Association of Nucleobases in Hydrated Ionic Liquid from Biased

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Association of Nucleobases in Hydrated Ionic Liquid from Biased Molecular Dynamics Simulations Sathish Dasari, and Bhabani S. Mallik J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b05778 • Publication Date (Web): 27 Sep 2018 Downloaded from http://pubs.acs.org on October 6, 2018

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The Journal of Physical Chemistry

Association of Nucleobases in Hydrated Ionic Liquid from Biased Molecular Dynamics Simulations Sathish Dasari† and Bhabani S. Mallik*,† †Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi-502285, Sangareddy, Telangana, India ABSTRACT: We employed metadynamics method based classical molecular dynamics simulations to methylated Adenine– Thymine (mA-mT) and Guanine–Cytosine (mG-mC) base pairs to see favorable conformations in various concentrations of hydrated 1-ethyl, 3-methyl imidazolium acetate. We investigated various stacked and hydrogen bonded conformations of association of base pairs through appropriately chosen collective variables. Stacked conformations are more favored in water for both base pairs, whereas Watson-Crick (WC) hydrogen bonding conformations are favored more in pure and hydrated ionic liquids except for 0.75 mole fraction of IL. We observe that EMIm cations surround the base pair in WC conformations creating a kind of hydrophobic cavity and protect the hydrogen bonds between base pairs. However, the five-membered heteroaromatic ring of cation stack with the nucleobases in cation-base-cation (π-π-π) model, which resembles the base-base-base stacking in DNA duplex. Interestingly, from additional simulations of 0.5 mole fraction of hydrated choline dihydrogen phosphate IL, we observe that the stacked conformations become more favored than WC conformation due to absence of π-bonds in cation. The calculated values of relative solubility of base pairs in pure and hydrated ionic liquids compared to pure water correlate well with the free energy values of WC and stacked conformations.

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INTRODUCTION Nucleobases are the nitrogen-containing compounds, which are the basic building blocks of the DNA that store and transfer the genetic information from one generation to another. DNA consists of four different types of bases: Adenine (A), Thymine (T), Guanine (G) and Cytosine (C). Adenine and guanine belong to the class of purine; other two belong to the class of pyrimidine nucleobase. In DNA, nucleobases undergo primarily two types of non-covalent interactions: hydrogen bonding and stacking. A-T base pair contains two hydrogen bonds between them, whereas G-C base pair has three hydrogen bonds. In aqueous solutions, DNA duplex having more GC content is more stable than the duplex with more A-T content.1,2 However, the balance between the hydrogen bonding and base stacking between these bases makes DNA more or less stable in a particular environment. To understand these noncovalent interactions, they were studied extensively as the model entities in different contexts. Because of the complexity of the gas phase experiments, there are very few studies on the base pairs, which reported the interaction enthalpies and their association constants.3,4 However, these investigations could not provide the structure of the base pairs. This drawback from experiments leads to the theoretical investigations on the base pairs, where one can get the information of stabilization energies, free energy, enthalpy as well as entropic contributions and geometries of the base pairs. Various groups studied the base pairs at different levels of theory from empirical, semiempirical, molecular dynamics to quantum mechanical calculations.5–9 Many studies investigating the hydrogen bonding and stacking conformations5–8,10–15 were also reported. The study of the base pairs in the gas phase indicated that the hydrogen-bonded conformations were more stable than the stacked conformations.5–8,10,16 However, the partially and completely solvated base pairs were favorable towards stacked

conformations when compared to the hydrogen-bonded ones.9,17 The formation of stacked conformations in water was also observed experimentally.3,18 Incorporating the methylated base pairs in a fully solvated system to a graphene layer or silicon surface showed that the hydrogen-bonded conformations became more favorable than the stacked conformation.19,20 Another study of base pairs on the hexagonal boron nitride sheet also revealed the preferred hydrogen-bonded conformations to stacked conformation.21 Depending on the environment, the propensity of making either H-bonded or stacked conformation of base pairs changes. On the other hand, room temperature ionic liquids (RTILs) have been playing an important role in various fields of scientific research, because of their unique and tunable chemical and physical properties.22–24 They show low vapor pressure, non-flammability, non-volatility, high ionic conductivity and high chemical and electrochemical stability.25,26 One of the advantages of ionic liquids is that their physicochemical properties can be modified by selecting appropriate cations and anions. Therefore, they are called as “designer solvents” and used as an alternative to the common organic solvents.24,27,28 They are also used in variety of bio-applications like media for bio-catalytic reactions, biosensors and bio-preservation.29,30 Fujita et al. reported enhanced solubility and stability of protein cytochrome c in pure and hydrated ionic liquids.31–33 The stability of α-chymotrypsin was obtained in ionic liquid using fluorescence and circular dichroism analysis.34 Using tryptophan residue as a spectroscopic handle, Baker group observed the enhanced thermodynamic stability of sweet protein monellin in the ionic liquid.30 Vijayaraghavan et al. reported that the structure and stability of DNA duplex was increased in hydrated ionic liquids when compared to the aqueous solution.35 The stability of DNA duplex was studied using both experimental method and molecular dynamics sim-

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ulation by Senapati and co-workers.36 DNA duplex with more A-T content was more stable than the DNA duplex with more G-C content in hydrated ionic liquids; this fact was contrary to the stability of DNA duplex in aqueous solution.37 DNA triplex also showed significant stability in hydrated ionic liquids compared to aqueous buffer solution.38 Molecular dynamics simulations were carried out to explain the solubility and stability of these biomolecules by many research groups.36,39–45 In a simulation study, the authors explained that the cation of ionic liquid replaced the water molecules from the protein surface, and protected the backbone hydrogen bonds.40 In another study, it was observed that the ionic liquid cations replaced the water molecules in the grooves of DNA duplex by protecting the hydrogen bonds between nucleobases from water molecules.43 Ding et al. characterized the molecular mechanism of interactions between 1-Butyl-3-methylimidazolium chloride, [BMIm][Cl], ionic liquid and DNA using several experimental techniques,46 and found coil to globule transition of DNA at low concentration of ionic liquid. 31P-NMR and FT-IR results indicated that the cationic head groups of cation interacted with the phosphate groups of DNA through electrostatic attraction and the hydrocarbon chains interact with the bases through strong hydrophobic association. The authors also observed that, in the presence of [BMIm][Cl], the IR band at 1713 cm-1 corresponding to base interactions was missing and DNA double helix was partially denatured. MD simulations by Cardoso et al. revealed the interactions between BMIM cation and DNA.47 They observed that cations also interacted with bases along with DNA main chain, and the cations interacted through hydrogen bond with oxygen, nitrogen acceptor atoms of guanine and amine groups of adenine. Wang et al. and others calculated the binding Gibbs free energy of ionic liquid with changing alkyl chain length of imidazolium cation.48,49 The results suggested that, electrostatic interaction between DNA and the cationic head group of IL was predominant and the non-covalent interaction between DNA and alkyl chain of IL increased with increasing alkyl chain length of cation. Recently, an experimental study shows that, the binding of imidazolium cation to DNA duplex happens through intercalation with increasing alkyl chain length.50 Jumbri et al. investigated the effect of temperature on the stability of DNA duplex in pure and hydrated imidazolium based ILs.51 The head and tail base pairs of DNA duplex, which exposed to the IL, showed more fluctuational dynamics than the bases in the middle of DNA duplex. The interaction of IL with these head and tail base pairs was different compared to the middle base pairs. Study of individual base pairs in pure and hydrated imidazolium ILs will help to understand the non-covalent interactions present between these head and tail bases, IL and their favorable conformations. So, it is interesting to investigate the favorable conformations of base pairs in pure and hydrated ionic liquids and understand the DNA duplex stability in hydrated ionic liquids. In this study, we address some of these aspects through metadynamics based classical molecular dynamics simulations.

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COMPUTATIONAL METHODS We performed classical molecular dynamics simulations to explore the energetics of conformational dynamics of methylated base pairs in pure and hydrated ionic liquid, 1-ethyl-3methylimidazolium [EMIm] acetate [Ac] with changing the mole fraction of ionic liquid using metadynamics method. We

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also performed additional simulations of 0.5 mole fraction of another ionic liquid, choline [Cho] dihydrogen phosphate [DHP], to see the effect of cations on base pair conformation. Here, the two cations differ structurally along with the presence of π-bonds. The methylated bases, cations and anions were optimized along with Merz-Kohlmann charge calculation52 using density functional theory method employing B3LYP exchange correlational functional. 6-31g(d) basis set was used for the methylated bases, and 6-311+g (2d, p) basis set was used for cations and anions using Gaussian 09 software package.53 The atomistic models are shown in Figure 1. We calculated restrained electrostatic potential charges (RESP)54 for entities mentioned above and modeled with generalized AMBER force field (GAFF)55 using Antechamber module of AMBER Tools.56 We scaled atomic charges to 0.8 for ions, which provided good density compared to experimental values.57 We prepared twelve systems, six for each mA-mT and mG-mC base pairs, with varying mole fractions of ionic liquid. The initial coordinates for all simulated systems were prepared using packmol software package.58 We fixed the number of ions (250) and varied the number of water molecules to obtain the required concentration of the mixture, the number of water and ions used in each system and corresponding densities are tabulated in Table 1. Water molecules were presented using SPC/E59 model. Initially, the systems were minimized using the steepest descent minimization algorithm for 2000 steps. Then, we performed annealing for 2 ns to get a homogeneous mixture of entities followed by 10 ns NpT simulation. Finally, 10 ns NVE was followed by 100 ns metadynamics simulations were carried out within same ensemble. The hills of bias potential were added at every 0.5 ps. We used Berendson V-rescale thermostat for temperature coupling and Berendson barostat for pressure coupling.60 We used 2 fs time step and 1 nm cutoff for van der Waals and electrostatic interactions. Particle Mesh Ewald (PME)61 was used to treat the long-range electrostatic interactions. LINCS algorithm was used to constrain the bonds. All metadynamics simulations were performed using Gromacs 5.0.462 molecular dynamics simulation package with Plumed 2.2.063 plug-in. The force field parameters and structures in xyz format are provided in the supporting information. We used two collective variables (CVs) by following the previous study of base pairs on graphene layer and silicon surface.19,20 These collective variables are called stacked (SStack) and WC hydrogen bonding (SWC). They are defined as coordination numbers: ! !!"#$%& !!"#$%$&$'( 𝑟 1 − !" 𝑟! 𝑆!"#$% = !" 𝑟 1 − !" 𝑟! ! ! for stacking, and !!"#$%& !!"#$%$&$'(

𝑆!" = !

!

1− 1−

𝑟!" 𝑟!"

!"

𝑟! !"

𝑟!

for hydrogen bonding. rij in SStack is the distance between the nine ring atoms of purine base and six ring atoms of the pyrimidine base. rij in SWC is the distance between hydrogen bond donors and acceptors of base pairs in WC form. The reference distances, r0, were 0.4 and 0.3 nm for SStack and SWC, respectively.


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The minima obtained from the metadynamics simulations for WC and stacked conformation were used to calculate the solvation free energy of base pairs. The solubility calculations give us the quantitative comparison with free energy calculations. We employed multistage free energy perturbation approach64–67 with the multi-state Bennett’s acceptance ratio method (MBAR).68–71 We used coupling parameter to regulate the Lennard-Jones (LJ) and electrostatic interactions between solute and solvent. The coupling parameters for LJ interactions were changed from 0 to 1 in six stages (0, 0.2, 0.4, 0.6, 0.8, 1.0) and the electrostatic interactions were changed in four stages (0.25, 0.5, 0.75, 1.0) keeping the LJ interaction as 1. Relative solubility of these base pairs in pure and hydrated ionic liquids with pure water were calculated using following equation,72,73 ln

𝑐!,! 𝑐!,!"#

%$!"#,! = 𝛽µ!,!"#$% 𝑇, 𝑃, 𝑁 = 1, 𝑁!"#$% !"#,! − 𝛽µ!,! 𝑇, 𝑃, 𝑁 = 1, 𝑁! ,

where c1,i and c1,water correspond to the molar concentration of base pair in solvent i (pure and hydrated ionic liquid) and wais the residual chemical potential of ter, respectively. µ𝑟𝑒𝑠,∞ 1,𝑤𝑎𝑡𝑒𝑟 is the residual base pair infinitely diluted in water and µ𝑟𝑒𝑠,∞ 1,𝑖 chemical potential of base pair infinitely diluted in pure and hydrated ionic liquid. Residual chemical potential is the difference between the chemical potentials of solute in the solution and gas phases. In the case of pure solvent, the difference between the chemical potentials of solute in solution and gas phase is equal to the solvation free energy of the solute.74 In this study, we assumed the hydrated ionic liquid mixtures as pure solvents to calculate the relative solubility of base pairs in hydrated ionic liquids with water. 𝛽µ!"# = 𝛽µ! − 𝛽µ ! 𝛽µ!"# = 𝛽(µ! − µ ! ) 𝛽µ!"# = 𝛽∆𝐺!"# β is the reciprocal of kBT, kB is the Boltzmann constant and T is the Kelvin temperature. µ𝑟𝑒𝑠 1,𝑖 was computed using python implementation of MBAR (pyMBER).75

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RESULTS AND DISCUSSION We considered the free energy difference between two local minima of WC and stacked conformations in the twodimensional free energy surface along the SStack collective variable as a function of the simulation time for quantitative assessment of the statistical convergence of the simulations. The convergence plots and stack collective variable along the simulation time for mA-mT and mG-mC base pairs with changing mole fraction of ionic liquid are shown in the supporting information (Figures S1 and S2). The values fluctuate much for the mA-mT base pair in all systems, but we do not see such fluctuations for the mG-mC base pair. The stack collective variable fluctuates very slowly in pure and hydrated ionic liquids, more fluctuation is observed in pure water for both the base pairs. The same is the case with the WC collective variable, which is shown in the supporting information (Figure S3). The free energy surfaces of base pair association in the pure ionic liquid and pure water for both base pairs obtained from biased metadynamics simulations are shown in Figure 2 with the snapshots corresponding to the free energy minima. The

free energy minimum represents a set of configurations with similar values of CVs rather than a free energy corresponding to a particular configuration. The extracted conformations are the structures with CV value close to the observed minima. In the pure water, we observe two major free energy minima corresponding to WC H-bonding and stacked conformations for both base pairs. In both the cases, we observe the free energy of stacked conformation is lower as compared to WC conformation. This demonstrates that stacked conformation is favored more than WC conformation in solvated environment as observed in both experimental and computational studies.3,9,17,18 From the extracted conformations, we can see hydrogen bonding between water and nucleobases which weakens the hydrogen bonding interactions between base pairs; this decreases the stability of WC conformations in pure water. Moreover, nucleobases with hydrophobic aromatic rings tend to stack together for a stable base pair to avoid contact with the hydrophilic water molecules. In the case of the mA-mT base pair, we observe another minimum that is close to WC minimum; this represents a Hoogsteen like base pair conformation, where N7 of purine base acts as an acceptor and N3 of pyrimidine acts as a donor. The free energy profile of WC conformation for the mG-mC base pair contains multiple local minima around the most stable structure that represents WC conformations with small tilt in the planar configuration of the base pair. On moving from pure water to pure ionic liquid, the free energy surface becomes more complicated with multiple local minima. These multiple minima can be due to various kinds of interactions possible like cation-cation, anion-anion, cationanion, base-base, base-cation and base-anion. Here, the free energy of stable WC conformation is more negative as compared to stacked mA-mT base pair as contrary to the conformations in the pure water. However, the values are very similar for the mG-mC base pair. The stability of WC conformation in ionic liquid is explained by investigating the structure extracted from the simulation trajectories. From the snapshot, we notice that imidazolium cations, having fivemembered aromatic ring and hydrophobic in nature, surrounds the base pair. Out of the total number of cations found in the vicinity, two of them make perfect stacked structure with the purine nucleobase from the top and the bottom in the case of the mA-mT base pair. It represents cation-base-cation (π-π-π) stacking, which resembles base-base-base (π-π-π) stacking in DNA duplex. Cations protects the hydrogen bonds between base pairs from acetate anions that can make hydrogen bonds with amine hydrogens of nucleobases. We observe an acetate anion makes hydrogen bond with one of the hydrogens of the amine group of purine nucleobase. Previously, it was observed that creating an artificial hydrophobic cavity around base pair induced and stabilized the base pair in H-bonded conformation.76 Here, the environment of cations around base pair acts as a hydrophobic cavity. In the case of the mG-mC base pair also, we find cations surrounding the base pair and one of them is stacking with purine nucleobase from the top, another one is stacking with pyrimidine nucleobase from the bottom. This cation-base stacking is similar to the base-base (π-π) stacking in the DNA duplex. We find two acetate anions, of which one is involved in hydrogen bonding with primary amine hydrogen atom of mG and other one makes a hydrogen bond with the primary amine hydrogen atom of mC. These hydrogen bonds between acetate anion and nucleobases destabilize the hydrogen bonds between base pairs. As a



result, the WC and stack conformations have similar free energy values for the mG-mC base pair in contrast to the mAmT base pair. Inspection of stacked conformations also reveals that cations stack with the nucleobases from the top and the bottom in both the cases. They form cation-base-base-cation (π-π-π-π) kind of stacking in which acetate anions form hydrogen bonds with hydrogen atoms of primary as well as secondary amine groups. Another minimum in the pure ionic liquid system for both pairs represents a partially dissociated base pair. In these partially dissociated base pairs also, we observe stacking of cations with individual bases. The free energy surfaces of base pairs corresponding to XIL=0.75 and 0.25 are shown in Figure 3. The stability of WC conformation is more favored than stacked conformation in XIL=0.25 similar to pure ionic liquid, however, the stability of conformations reversed in 0.75 mole fraction for both base pairs. In XIL=0.75, the free energy of WC conformations is more compared to stacked conformations for both base pairs. Inspection of corresponding minimum energy structures revealed that, even though nucleobases are surrounded by EMIm cations none of them is properly stacking with cations. In 0.25 mole fraction of ionic liquid for mA-mT base pair, we observe two cations stacking with mA base cation base cation (π-π-π) fashion whereas, one cation stacking with mC base for mGmC base pair. The reversal of conformational stability of base pairs in these two mole fractions can be addressed by the stacking properties of EMIm cations with changing mole fraction of water. It was observed, in previous computational study that the percentage of stacked EMIm cations decreases from pure ionic liquid through 0.4 mole fraction of water. It increases for 0.5 mole fraction of water and decreases up to 0.8 mole fraction of water. It again increases suddenly for 0.9 mole fraction of water due to clustering of cations.77 Another minimum that represents a Hoogsteen type structure, which is found in the pure water, is noticed in 0.75 mole fraction of IL for the mA-mT base pair. For mG-mC base pair (XIL=0.75), a minimum corresponding to T-shape conformation is also noticed. However, other minimum appeared in XIL=0.25 represents partially dissociated base pair. The free energy surfaces of base pairs in 0.5 mole fraction of [EMIm][Ac] and [Cho][DHP] with snapshots are shown in Figure 4. In this case, we observe the WC conformation is favored over stacked conformation for both base pairs in [EMIm][Ac]. Here we observe three cations stacking with the mAmT base pair in WC conformation two of which stacking with mA base cation-base-cation (π-π-π) fashion, one stacking with mT base and one acetate anion is hydrogen bonding with the amine group of mA. Whereas, we see only one cation stacking with the mG-mC base pair and one acetate anion is hydrogen bonding with the amine group of mG. One water molecule is hydrogen bonding with the amine group of mC, which was hydrogen bonding with acetate anion in pure ionic liquid. When compared to acetate anion, water molecules are not a strong hydrogen bond acceptor; so the extent of weakening the hydrogen bond between base pairs is less in this case. The stacked conformation of mA-mT base pair stacked by two cations from top and bottom but we observe only one cation stacking with the stacked conformation of mG-mC base pair. Acetate anions, water molecules are hydrogen bonding with oxygen atoms and hydrogen atoms of amine groups of bases in stacked conformations. Apart from these two conformations for the mA-mT base pair, we also observe a minimum corre-

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sponding to partially dissociated base pair. For mG-mC base pair, we observe a minimum close to the WC minimum that corresponds to a T-shape conformation of base pair. To investigate the effect of IL cation, we also performed metadynamics simulations of both base pairs in 0.5 mole fraction of [Cho][DHP]. The results are interesting; we observe that the stacked conformations are more favored compared with WC conformations for both base pairs in this ionic liquid. This is contrary to the most favored WC conformation over stacked conformation in [EMIm][Ac]. In [Cho][DHP], both the cation and anion are polar in nature. Moreover, choline cation has a hydroxyl group, which can act as hydrogen bond donor as well as hydrogen bond acceptor. It also has three methyl groups, acidic in nature, attached to a quaternary nitrogen atom. Dihydrogen phosphate has four oxygen atoms, which can act as hydrogen bond acceptors and two hydrogen atoms acts as hydrogen bond donors. In WC conformations of mA-mT and mG-mC base pairs, we observe hydrogen bonding between phosphate oxygen atoms and amine hydrogen atoms. Exocyclic oxygen atoms and ring nitrogen atoms of bases are hydrogen bonding with polar hydrogens of choline cation and DHP anion. We also observe hydrogen bonding of water molecules with amine hydrogens. All these interactions destabilize the WC conformation in this ionic liquid by weakening the hydrogen bonds between base pairs. The polar nature of [Cho][DHP] is unable to protect the hydrogen bonds between base pairs similar to pure water. In a previous study, choline cations stabilized the DNA duplex with more A-T content than the DNA with more G-C content.37 This phenomenon was explained from molecular dynamics simulations, where choline cations disrupted hydrogen bonds between G-C base pair from both minor and major groove side. However, choline cations did not disrupt the hydrogen bonding between A-T base pair, however, they formed hydrogen bonds with other atoms of bases.43 Our simulations also support these results from free energy point of view; WC conformation of mA-mT base pair is more stable (-10 kcal mol-1) than WC conformation of mG-mC base pair (-8 kcal mol-1) in [Cho][DHP] ionic liquid. In our recent study, the possible interactions between methylated nucleobases and [EMIm][Ac] ionic liquid with changing mole fraction of water was investigated using radial distribution functions (RDFs), spatial distribution functions (SDFs) and stacking angle distribution of EMIm cation with methylated nucleobases quantitatively.78 From RDFs and SDFs, it was evident that the acetate anions and water molecules were making strong hydrogen bonds with amine hydrogen atoms of nucleobases. The stacking angle distribution demonstrated that, the EMIm cations were stacking with methylated nucleobases from above and below and the stacking affinity changes with nucleobase. The ability of imidazolium cation to stack with nucleobase is the reason for the intercalative binding mode of imidazolium cations with DNA duplex as observed in the experimental study.50 Intercalation of cation between base pairs of DNA duplex disturbs the base association, which destabilizes the DNA duplex. We find the hydrogen bonding of acetate anions with bases that destabilizes the WC conformation of base pairs. This could be the reason that the head and tail base pairs in DNA duplex have more fluctuating dynamics than the middle bases observed in previous study.51


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The extracted structures of conformations of WC and stacked conformations for mA-mT base pair are aligned with purine nucleobase to see the variation in their conformations with changing mole fraction of ionic liquid. The aligned superimposed conformations are shown in Figure 5. The conformations are almost similar for WC base pair except with some tilt of pyrimidine nucleobase from planarity, whereas for stacked conformation, we notice that pyrimidine nucleobase stacks to the purine nucleobase from the top in some cases and from down in some other. The free energy surfaces in pure ionic liquid and XIL=0.75 mixture indicate two different minima corresponding to these two different stacking conformations. In other mole fractions, we find only one minimum corresponding to the stacked conformation. In XIL=0.5 and 0.75 of [EMIm][Ac] for the mG-mC base pair, two minima are found corresponding two different stacking conformations. The values of free energy for WC and stacked conformations of both base pairs with changing mole fraction of ionic liquid are presented in Figure 6. No significant effect of the ionic liquid on the stacked conformation is observed for both the base pairs. As we see, free energy values are not changing much when we move from water to pure ionic liquid, but it affects the stability of WC conformation significantly. Free energies are more negative, for mA-mT base pair compared with mG-mC base pair in all systems for both the conformations; this reveals that the mA-mT conformations are more stable than the mG-mC conformations in pure and hydrated ionic liquids. This is in agreement with the previous study where they found the stability of DNA duplex with high A-T content over high G-C content in hydrated ionic liquids.37

base interactions destabilizing DNA. Simulations of base pairs were conducted in 0.5 mole fraction of [Cho][DHP] to investigate the effect of cation. We find stacked conformation is more favored than WC for both base pairs in this ionic liquid, which is similar to pure water. The free energies of the mAmT base pair are more negative compared to mG-mC base pair, which supports the stability of DNA duplex with more AT content than G-C content in hydrated ionic liquids as found in the previous study.37 The WC and stacked conformations are aligned with purine nucleobase in all mole fractions of ionic liquid for mA-mT base pair. This helped us to predict two different stacked conformations belonging to different minima. Relative solubility of base pairs in pure and hydrated ionic liquids with respect to pure water show that they are more soluble in ionic liquid compared to water. Relative solubility of WC and stacked conformations are in correlation with free energy values. Our findings are in agreement with recent studies of nucleobase solubility in pure and hydrated ionic liquids.79–82

The relative solubility of WC and stacked conformations for both base pairs in pure and hydrated ionic liquid concerning pure water are shown in Figure 7. The conformations are more soluble in pure and hydrated ionic liquids when compared to pure water. This is in nice agreement with the recent solubility studies of nucleobases in pure and hydrated ionic liquids.78–82 If the relative solubility of a conformation is positive, and then the conformation is more stable, which corresponds to the more negative free energy. The fluctuation in relative solubility is in correlation with the free energy of conformations with changing mole fraction of ionic liquid. In conclusion, the free energy surfaces were constructed and analyzed using biased molecular dynamics simulations to observe the more favorable conformations of mA-mT and mGmC base pairs in pure and hydrated ionic liquid solutions with varying concentration. Stacked conformation are more favored than WC conformation in pure water, which is in agreement with the previous studies.17,9 WC conformation are favored more than stacked conformation in pure and hydrated ionic liquids of [EMIm][Ac] except in 0.75 mole fraction of ionic liquid system. Investigation of corresponding conformations with surrounding molecules revealed that hydrophobic cations stabilize the WC conformation protecting the hydrogen bonds between base pairs from acetate anion and water molecules. The EMIm cations also have an aromatic five-membered ring that is stacking with the nucleobases. We observe cation-basecation (π-π-π) stacking for WC conformations, which resembles the base-base-base stacking in DNA duplex. The effect of the ionic liquid on stacked conformation is insignificant. Cation-base-base-cation (π-π-π-π) stacking is observed in stacked conformations. The stacking affinity of EMIm cation with nucleobase is the reason that the binding mode of imidazolium cations with DNA duplex is intercalative which disrupt the

n AUTHOR INFORMATION

ASSOCIATED CONTENT Figure S1 presents the convergence and stack collective variable of the mA-mT base pair along the simulation time with changing the mole fraction of ionic liquid. Figure S2 presents the convergence and stack collective variable of the mG-mC base pair along the simulation time with changing the mole fraction of ionic liquid. Figure S3 WC collective variable of mA-mT and mG-mC base pair along the simulation time with changing mole fraction of ionic liquid. Figure S4, S5, S6 represent the enlarged figures of structures showed in Figure 2, 3 and 4.

Corresponding Author *E-mail: [email protected], Tel. no. +91 40 2301 7051 Notes The authors declare no competing financial interest.

n ACKNOWLEDGEMENTS The authors acknowledge financial support (SB/EMEQ375/2014) for this work from Department of Science and Technology, India. Sathish Dasari also likes to thank CSIR, India for his PhD fellowship.



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Pairs. J. Am. Chem. Soc. 1994, 116 (6), 2493– 2499.

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Table 1. Number of ion pairs of ionic liquid and water molecules taken in each system and the corresponding densities. The subscripts ‘a’ and ‘b’ for [EMIm][Ac] and [Cho][DHP] ionic liquids, respectively. XIL

Number of water molecules

Number of ion pairs

Density[gm.cm-3] mA-mT

Density[gm.cm-3] mG-mC

0

2000

0

1.0

1.0

0.25

750

250

1.082

1.089

a

250

250

1.084

1.092

0.5b

250

250

1.397

1.417

0.75

85

250

1.082

1.089

1

0

250

1.08

1.087

0.5

11



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Figure 1. Models of methylated nucleic acid bases and ionic liquid. (a) m-Adenine (b) m-Thymine (c) m-Guanine (d) m-Cytosine (e) EMIm cation (f) Acetate anion. (g) Choline cation (h) Dihydrogen phosphate anion

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Figure 2. Free energy surfaces of methylated base pairs in pure water and pure ionic liquid with corresponding minimum energy structures. Stacked conformation is favored in pure water for both base pairs. WC conformation is favored in pure ionic liquid.

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Figure 3. Free energy surfaces of methylated base pairs in 0.75 and 0.25 mole fraction of ionic liquid solution with corresponding minimum energy structures. Stacked conformation is favored in X =0.75 for both base pairs. WC conformation is favored in X =0.25 for both base pairs. IL

IL

14


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Figure 4. Free energy surfaces of methylated base pairs in 0.5 mole fraction of [EMIm][Ac] and [Cho][DHP] ionic liquid solutions with corresponding minimum energy structures. WC conformation is favored in [EMIm][Ac] for both base pairs. Stacked conformation is favored in [Cho][DHP] for both the base pairs.

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Figure 5. Structures extracted and aligned with respect to methylated adenine from different mole factions for mA-mT base pair. (a) WC from side view (b) WC top view (c) Stacked side view. Small tilt is observed in WC conformation with changing mole fraction. Two different stacking modes observed in stacked conformations.

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Figure 6. Free energies of WC and Stack conformations with changing mole fraction of ionic liquid, The panels (a) and (b) depict mA-mT and mG-mC pairs, respectively. The free energy values are more negative for mA-mT base pair than mG-mC base pair.

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Figure 7. Relative solubility values of WC and stacked conformers with changing mole fraction of ionic liquid, (a) mA-mT (b) mG-mC. More solubility represents more negative free energy, which is correlating with free energy of base pair conformations.

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TOC Graphic

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Association of Nucleobases in Hydrated Ionic Liquid from Biased

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