Atomistic level understanding of the stabilization of protein Trp cage in denaturing and mixed osmolyte solutions

Borgohain, Gargi; Paul, Sandip

doi:10.1016/j.comptc.2018.03.013

Cited by 11 publications

(13 citation statements)

References 77 publications

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“…It is worth mentioning here that we have determined the number of hydrogen bonds of R500 system, before the G-quadruplex DNA starts unfolding, that is, up to 150 ns of the simulation run. We have set two requirements to determine the hydrogen bonds as followed by preceding researches, − where (i) the distance cutoff between donor (D) and acceptor (A) is less than or equal to 3.5 Å and at the same time (ii) the donor(D)–acceptor(A)–hydrogen(H) angle cutoff is less than or equal to 45°. In Figure , we present the average number of hydrogen bonds between each residues of the c-kit DNA and the reline molecules.…”

Section: Results and Discussionsupporting

confidence: 61%

Understanding The Role of Reline, a Natural DES, on Temperature-Induced Conformational Changes of C-Kit G-Quadruplex DNA: A Molecular Dynamics Study

Pal

Paul

2020

J. Phys. Chem. B

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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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Section: Results and Discussionsupporting

confidence: 61%

Understanding The Role of Reline, a Natural DES, on Temperature-Induced Conformational Changes of C-Kit G-Quadruplex DNA: A Molecular Dynamics Study

Pal

Paul

2020

J. Phys. Chem. B

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“…We have estimated the average number of hydrogen bonds formed by quadruplex-TBA with choline, urea, and water molecules. For this, following previous studies, − a set of geometric criteria are assigned. If the distance between the donor (D) and acceptor (A) is ≤3.5 Å and, simultaneously, the angle of D–H–A is ≤45°, then a hydrogen bond is considered.…”

Section: Results and Discussionmentioning

confidence: 99%

Effect of Hydrated and Nonhydrated Choline Chloride–Urea Deep Eutectic Solvent (Reline) on Thrombin-Binding G-quadruplex Aptamer (TBA): A Classical Molecular Dynamics Simulation Study

Pal

Paul

2019

J. Phys. Chem. C

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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.

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“…It has a stable and well-defined tertiary structure in aqueous media at room temperature and unfolds only above 317 K. The native structure of Trp-cage in water includes of α-helix (Leu2-Lys8), a 3 10 -helix (Gly11-Ser14), and a polyproline II helix (Pro17-Pro19), which is stabilized by the salt bridge formed between the Asp9 and Arg16 residues and a hydrogen bond between the carbonyl oxygen of Arg16 and Hϵ1 of Trp6. It also consists of a hydrophobic cage formed by the packing of Tyr and Trp6 residues around Gly11, Pro12, Pro18, and Pro19 residues, which is crucial for maintaining the integrity of the structure. − …”

Section: Introductionmentioning

confidence: 99%

Potential of a Natural Deep Eutectic Solvent, Glyceline, in the Thermal Stability of the Trp-Cage Mini-protein

2020

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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.

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Atomistic level understanding of the stabilization of protein Trp cage in denaturing and mixed osmolyte solutions

Cited by 11 publications

References 77 publications

Understanding The Role of Reline, a Natural DES, on Temperature-Induced Conformational Changes of C-Kit G-Quadruplex DNA: A Molecular Dynamics Study

Understanding The Role of Reline, a Natural DES, on Temperature-Induced Conformational Changes of C-Kit G-Quadruplex DNA: A Molecular Dynamics Study

Effect of Hydrated and Nonhydrated Choline Chloride–Urea Deep Eutectic Solvent (Reline) on Thrombin-Binding G-quadruplex Aptamer (TBA): A Classical Molecular Dynamics Simulation Study

Potential of a Natural Deep Eutectic Solvent, Glyceline, in the Thermal Stability of the Trp-Cage Mini-protein

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