensity.     

N-Amino peptide scanning reveals inhibitors of Aβ42 aggregation

The aggregation of amyloids into toxic oligomers is believed to be a key pathogenic event in the onset of Alzheimer''s disease. Peptidomimetic modulators capable of destabilizing the propagation of an extended network of β-sheet fibrils represent a potential intervention strategy. Modifications to amyloid-beta (Aβ) peptides derived from the core domain have afforded inhibitors capable of both antagonizing aggregation and reducing amyloid toxicity. Previous work from our laboratory has shown that peptide backbone amination stabilizes β-sheet-like conformations and precludes β-strand aggregation. Here, we report the synthesis of N-aminated hexapeptides capable of inhibiting the fibrillization of full-length Aβ₄₂. A key feature of our design is N-amino substituents at alternating backbone amides within the aggregation-prone Aβ_16–21 sequence. This strategy allows for maintenance of an intact hydrogen-bonding backbone edge as well as side chain moieties important for favorable hydrophobic interactions. An N-amino scan of Aβ_16–21 resulted in the identification of peptidomimetics that block Aβ₄₂ fibrilization in several biophysical assays.

Structure-based design of backbone-aminated peptides affords novel β-strand mimics that inhibit amyloid-beta fibrillogenesis.     

Mapping molecular binding by means of conformational dynamics measurements

Protein–protein interactions are key in virtually all biological processes. The study of these interactions and the interfaces that mediate them play a key role in the understanding of biological function. In particular, the observation of protein–protein interactions in their dynamic environment is technically difficult. Here two surface analysis techniques, dual polarization interferometry and quartz crystal microbalance with dissipation monitoring, were paired for real-time mapping of the conformational dynamics of protein–protein interactions. Our approach monitors this dynamics in real time and in situ, which is a great advancement within technological platforms for drug discovery. Results agree with the experimental observations of the interaction between the TRIM21α protein and circulating autoantibodies via a bridging bipolar mechanism. This work provides a new chip-based method to monitor conformational dynamics of protein–protein interactions, which is amenable to miniaturized high-throughput determination.

Protein–protein interactions are key in virtually all biological processes.     

Opiates Transdeactivate Chemokine Receptors: δ and μ Opiate Receptor–mediated Heterologous Desensitization

An intact chemotactic response is vital for leukocyte trafficking and host defense. Opiates are known to exert a number of immunomodulating effects in vitro and in vivo, and we sought to determine whether they were capable of inhibiting chemokine-induced directional migration of human leukocytes, and if so, to ascertain the mechanism involved. The endogenous opioid met-enkephalin induced monocyte chemotaxis in a pertussis toxin–sensitive manner. Met-enkephalin, as well as morphine, inhibited IL-8–induced chemotaxis of human neutrophils and macrophage inflammatory protein (MIP)-1α, regulated upon activation, normal T expressed and secreted (RANTES), and monocyte chemoattractant protein 1, but not MIP-1β–induced chemotaxis of human monocytes. This inhibition of chemotaxis was mediated by δ and μ but not κ G protein–coupled opiate receptors. Calcium flux induced by chemokines was unaffected by met-enkephalin pretreatment. Unlike other opiate-induced changes in leukocyte function, the inhibition of chemotaxis was not mediated by nitric oxide. Opiates induced phosphorylation of the chemokine receptors CXCR1 and CXCR2, but neither induced internalization of chemokine receptors nor perturbed chemokine binding. Thus, inhibition of chemokine-induced chemotaxis by opiates is due to heterologous desensitization through phosphorylation of chemokine receptors. This may contribute to the defects in host defense seen with opiate abuse and has important implications for immunomodulation induced by several endogenous neuropeptides which act through G protein–coupled receptors.     

The F19W mutation reduces the binding affinity of the transmembrane Aβ11–40 trimer to the membrane bilayer

Alzheimer''s disease is linked to the aggregation of the amyloid-β protein (Aβ) of 40 or 42 amino acids. Lipid membranes are known to modulate the rate and mechanisms of the Aβ aggregation. Point mutations in Aβ can alter these rates and mechanisms. In particular, experiments show that F19 mutations influence the aggregation rate, but maintain the fibril structures. Here, we used molecular dynamics simulations to examine the effect of the F19W mutation in the 3Aβ_11–40 trimer immersed in DPPC lipid bilayers submerged in aqueous solution. Substituting Phe by its closest (non-polar) aromatic amino acid Trp has a dramatic reduction in binding affinity to the phospholipid membrane (measured with respect to the solvated protein) compared to the wild type: the binding free energy of the protein–DPPC lipid bilayer increases by 40–50 kcal mol⁻¹ over the wild-type. This is accompanied by conformational changes and loss of salt bridges, as well as a more complex free energy surface, all indicative of a more flexible and less stable mutated trimer. These results suggest that the impact of mutations can be assessed, at least partially, by evaluating the interaction of the mutated peptides with the lipid membranes.

Dominant conformations of F19W 3Aβ_11–40 immersed in transmembrane DPPC lipid bilayer submerged in aqueous solution.     

Inhibition of metal-induced amyloid β-peptide aggregation by a blood–brain barrier permeable silica–cyclen nanochelator

Alzheimer''s disease (AD) is a neurodegenerative malady associated with amyloid β-peptide (Aβ) aggregation in the brain. Metal ions play important roles in Aβ aggregation and neurotoxicity. Metal chelators are potential therapeutic agents for AD because they could sequester metal ions from the Aβ aggregates and reverse the aggregation. The blood–brain barrier (BBB) is a major obstacle for drug delivery to AD patients. Herein, a nanoscale silica–cyclen composite combining cyclen as the metal chelator and silica nanoparticles as a carrier was reported. Silica–cyclen was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) and dynamic light scattering (DLS). The inhibitory effect of the silica–cyclen nanochelator on Zn²⁺- or Cu²⁺-induced Aβ aggregation was investigated by using a BCA protein assay and TEM. Similar to cyclen, silica–cyclen can effectively inhibit the Aβ aggregation and reduce the generation of reactive oxygen species induced by the Cu–Aβ₄₀ complex, thereby lessening the metal-induced Aβ toxicity against PC12 cells. In vivo studies indicate that the silica–cyclen nanochelator can cross the BBB, which may provide inspiration for the construction of novel Aβ inhibitors.

A BBB-passable nanoscale silica–cyclen chelator effectively reduces the metal-induced Aβ aggregates and related ROS, thereby decreasing the neurotoxicity of Aβ.     

Protein–lipid complexes: molecular structure,current scenarios and mechanisms of cytotoxicity

Some natural proteins can be complexed with oleic acid (OA) to form an active protein–lipid formulation that can induce tumor-selective apoptosis. The first explored protein was human milk α-lactalbumin (α-LA), called HAMLET when composed with OA in antitumor form. Several groups have prepared active protein–lipid complexes using a variety of approaches, all of which depend on target protein destabilization or direct OA–protein incubation to alter pH to acid or alkaline condition. In addition to performing vital roles in inflammatory processes and immune responses, fatty acids can disturb different metabolic pathways and cellular signals. Therefore, the tumoricidal action of these complexes is related to OA rather than the protein that keeps OA in solution and acts as a vehicle for transferring OA molecules to tumor cells. However, other studies have suggested that the antitumor efficacy of these complexes was exerted by both protein and OA together. The potential is not limited to the anti-tumor activity of protein–lipid complexes but extends to other functions such as bactericidal activity. The protein shell enhances the solubility and stability of the bound fatty acid. These protein–lipid complexes are promising candidates for fighting various cancer types and managing bacterial and viral infections.

Some natural proteins can be complexed with oleic acid (OA) to form an active protein–lipid formulation that can induce tumor-selective apoptosis.     

T Cell Receptor (TCR) Interacting Molecule (TRIM), A Novel Disulfide-linked Dimer Associated with the TCR–CD3–ζ Complex,Recruits Intracellular Signaling Proteins to the Plasma Membrane

The molecular mechanisms regulating recruitment of intracellular signaling proteins like growth factor receptor–bound protein 2 (Grb2), phospholipase Cγ1, or phosphatidylinositol 3-kinase (PI3-kinase) to the plasma membrane after stimulation of the T cell receptor (TCR)– CD3–ζ complex are not very well understood. We describe here purification, tandem mass spectrometry sequencing, molecular cloning, and biochemical characterization of a novel transmembrane adaptor protein which associates and comodulates with the TCR–CD3–ζ complex in human T lymphocytes and T cell lines. This protein was termed T cell receptor interacting molecule (TRIM). TRIM is a disulfide-linked homodimer which is comprised of a short extracellular domain of 8 amino acids, a 19–amino acid transmembrane region, and a 159–amino acid cytoplasmic tail. In its intracellular domain, TRIM contains several tyrosine-based signaling motifs that could be involved in SH2 domain–mediated protein–protein interactions. Indeed, after T cell activation, TRIM becomes rapidly phosphorylated on tyrosine residues and then associates with the 85-kD regulatory subunit of PI3-kinase via an YxxM motif. Thus, TRIM represents a TCR-associated transmembrane adaptor protein which is likely involved in targeting of intracellular signaling proteins to the plasma membrane after triggering of the TCR.     

Interactions between β-cyclodextrin and tea catechins,and potential anti-osteoclastogenesis activity of the (−)-epigallocatechin-3-gallate–β-cyclodextrin complex

Galloylated catechins, the most important secondary metabolites in green tea including (−)-epigallocatechin-3-gallate (EGCG) and (−)-epicatechin-3-gallate, constitute nearly 75% of all tea catechins and have stronger health effects than non-galloylated catechins such as (−)-epigallocatechin and (−)-epicatechin. EGCG is the most abundant, active, and thoroughly investigated compound in green tea, and its bioactivity might be improved by complexing with β-cyclodextrin (β-CD). We investigated interactions between four catechins and β-CD in a PBS buffer solution of pH 6.5 at 25 °C using biolayer interferometry and isothermal titration calorimetry, and to determine whether β-CD could enhance the anti-osteoclastogenesis effect of EGCG. β-CD could directly bind galloylated catechins at a stoichiometric ratio close to 1 : 1, with high specificities and affinities, and these inclusion interactions were primarily enthalpy-driven processes. We synthesized the EGCG–β-CD complex and identified it using infrared radiation and nuclear magnetic resonance spectra. Interestingly, we revealed that the EGCG–β-CD complex could inhibit osteoclastogenesis significantly more than EGCG.

The EGCG–β-CD complex inhibited osteoclastogenesis significantly more than EGCG, and the molecular mechanism was closely associated with the downregulation of NFATc1.     

Modelling of interactions between Aβ(25–35) peptide and phospholipid bilayers: effects of cholesterol and lipid saturation

Aggregation of amyloid beta (Aβ) peptides in neuronal membranes is a known promoter of Alzheimer’s disease. To gain insight into the molecular details of Aβ peptide aggregation and its effect on model neuronal membranes, we carried out molecular dynamics simulations of the Aβ(25–35) fragment of the amyloid precursor protein in phospholipid bilayers composed of either fully saturated or highly unsaturated lipids, in the presence or absence of cholesterol. It was found that the peptide does not penetrate through any of the considered membranes, but can reside in the headgroup region and upper part of the lipid tails showing a clear preference to a polyunsaturated cholesterol-free membrane. Due to the ordering and condensing effect upon addition of cholesterol, membranes become more rigid facilitating peptide aggregation on the surface. Except for the case of the cholesterol-free saturated lipid bilayer, the peptides have a small effect on the membrane structure and ordering. It was also found that the most “active” amino-acid for peptide–lipid and peptide–cholesterol interaction is methionine-35, followed by asparagine-27 and serine-26, which form hydrogen bonds between peptides and polar atoms of lipid headgroups. These amino acids are also primarily responsible for peptide aggregation. This work will be relevant for designing strategies to develop drugs to combat Alzheimer’s disease.

Molecular dynamics simulations of Aβ(25–35) peptides in phospholipid bilayers are carried out to investigate the effect of polyunsaturated lipids and cholesterol on aggregation of the peptides.     

Fabrication of BP2T functionalized graphene via non-covalent π–π stacking interactions for enhanced ammonia detection

Graphene has stimulated great enthusiasm in a variety of fields, while its chemically inert surface still remains challenging for functionalization towards various applications. Herein, we report an approach to fabricate non-covalently functionalized graphene by employing π–π stacking interactions, which has potentialities for enhanced ammonia detection. 5,5′-Di(4-biphenylyl)-2,2′-bithiophene (BP2T) molecules are used in our work for the non-covalent functionalization through strong π–π interactions of aromatic structures with graphene, and systematic investigations by employing various spectroscopic and microscopic characterization methods confirm the successful non-covalent attachment of the BP2T on the top of graphene. From our gas sensing experiments, the BP2T functionalized graphene is promising for ammonia sensing with a 3-fold higher sensitivity comparing to that of the pristine graphene, which is mainly attributed to the enhanced binding energy between the ammonia and BP2T molecules derived by employing the Langmuir isotherm model. This work provides essential evidence of the π–π stacking interactions between graphene and aromatic molecules, and the reported approach also has the potential to be widely employed in a variety of graphene functionalizations for chemical detection.

Non-covalent functionalization of graphene has been achieved by employing π–π stacking interactions, and it is promising for ammonia detection with greatly enhanced sensitivity.     

Neutrophil AKT2 regulates heterotypic cell-cell interactions during vascular inflammation

Interactions between platelets, leukocytes, and activated endothelial cells are important during microvascular occlusion; however, the regulatory mechanisms of these heterotypic cell-cell interactions remain unclear. Here, using intravital microscopy to evaluate mice lacking specific isoforms of the serine/threonine kinase AKT and bone marrow chimeras, we found that hematopoietic cell–associated AKT2 is important for neutrophil adhesion and crawling and neutrophil-platelet interactions on activated endothelial cells during TNF-α–induced venular inflammation. Studies with an AKT2-specific inhibitor and cells isolated from WT and Akt KO mice revealed that platelet- and neutrophil-associated AKT2 regulates heterotypic neutrophil-platelet aggregation under shear conditions. In particular, neutrophil AKT2 was critical for membrane translocation of αMβ2 integrin, β2-talin1 interaction, and intracellular Ca²⁺ mobilization. We found that the basal phosphorylation levels of AKT isoforms were markedly increased in neutrophils and platelets isolated from patients with sickle cell disease (SCD), an inherited hematological disorder associated with vascular inflammation and occlusion. AKT2 inhibition reduced heterotypic aggregation of neutrophils and platelets isolated from SCD patients and diminished neutrophil adhesion and neutrophil-platelet aggregation in SCD mice, thereby improving blood flow rates. Our results provide evidence that neutrophil AKT2 regulates αMβ2 integrin function and suggest that AKT2 is important for neutrophil recruitment and neutrophil-platelet interactions under thromboinflammatory conditions such as SCD.     

Extent of Laminin-5 Assembly and Secretion Effect Junctional Epidermolysis Bullosa Phenotype

Junctional epidermolysis bullosa (JEB) is an autosomal recessive skin blistering disease with both lethal and nonlethal forms, with most patients shown to have defects in laminin-5. We analyzed the location of mutations, gene expression levels, and protein chain assembly of the laminin-5 heterotrimer in six JEB patients to determine how the type of genetic lesion influences the pathophysiology of JEB. Mutations within laminin-5 genes were diversely located, with the most severe forms of JEB correlating best with premature termination codons, rather than mapping to any particular protein domain. In all six JEB patients, the laminin-5 assembly intermediates we observed were as predicted by our previous work indicating that the α3β3γ2 heterotrimer assembles intracellularly via a β3γ2 heterodimer intermediate. Since assembly precedes secretion, mutations that disrupt protein–protein interactions needed for assembly are predicted to limit the secretion of laminin-5, and likely to interfere with function. However, our data indicate that typically the most severe mutations diminish mRNA stability, and serve as functional null alleles that block chain assembly by resulting in either a deficiency (in the nonlethal mitis variety) or a complete absence (in lethal Herlitz-JEB) of one of the chains needed for laminin-5 heterotrimer assembly.     

Chemical synthesis,inhibitory activity and molecular mechanism of 1-deoxynojirimycin–chrysin as a potent α-glucosidase inhibitor

Hyperglycemia can be efficaciously regulated by inhibiting α-glucosidase activity and this is regarded as an effective strategy to treat type 2 diabetes. 1-Deoxynojimycin, an α-glucosidase inhibitor, can penetrate cells rapidly to potently inhibit α-glucosidase in a competitive manner. However, the application of 1-deoxynojimycin is limited by its poor lipophilicity and low bioavailability. Herein, three 1-deoxynojimycin derivatives 4–6 were designed and synthesized by linking 1-deoxynojimycin and chrysin to ameliorate the limitations of 1-deoxynojimycin. Among them, compound 6, a conjugate of 1-deoxynojimycin and chrysin linked by an undecane chain, could better bind to the α-glucosidase catalytic site, thereby exhibiting excellent α-glucosidase inhibitory activity (IC₅₀ = 0.51 ± 0.02 μM). Kinetics analyses revealed that compound 6 inhibited the activity of α-glucosidase in a reversible and mixed competitive manner. Fluorescence quenching and UV-Vis spectra showed that compound 6 changed the conformation of the α-glucosidase via complex formation, which triggered a static fluorescence quenching of the enzyme protein.

Hyperglycemia can be efficaciously regulated by inhibiting α-glucosidase activity and this is regarded as an effective strategy to treat type 2 diabetes.     

A ratiometric fluorescent probe for the detection of β-galactosidase and its application

Herein, a coumarin fluorescent probe (Probe 1) was developed for the ratiometric detection of β-galactosidase (β-gal) activity. The detection range was 0–0.1 U mL⁻¹ and 0.2–0.8 U mL⁻¹, and the limit of detection (LOD) was 0.0054 U mL⁻¹. Moreover, the luminous intensity of Probe 1 increased gradually with increase in β-gal activity. It could be observed under 254 nm UV irradiation by the naked eye. Furthermore, this method only required a small amount of sample (20 μL) and a short analytical time (30 min) for the detection of β-gal activity with a low LOD. Probe 1 was successfully used to detect β-gal activity in real fruit samples, and can be applied to the quantitative and qualitative detection of β-gal activity.

A ratiometric fluorescent probe was successfully used as a tool to determine β-galactosidase activity in fruits.     

Human Interferon-γ–inducible Protein 10 (IP-10) Inhibits Constitutive Signaling of Kaposi's Sarcoma–associated Herpesvirus G Protein–coupled Receptor

A G protein–coupled receptor (GPCR) is encoded within the genome of Kaposi''s sarcoma– associated herpesvirus (KSHV)/human herpesvirus 8, a virus that may be involved in the pathogenesis of Kaposi''s sarcoma and primary effusion lymphomas. KSHV-GPCR exhibits constitutive signaling activity that causes oncogenic transformation. We report that human interferon (IFN)-γ–inducible protein 10 (HuIP-10), a C-X-C chemokine, specifically inhibits signaling of KSHV-GPCR. In contrast, monokine induced by IFN-γ (HuMig), which like HuIP-10 is an agonist of C-X-C chemokine receptor 3, does not inhibit KSHV-GPCR signaling. Moreover, HuIP-10, but not HuMig, inhibits KSHV-GPCR–induced proliferation of NIH 3T3 cells. These results show that HuIP-10 is an inverse agonist that converts KSHV-GPCR from an active to an inactive state. Thus, a human chemokine inhibits constitutive signaling and cellular proliferation that is mediated by a receptor encoded by a human disease-associated herpesvirus.     

Atypical Pulmonary Eosinophilia Is Mediated by a Specific Amino Acid Sequence of the Attachment (G) Protein of Respiratory Syncytial Virus

We analyzed the immune responses evoked by a series of overlapping peptides to better understand the molecular basis for respiratory syncytial virus (RSV) G protein–induced eosinophilia in BALB/c mice. In vitro stimulation of spleen cells from natural G protein–primed mice showed dominant proliferative and cytokine (interferon [IFN]-γ and interleukin [IL]-5) responses to a peptide encompassing amino acids 184–198. Mice vaccinated with peptide 184– 198 conjugated to keyhole limpet hemocyanin showed significant pulmonary eosinophilia (39.5%) after challenge with live RSV. In contrast, mice immunized with a peptide (208–222) conjugate associated with induction of IFN-γ secreting spleen cells did not exhibit pulmonary eosinophilia after challenge. The in vivo depletion of CD4⁺ cells abrogated pulmonary eosinophilia in mice vaccinated with the peptide 184–198 conjugate, whereas the depletion of CD8⁺ cells had a negligible effect. Therefore, we have identified an association between peptide 184– 198 of natural G protein and the CD4⁺ T cell–mediated induction of pulmonary eosinophilia after live RSV challenge. Out of 43 human donors, 6 provided peripheral blood mononuclear cells that showed reactivity to G protein from RSV A2, 3 of which responded to peptide 184– 198. The results have important implications for the development of a vaccine against RSV.     

Flaxseed orbitides,linusorbs, inhibit LPS-induced THP-1 macrophage inflammation

Linusorbs (flaxseed orbitides) are a family of naturally-occurring cyclic peptides. Previously, we reported that their anticancer effects were associated with their structures. In this study, we investigated the anti-inflammatory activities of 2 different linusorbs ([1–9-NαC]-linusorb B2 and [1–9-NαC]-linusorb B3) in lipopolysaccharide (LPS)-induced THP-1 macrophage activation as well as the underlying mechanism of this inflammatory response. Both molecules suppressed pro-inflammatory mediators (TNF-α, IL-1β, IL-6, NO and COX-2) and were involved in downregulating the NF-κB signaling pathway. The suppressive effects on pro-inflammatory mediators were comparable and the concentration range of action was similar (1–4 μM). However, the concentration of compound that induced downregulation of the NF-κB pathway was different for each compound. While [1–9-NαC]-linusorb B3 could inhibit the activation of the NF-κB pathway at concentrations of 1 and 2 μM, [1–9-NαC]-linusorb B2 induced a comparable inhibitory effect at a concentration of 4 μM.

Linusorbs (flax orbitides) are a family of plant cyclic peptides. We investigate the anti-inflammatory activities of two different linusorbs ([1–9-NaC]-linusorb B2 and [1–9-NaC]-linusorb B3) and the underlying mechanism of this inflammatory response.     

Inhibitory effect of coumarin and its analogs on insulin fibrillation /cytotoxicity is depend on oligomerization states of the protein

Looking through a historical lens, attention to the stabilization of pharmaceutical proteins/peptides has been dramatically increased. Human insulin is the most challenging and the most widely used pharmaceutical protein in the world. In this study, the protein and coumarin as a plant-derived phenolic compound and two coumarin analogs with different moieties were investigated to evaluate the protein fibrillation and cytotoxicity. The obtained data showed that with a change in environmental pH, the behavior of the compounds on the process of insulin fibrillation will be changed completely. Coumarin (C1) and its hydrophobic analog, 7-methyl coumarin (C2), in an acidic environment, inhibit insulin fibrillation, change the oligomerization state of insulin and produce fibrils with notable lateral interactions with low cytotoxicity. However, negatively-charged 3-trifluoromethyl coumarin (C3) without significant changes in insulin structure and by altering the oligomerization state of the protein, slightly accelerates hormone fibrillation. Also, the compounds showed a disulfide protecting role during protein aggregation. Regarding the toxicity of the fibrils, it was observed that in addition to the secondary structures of proteinous fibrils, the ability to destroy the cell membrane is also related to the length of the fibrils and their degree of lateral interactions. By and large, this work can be useful in finding a better formulation for bio-pharmaceutical macro-molecules.

The effect of the applied compounds on insulin fibrillation at two pHs. By and large, the compounds through changing the oligomerization states and altering structure integrity of insulin can govern the fibrillation process.