The oligomerization of Aβ16–22 peptide, which is the hydrophobic core region of full-length Aβ1–42, causes Alzheimer’s disease (AD). This progressive neurodegenerative disease affects over 44 million people worldwide. However, very few synthesized drug molecules are available to inhibit the aggregation of Aβ. Recently, experimental studies have shown that the biological ATP molecule prevents Aβ fibrillation at the millimolar scale; however, the significance of ATP molecules on Aβ fibrillation and the mechanism behind it remain elusive. We have carried out a total of 7.5 μs extensive all-atom molecular dynamics and 8.82 μs of umbrella sampling in explicit water using AMBER14SB, AMBER99SB-ILDN, and AMBER-FB15 force fields for Aβ16–22 peptide, to investigate the role of ATP on the disruption of Aβ16–22 prefibrils. From various analyses, such as secondary structure analysis, residue-wise contact map, SASA, and interaction energies, we have observed that, in the presence of ATP, the aggregation of Aβ16–22 peptide is very unfavorable. Moreover, the biological molecule ATP interacts with the Aβ16–22 peptide via hydrogen bonding, π–π stacking, and NH−π interactions which, ultimately, prevent the aggregation of Aβ16–22 peptide. Hence, we assume that the deficiency of ATP may cause Alzheimer’s disease (AD).

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.

Guanine-rich quadruplex nucleic acid (G-DNA) sequence is highly polymorphic. The obtained structure of G-DNA is exquisitely impressible to its sequence and the chemical environment. Due to its controllable different structures, G-DNA has acquired much attention in various research areas such as nanotechnology, medicinal chemistry, and molecular biology. However, the applications of G-DNA are mainly restricted to the aqueous media, although a large number of important chemical reactions, nanodevices, etc. have also been carried out in purely water-free medium. Recently, deep eutectic solvents (DESs) such as choline−urea (1:2) eutectic mixture, namely, reline, has widely been used as a reaction medium and also water-free storage medium for biological systems like different types of nucleic acids. Hence, it is very important to figure out the effect of the deep eutectic solvent with DNA. In this research work, we have discussed the interaction between reline with guanine-rich quadruplex thrombin-binding aptamer (TBA) DNA at 300 K, for different reline concentrations. To understand the conformational behavior of quadruplex TBA in reline DES, we have performed 10 μs all-atom molecular dynamics simulations. Here, we note that the structure of TBA deviates much more from its NMR structure at low reline concentrations. In other way, at high reline concentrations, the quadruplex TBA is much more rigid or less flexible than comparatively lower reline concentrations. Moreover, from the spatial distribution function study, the density of reline is higher near sugar phosphate backbone region than the others. Furthermore, at lower reline concentrations, guanine-8 and thymine-9 of loop-2 stack to each other, which is not noted at higher reline concentrations.

The noncanonical guanine-rich DNAs have drawn particular attention to the scientific world due to their controllable diverse and polymorphic structures. Apart from biological and medical significance, G-quadruplex DNAs are widely used in various fields such as nanotechnology, nanomachine, biosensors, and biocatalyst. So far, the applications of the G-quadruplex DNA are mainly limited in the water medium. Recently, a new generation of solvent named deep eutectic solvent (DES) has become very popular and has been widely used as a reaction medium of biocatalytic reactions and long-term storage medium for nucleic acids, even at high temperature. Hence, it is essential to understand the role of DES on temperature-induced conformational changes of a G-quadruplex DNA. In this research work, we have explored the temperature-mediated conformational dynamics of c-kit oncogene promoter G-quadruplex DNA in reline medium in the temperature range of 300–500 K, using a total of 10 μs unbiased all-atom molecular dynamics simulation. Here, from RMSD, RMSF, R g and principal component analyses, we notice that the c-kit G-quadruplex DNA is stable up to 450 K in reline medium. However, it unfolds in water medium at 450 K. It is found that the hydrogen bonding interactions between c-kit G-quadruplex DNA and reline play a key role in the stabilization of the G-quadruplex DNA even at high temperature. Furthermore, in this work we have observed a very interesting and distinctive phenomenon of the central cation of the G-quadruplex DNA. Its position was seen to fluctuate between the two tetrad cores, that is, the region between tetrad-1 and tetrad-2 and that between tetrad-2 and tetrad-3 and vice versa at 450 and 500 K in reline medium which is absent in water medium at 450 K. Moreover, the rate of its oscillation is increased when temperature is increased.

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The self-assembly of N-and C-protected alternating L/L and D/L amino acids containing dipeptides, Boc-L-Val-L-Ile-OMe (1), Boc-D-Val-L-Ile-OMe (2), Boc-L-Ile-L-Val-OMe (3), and Boc-L-Ile-D-Val-OMe (4) has been investigated. Field emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM) images indicated that 1 and 3 self-associated to form highly organized straight net microrods, whereas 2 and 4 self-assembled to form hexagonal hollow microtube-like architecture in the acetonitrile-water medium. To understand the physical basis of such differential behavior, we performed X-ray diffraction pattern analyses. The singlecrystal X-ray diffraction (SC-XRD) study revealed that 1 and 2 self-assembled to form slightly different helix-like architectures. The higher-order association of 2 exhibited a hollow hexagonal tube-like superstructure. The thermal stability of the nanostructures also varied based on the chiroptical composition of the dipeptides. Experimental findings were corroborated well with computational studies. The obtained results may be helpful in nano-biotechnology as well as in material science.

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.

Identification of the top, bottom and side loop binding modes of the APTO-253 ligand on c-KIT G-quadruplex DNA.