Deep eutectic solvents (DESs) are the new class of green and inexpensive anhydrous solvents, which are alternatives of ionic liquids. The applications of these promising anhydrous sustainable solvents in biological media have been explored. However, the behavior and stability of biomolecules in DES are not clearly understood. In this study, we have investigated the stability of Trp-cage mini-protein in glyceline, which is a natural deep eutectic mixture (NADES) of choline chloride and glycerol. A series of all-atom molecular dynamics at different temperatures are carried out, and it is found that the protein is stable at much higher temperatures in a DES solvent than in water medium. It is observed that at 400 K this protein denatures from its native state in water medium whereas it retains its native structure up to 400 K temperature in DES medium. Through various analyses, it is also noticed that the interaction between the protein and the glycerol and the choline molecules decreases with the increase in temperature from 300 to 400 K. The crucial parameters, which help in the stabilization of the folded conformation of Trp-cage mini-protein, are maintained in glyceline up to a temperature of 400 K, but they disintegrate at 450 K. The low diffusion coefficient of the glyceline molecules helps to maintain the folded conformation of Trp-cage, which increases at high temperature, causing distortion in the stable interactions between the mini-protein and the solvent molecules. This ultimately leads to the unfolding of the mini-protein. Since Trp-cage mini-protein is a prototypical protein, the thermal stability of this protein in this NADES proves this solvent as an ideal medium for biocatalytic reactions and long-time storage of biomolecules.
The search for an appropriate drug to completely eradicate type II diabetes (T2D), a metabolic disorder from which over 40 million people suffer worldwide, has not yet led to any satisfactory result. The misfolding of human islet amyloid polypeptide (hIAPP) into toxic oligomers is a pathogenic feature of this disease, due to which the prevention of hIAPP aggregation is considered the rational approach to combat T2D. Hence, we study the role of a catecholamine, norepinephrine, on the amyloid aggregation of hIAPP, which has previously displayed inhibitory effect on amyloid-β aggregation. Via all-atom molecular dynamics simulations, we observe that norepinephrine can not only inhibit the aggregation of hIAPP but also partially disassemble the preformed fibrils. For comparison, the influence of two other molecules (aspirin and benzimidazole, both of which have previously reported to have no inhibitory impact on hIAPP aggregation) is also analyzed. We observe that the conformational preference of hIAPP changes from a β-sheet conformation to a disordered state when norepinephrine is added to the peptides. However, no such effect is observed in the presence of aspirin or benzimidazole. In-depth investigation reveals that the β-sheets formed between Leu12–His18 and Leu27–Gly33 enhance the peptide–peptide interactions that are broken by norepinephrine, which itself interacts with the peptides via hydrogen bonding, hydrophobic, and aromatic stacking interactions, preferentially with the C-terminal residues of hIAPP. The molecular mechanism action of norepinephrine on hIAPP aggregation can provide useful insight for the drug design against T2D.
The aggregation of an intrinsically disordered protein, human islet amyloid polypeptide (hIAPP), leads to one of the most prevalent endocrine disorders, type II diabetes mellitus (T2DM). Hence inhibition of hIAPP aggregation provides a possible therapeutic approach for the treatment of T2DM. In this regard, a new aspect of adenosine triphosphate (ATP), which is widely known as the energy source for biological reactions, has recently been discovered, where it can inhibit the formation of protein aggregates and simultaneously dissolve preformed aggregates at a millimolar concentration scale. In this work, we investigate the effect of ATP on the aggregation of an amyloidogenic segment of hIAPP, hIAPP22–28, and also of the full length sequence. Using all-atom classical molecular dynamics simulations, we observe that the tendency of hIAPP to oligomerize into β-sheet conformers is inhibited by ATP, due to which the peptides remain distant, loosely packed random monomers. Moreover, it can also disassemble preformed hIAPP protofibrils. ATP preferentially interacts with the hydrophobic residues of hIAPP22–28 fragment and the terminal and turn residues of the full length peptide. The hydrogen bonding, hydrophobic, π–π, and N–H−π stacking interactions are the driving forces for the ATP induced inhibition of hIAPP aggregation. Interestingly, the hydrophobic adenosine of ATP is found to be more in contact with the peptide residues than the hydrophilic triphosphate moiety. The insight into the inhibitory mechanism of ATP on hIAPP aggregation can prove to be beneficial for the design of novel amyloid inhibitors in the future.
The onset of amyloidogenic diseases is associated with the misfolding and aggregation of proteins. Despite extensive research, no effective therapeutics are yet available to treat these chronic degenerative diseases. Targeting the aggregation of disease-specific proteins is regarded as a promising new approach to treat these diseases. In the past few years, rapid progress in this field has been made in vitro, in vivo, and in silico to generate potential drug candidates, ranging from small molecules to polymers to nanoparticles. Small molecular probes, mostly those derived from natural sources, have been of particular interest among amyloid inhibitors. Here, we summarize some of the most important natural small molecular probes which can inhibit the aggregation of Aβ, hIAPP, and α-syn peptides and discuss how their binding efficacy and preference for the peptides vary with their structure and conformation. This provides a comprehensive idea of the crucial factors which should be incorporated into the future design of novel drug candidates useful for the treatment of amyloid diseases.
The aggregation of Tau protein, which are involved in Alzheimer’s disease, are associated with the self-assembly of the hexapeptide sequence, paired helical filament 6 (PHF6) from repeat 3 of Tau. In order to treat Alzheimer’s disease and other such tauopathies, one of the therapeutic strategies is to inhibit aggregation of Tau and its nucleating segments. Therefore, we have studied the effect of adenosine triphosphate (ATP) on the aggregation of PHF6. ATP has, interestingly, demonstrated its ability to inhibit and dissolve protein aggregates. Using classical molecular dynamics simulations, we observed that the hydrophobic core of PHF6 segment displays extended β-sheet conformation, which stabilizes PHF6 aggregates. However, the distribution of ATP around the vicinity of the peptides enables PHF6 to remain discrete and attain random coil conformers. The interpeptide interactions are substituted by PHF6–ATP interactions through hydrogen bonding and hydrophobic interactions (including π–π stacking). Furthermore, the adenosine moiety of ATP contributes more than the triphosphate chain toward PHF6–ATP interaction. Ultimately, this work establishes the inhibitory activity of ATP against Tau aggregation; hence, the therapeutic effect of ATP should be explored further in regard to the effective treatment of Alzheimer’s disease.
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