Amyloidogenesis, with its multifaceted nature spanning from peptide self-assembly to membrane-mediated structural transitions, presents a significant challenge for the interdisciplinary scientific community. Here, we emphasize on how Singular Value Decomposition (SVD) can be employed to reveal hidden patterns and dominant modes of interaction that govern the complex process of amyloidogenesis. We first utilize SVD analysis on Circular Dichroism (CD) spectral datasets to identify the intermediate structural species emerging during peptide-membrane interactions and to determine binding constants more precisely than conventional methods. We investigate the monomer loss kinetics associated with peptide self-assembly using Nuclear Magnetic Resonance (NMR) dataset and determine the global kinetic parameters through SVD. Furthermore, we explore the seeded growth of amyloid fibrils by analyzing a time-dependent NMR dataset, shedding light on the kinetic intricacies of this process. Our analysis uncovers two distinct states in the aggregation of Aβ40 and pinpoints key residues responsible for this seeded growth. To strengthen our findings and enhance their robustness, we validate those using simulated data, thereby highlighting the physical interpretations derived from SVD. Overall, SVD analysis offers a model-free, global kinetic perspective, enabling the selection of optimal kinetic models. This study not only contributes valuable insights into the dynamics but also highlights the versatility of SVD in unravelling complex processes of amyloidogenesis.

The calcium ion (Ca2+) has been linked to type 2 diabetes mellitus (T2DM), although the role of Ca2+ in this disorder is the subject of intense investigation. Serum Ca2+ dyshomeostasis is associated with the development of insulin resistance, reduced insulin sensitivity, and impaired glucose tolerance. However, the molecular mechanisms involving Ca2+ ions in pancreatic β-cell loss and subsequently in T2DM remain poorly understood. Implicated in the decline in β-cell functions are aggregates of human islet amyloid polypeptide (hIAPP), a small peptide secreted by β-cells that shows a strong tendency to self-aggregate into β-sheet-rich aggregates that evolve toward the formation of amyloid deposits and mature fibrils. The soluble oligomers of hIAPP can permeabilize the cell membrane by interacting with bilayer lipids. Our study aimed to evaluate the effect of Ca2+ on the ability of the peptide to incorporate and form ion channels in zwitterionic planar lipid membranes (PLMs) composed of palmitoyl-oleoyl-phosphatidylcholine (POPC) and on the aggregation process of hIAPP molecules in solution. Our results may help to clarify the link between Ca2+ ions, hIAPP peptide, and consequently the pathophysiology of T2DM.

β-Carboline alkaloids have a variety of pharmacological activities, such as antitumor, antibiosis and antidiabetes. Harmine and harmol are two structurally similar β-carbolines that occur in many medicinal plants. In this work, we chose harmine and harmol to impede the amyloid fibril formation of human islet amyloid polypeptide (hIAPP) associated with type 2 diabetes mellitus (T2DM), by a series of physicochemical and biochemical methods. The results indicate that harmine and harmol effectively prevent peptide fibril formation and alleviate toxic oligomer species. In addition, both small molecules exhibit strong binding affinities with hIAPP mainly through hydrophobic and hydrogen bonding interactions, thus reducing the cytotoxicity induced by hIAPP. Their distinct binding pattern with hIAPP is closely linked to the molecular configuration of the two small molecules, affecting their ability to impede peptide aggregation. The study is of great significance for the application and development of β-carboline alkaloids against T2DM.

Aggregation of the human islets amyloid polypeptide, or hIAPP, is linked to β-cell death in type II diabetes mellitus (T2DM). Different pancreatic β-cell environmental variables such as pH, insulin and metal ions play a key role in controlling the hIAPP aggregation. Since insulin and hIAPP are co-secreted, it is known from numerous studies that insulin suppresses hIAPP fibrillation by preventing the initial dimerization process. On the other hand, zinc and copper each have an inhibitory impact on hIAPP fibrillation, but copper promotes the production of toxic oligomers. Interestingly, the insulin oligomeric equilibrium is controlled by the concentration of zinc ions when the effect of insulin and zinc has been tested together. Lower zinc concentrations cause the equilibrium to shift towards the monomer and dimer states of insulin, which bind to monomeric hIAPP and stop it from developing into a fibril. On the other hand, the combined effects of copper and insulin have not yet been studied. In this study, we have demonstrated how the presence of copper affects hIAPP aggregation and the toxicity of the resultant conformers with or without insulin. For this purpose, we have used a set of biophysical techniques, including NMR, fluorescence, CD etc., in combination with AFM and cell cytotoxicity assay. In the presence and/or absence of insulin, copper induces hIAPP to form structurally distinct stable toxic oligomers, deterring the fibrillation process. More specifically, the oligomers generated in the presence of insulin have slightly higher toxicity than those formed in the absence of insulin. This research will increase our understanding of the combined modulatory effect of two β-cell environmental factors on hIAPP aggregation.

The misfolding and un-natural fibrillation of proteins/peptides are associated with many conformation diseases, such as human islet amyloid polypeptide (hIAPP) in type 2 diabetes (T2D). Inspired by molecular chaperones maintaining protein homeostasis in vivo, many polymer-based artificial chaperones were introduced to regulate protein/peptide folding and fibrillation. However, the pure polymer chaperones prefer to agglomerate into large-size micelles in the physiological environment and thus lose their chaperone functions, which greatly restricts the application of polymer-based chaperones. Here, we designed and prepared a core-shell artificial chaperone based on a dozen poly-(N-isopropylacrylamide-co-N-acryloyl-O-methylated-l-arginine) (PNAMR) anchored on a gold-nanocluster (AuNC) core. The introduction of the AuNC core significantly reduced the size and enhanced the efficacy and stability of polymer-based artificial chaperones. The PNAMR@AuNCs, with a diameter of 2.5 ± 0.5 nm, demonstrated exceptional ability in maintaining the natively unfolded conformation of protein away from the misfolding and the following fibrillation by directly binding to the natively unfolded monomolecular hIAPP and hence in preventing their conversion into toxic oligomers. More excitingly, the PNAMR@AuNCs were able to restore the natural unfolded conformation of hIAPP via dissolving the β-sheet-rich hIAPP fibrils. Considering the uniform molecular mechanism of protein misfolding and fibrillation in conformation disorders, this finding provides a generic therapeutic strategy for neurodegenerative diseases and other conformation diseases by using PNAMR@AuNC artificial chaperones to restore and maintain the native conformation of amyloid proteins.

The pathogenesis of type 2 diabetes (T2D) is highly related to the abnormal self-assembly of the human islet amyloid polypeptide (hIAPP) into amyloid aggregates. To inhibit hIAPP aggregation is considered a promising therapeutic strategy for T2D treatment. Melatonin (Mel) was reported to effectively impede the accumulation of hIAPP aggregates and dissolve preformed fibrils. However, the underlying mechanism at the atomic level remains elusive. Here, we performed replica-exchange molecular dynamics (REMD) simulations to investigate the inhibitory effect of Mel on hIAPP oligomerization by using hIAPP20-29 octamer as templates. The conformational ensemble shows that Mel molecules can significantly prevent the β-sheet and backbone hydrogen bond formation of hIAPP20-29 octamer and remodel hIAPP oligomers and transform them into less compact conformations with more disordered contents. The interaction analysis shows that the binding behavior of Mel is dominated by hydrogen bonding with a peptide backbone and strengthened by aromatic stacking and CH-π interactions with peptide sidechains. The strong hIAPP-Mel interaction disrupts the hIAPP20-29 association, which is supposed to inhibit amyloid aggregation and cytotoxicity. We also performed conventional MD simulations to investigate the influence and binding affinity of Mel on the preformed hIAPP1-37 fibrillar octamer. Mel was found to preferentially bind to the amyloidogenic region hIAPP20-29, whereas it has a slight influence on the structural stability of the preformed fibrils. Our findings illustrate a possible pathway by which Mel alleviates diabetes symptoms from the perspective of Mel inhibiting amyloid deposits. This work reveals the inhibitory mechanism of Mel against hIAPP20-29 oligomerization, which provides useful clues for the development of efficient anti-amyloid agents.

Human islet amyloid polypeptide (hIAPP) is associated with the pathology of Type II diabetes (T2DM) due to its misfolding and amyloid deposition. The peptide is widely concerned as a potential drug target, and the prevention of hIAPP fibrillation is a rational therapeutic strategy for T2DM. Platinum complexes are promising anticancer agents with good biocompatibility, they can resist the aggregation of amyloid peptides, while the effects of oxaliplatin and carboplatin on hIAPP fibrillation are unknown. In the present work, we selected the two platinum drugs to reveal their inhibition and disaggregation against hIAPP fibrillation by various biophysical methods. The two complexes impeded hIAPP fibril formation and dispersed the aggregates into small oligomers and most monomers. They also reduced peptides oligomerization and promoted rat insulinoma β-cells viability. They bound to hIAPP mainly through metal coordination and hydrophobic interactions. Moreover, oxaliplatin showed better inhibition and regulation on peptides aggregation and cytotoxicity than carboplatin. This work is of important biomedical values for clinical platinum drugs against T2DM and other amyloidosis related diseases.

Type 2 diabetes mellitus (T2DM) and other metabolic disorders are often silent and go unnoticed in patients because of the lack of suitable prognostic and diagnostic markers. The current therapeutic regimens available for managing T2DM do not reverse diabetes; instead, they delay the progression of diabetes. Their efficacy (in principle) may be significantly improved if implemented at earlier stages. The misfolding and aggregation of human islet amyloid polypeptide (hIAPP) or amylin has been associated with a gradual decrease in pancreatic β-cell function and mass in patients with T2DM. Hence, hIAPP has been recognized as a therapeutic target for managing T2DM. This review summarizes hIAPP\'s role in mediating dysfunction and apoptosis in pancreatic β-cells via induction of endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction, inflammatory cytokine secretion, autophagy blockade, etc. Furthermore, it explores the possibility of using intermediates of the hIAPP aggregation pathway as potential drug targets for T2DM management. Finally, the effects of common antidiabetic molecules and repurposed drugs; other hIAPP mimetics and peptides; small organic molecules and natural compounds; nanoparticles, nanobodies, and quantum dots; metals and metal complexes; and chaperones that have demonstrated potential to inhibit and/or reverse hIAPP aggregation and can, therefore, be further developed for managing T2DM have been discussed.

hIAPP is a hormone consisting of 37 aminoacids that shows a strong tendency to self-assemble into β-sheet-rich aggregates, which evolve to form insoluble aggregates that seem to be associated with β-cell degeneration in Type 2 Diabetes Mellitus. Numerous factors, intrinsic and extrinsic to the peptide molecule, appear to influence the hIAPP aggregation process. Different metal ions are able to interact with the hIAPP molecule, modulating its secondary structure and subsequently the peptide\'s capacity to aggregate. In this study, the effect of Hg2+ and Cd2+ on the hIAPP aggregation process was evaluated using direct and indirect methods. The kinetics and morphology of amyloid aggregate formation were respectively evaluated with Thioflavin T assays and electron microscopy, while the ability of the peptide to incorporate into POPC PLMs and form ion channels was monitored by single-channel current measurements. Hg2+ and Cd2+ each seem to modulate the peptide\'s ability to aggregate in a different way, suggesting a different mechanism of hIAPP toxicity.

The molecular structure of membrane lipids is formed by mono- or polyunsaturations on their aliphatic tails that make them susceptible to oxidation, facilitating the incorporation of hydroperoxide (R-OOH) functional groups. Such groups promote changes in both composition and complexity of the membrane significantly modifying its physicochemical properties. Human Langerhans islets amyloid polypeptide (hIAPP) is the main component of amyloid deposits found in the pancreas of patients with type-2 diabetes (T2D). hIAPP in the presence of membranes with oxidized lipid species accelerates the formation of amyloid fibrils or the formation of intermediate oligomeric structures. However, the molecular bases at the initial stage of the anchoring and stabilization of the hIAPP in a hydroperoxidized membrane are not yet well understood. To shed some light on this matter, in this contribution, three bilayer models were modeled: neutral (POPC), anionic (POPS), and oxidized (POPCOOH), and full atom Molecular Dynamics (MD) simulations were performed. Our results show that the POPCOOH bilayer increases the helicity in hIAPP when compared to POPC or POPS bilayer. The modification in the secondary structure covers the residues of the so-called amyloidogenic core of the hIAPP. Overall, the hydroperoxidation of the neutral lipids modifies both the anchoring and the stabilization of the peptide hIAPP by reducing the random conformations of the peptide and increasing of hydrogen bond population with the hydroperoxidized lipids.