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Probing the interactions between DNA nucleotides and biocompatible liquids: COSMO-RS and molecular simulation study
Accepted Manuscript Probing the interactions between DNA nucleotides and biocompatible liquids: COSMO-RS and molecular simulation study Girma Gonfa, Nawshad Muhammad, Mohamad Azmi Bustam PII: DOI: Reference:
S1383-5866(17)31266-2 http://dx.doi.org/10.1016/j.seppur.2017.08.033 SEPPUR 13975
To appear in:
Separation and Purification Technology
Received Date: Revised Date: Accepted Date:
20 April 2017 28 July 2017 11 August 2017
Please cite this article as: G. Gonfa, N. Muhammad, M. Azmi Bustam, Probing the interactions between DNA nucleotides and biocompatible liquids: COSMO-RS and molecular simulation study, Separation and Purification Technology (2017), doi: http://dx.doi.org/10.1016/j.seppur.2017.08.033
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Probing
the
interactions
between
DNA
nucleotides
and
biocompatible liquids: COSMO-RS and molecular simulation study Girma Gonfa*a,b, Nawshad Muhammad c , Mohamad Azmi Bustamb a
College of Biological and Chemical Engineering, Addis Ababa Science and Technology
University, 16417 Addis Ababa, Ethiopia b
Chemical Engineering Department, Universiti Teknologi PETRONAS, Bandar Seri Iskandar,
31750 Tronoh, Perak, Malaysia c
Interdisciplinary Research Center in Biomedical Materials, COMSATS Institute of Information
Technology, Lahore, Pakistan.
*
Corresponding author:
Girma Gonfa Email: [email protected] Tel: +60175667304 1
Abstract Ionic liquid (ILs) have been attracting significant attention as an alternative solvent for DNA extraction/purification and stabilization/storage. In this work, we investigated the interaction between DNA nucleotides and bio-base ILs to get insight into the effect of structural variations of the ILs on the ILs-DNA complex formations. COSMO-RS based quantum calculations and molecular simulation were used to investigate the interaction between the bio-base ILs and DNA nucleotides. Deoxyadenosine 5' monophosphate (A), Deoxythymidyine 5' monophosphate (T), Deoxycytidine 5' monophosphate (C), Deoxyguanosine 5' monophosphate (G) and their dimers were used to model DNA. 260 ILs (13 cations and 20 amino acid based anions) were evaluated. Activity coefficients at infinite dilution of the DNA nucleotides and excess enthalpy of mixing of the systems were predicted using COSMO-RS model. Solvation free energies of the DNA nucleotides were estimated employing molecular dynamics simulations. The activity coefficients of DNA nucleotides decrease with increasing nucleotides chain length. This implies solubility of the nucleotides is higher for longer DNA nucleotide chain. Piperidinium and pyrrolidinium based ILs show lower activity coefficient than choline and morpholinium based ILs. ILs with anions containing nonpolar side chain amino acids show lower activity coefficient compared to those with polar side chains. This implies strong interaction between the nucleotides and ILs with anions containing nonpolar side chain amino acids compared to anions with polar side chains. Moreover, ILs based on anions with nonpolar side chain show higher negative excess enthalpy of mixing compared to those with polar side chain. Further, solvation free energies of DNA nucleotides in the ILs are negative. Solvation free energy is more negative for dimers compared to monomer nucleotides. ILs based on anions with nonpolar side chain show more negative solvation free energies compared to those with polar side chains.
2
Keywords: DNA nucleotide; Ionic liquid; COSMO-RS; Molecular dynamics
3
1. Introduction DNA is an important biomolecule containing the genetic information necessary for the viability of virtually every organism. Moreover, DNA can also be regarded as a kind of structurally precise nanomaterials. Today, DNA emerged as a fundamental and an intelligent molecule to assist construction and functionalization of nanodevices in the field of nanotechnology such as biosensor [1, 2], nanodevice construction [3, 4], drug delivery [4]. However, to find a medium (solvent) in which DNA is both soluble (for extraction) with long term stability (for storage) is a bottleneck in DNA technology [5]. Recently, ionic liquid (ILs) have been attracted significant attention as alternative solvent for DNA extraction/purification [6-8] and stabilization [9-11]. ILs are used for DNA extraction/purification and storage because of their many advantages, including the enhanced solubility and excellent stability of DNA in ILs [11] and wide temperature range for liquid phase [12]. More importantly, the properties of ILs can be finely tuned through the careful selection of cations and anions to adjust important properties for DNA extraction and storage [5]. Moreover, considerable effort has been devoted to understand the mechanism of DNA and its interactions with ILs and to develop new bio-ILs for dissolution of DNA [7, 10, 13-15].
For instance, Ding et al. [10] have shown that 1-butyl-3-
methylimidazolium chloride can bind to DNA to form IL-DNA complex through electrostatic interaction between the imidazolium cation head groups and DNA phosphates, and hydrophobic association between the cation hydrocarbon chains and the nucleotide of DNA. This shows that ILs-DNA binding cab involve both electrostatic and non-electrostatic interactions. Other experimental and molecular dynamics simulations works also showed the importance of electrostatic interactions occurred between ILs cation head and DNA phosphate groups and hydrophobic interactions between the cation alkyl chain length of the ILs and hydrophobic
4
moieties of DNA nucleotides [13, 16, 17]. These studies suggested that cations tend to move close to the DNA main chain due to the strong electrostatic interactions with the phosphate groups as well as hydrogen bonding and edge-to-face NH···?? interactions with the DNA bases, while anions mainly form hydrogen bonds with cytosine, adenine, thymine and guanine nitrogenous bases [17]. However, the effects of structural variations of ILs on DNA-ILs interactions and the chemistry behind the dissolution of DNA and stability of DNA in ILs were not systematically explored. The aim of the current work is to probe the interaction between some biocompatible ILs and DNA nucleotides to get insight into the effect of structural variations of the ILs on the ILs-DNA complex formations. We chose biocompatible ILs since they have attracted attention for extraction and storage of DNA due to their low toxicity and high biodegradability [9, 11, 18]. The biocompatible ILs were selected by combining biocompatible cations and anions [19, 20]. Quantum calculations and molecular simulation were used to contribute to a deeper insight into the interaction between these ILs and DNA nucleotides. Four DNA nucleotides (Deoxyadenosine 5' monophosphate, Deoxythymidyine 5' monophosphate, Deoxycytidine 5' monophosphate, Deoxyguanosine 5' monophosphate) were used as model molecule for DNA nucleotide. 260 ILs were selected for this study by combining 13 cations and 20 amino acid based anions. The nomenclature and abbreviations of the cations and anions of the studied ILs are shown in Table 1. The rationale for selection of the studied ILs will be presented in result and discussion (section 3.1). This study helps to understand the effect of structural variations of biocompatible ILs on their interaction with DNA nucleotides and to develop new bio-ILs for extraction and storage of DNA.
5
Table 1. Nomenclature and abbreviations of cations and anions if studied ILs. Cations
Anions
No Nomenclature
Acronym
No
Nomenclature
1.
Choline
[Ch]
1.
Cysteinate
[Cys]
2.
1-butyl-1-methylpiperidinium
[C4 C1im]
2.
Phenylalaninate
[Phe]
3.
1-(3-hydroxypropyl)-1-methylpiperidinium
[HOC3C1pip]
3.
Tryptophanate
[Trp]
4.
1-(ethoxymethyl)-1-methylpiperidinium
[C2O C1C1pip]
4.
Tyrosinate
[Tyr]
5.
1-(cyanomethyl)-1-methylpiperidinium
[CNC1C1pip]
5.
Alaninate
[Ala]
6.
1-butyl-1-methylpyrrolidinium
[C4 C1pyr]
6.
Argininate
[Arg]
7.
1-(3-hydroxypropyl)-1-methylpyrrolidinium [HOC3C1pyr]
7.
Asparaginate
[Asg]
8.
1-(ethoxymethyl)-1-methylpyrrolidinium
[C2O C1C1pyr]
8.
Aspartate
[Asp]
9.
1-(cyanomethyl)-1-methylpyrrolidinium
[CNC1C1pyr]
9.
Glutamate
[Glu]
[C4 C1mor]
10.
Glutaminate
[Gln]
11. 4-(3-hydroxypropyl)-4-methylmorpholinium [HOC3C1mor]
11.
Glycinate
[Gly]
12. 4-(ethoxymethyl)-4-methylmorpholinium
[C2O C1C1mor]
12.
Histidinate
[His]
13. 4-(cyanomethyl)-4-methylmorpholinium
[CNC1C1mor]
13.
Isoleucinate
[Ise]
14.
Leucinate
[Leu]
15.
Lysinate
[Lys]
16.
Methioninate
[Met]
17.
Prolinate
[Pro]
18.
Serinate
[Ser]
19.
Threoninate
[Thr]
20.
Valinate
[Val]
10. 4-butyl-4-methylmorpholinium
Acronym
2. Computational details 2.1. COSMO-RS calculation The COSMO-RS calculations were carried out following a multistep procedure. The geometries and the continuum solvation COSMO calculations for each DNA nucleotides, cations and anions of targeted ILs were optimized and COSMO-files were obtained using TURBOMOLE program 6
package [21] . Density functional theory (DFT) calculations were performed with BeckePerdew-86 (BP86) functional [22] using triple zeta valance potential (TZVP) basis set and resolution of identity standard (RI) approximation [23]. After geometries optimization, the COSMO-files were generated and were used for the estimation of activity coefficients at infinite dilutions and other related properties. COSMO-RS calculations were performed using COSMOthermX, Version C2.1 using the parameter file BP_TZVP_C20_0111 (COSMOlogic GmbH & Co KG, Leverkusen, Germany) [24]. Electroneutral molecular model was applied to simulate the ILs in the COSMO-RS calculation. In this approach, ILs are treated as an equimolar mixture of cations and anions [25]. The details of the calculation procedures of estimating activity coefficient of solutes in ILs using COSMO-RS can be found elsewhere [26-29]. 2.2. Solvation free energies The structures of the DNA nucleotides were extracted from calf-thymus DNA structure. The structure of calf-thymus DNA (Ct-DNA) was obtained from RCSB Protein Data Bank (RCSB PDB) with a PDB ID 425D [30]. The geometries of DNA nucleotides, cations and anions of the studied ILs were optimized using the DFT calculation with Generalized Gradient Approximations (GGA) and Perdew−Wang exchange and correlation functional (PW91) basis set. Initially cubic boxes (primitive cells) of 32 × 32 ×32 Å were created using Material studio visualizer. The DNA nucleotides were placed at the centre of the box and ILs were packed to the box using Amorphous cell module. The nucleotides were solvated with 100 ILs (100 cations and 100 anions) by packing the ILs into the cells. Geometry optimizations were performed to relax the cell and equally distribute the DNA nucleotides the ions. The COMPASS force field were adopted to represent the interaction potentials of nucleotides and ILs throughout the calculations. The energy minimizations were performed with the following convergence criteria: energy (10-4
7
kcal/mol), force (0.005 kcal/mol/Å) and displacement (5×10-5Å). The cells were further equilibrated using Molecular Dynamics (MD) with the constant-temperature (NVT) ensemble followed by Constant-pressure (NPT) ensemble for 100 ps with no position restraints applied. Temperature and pressure control were implemented using the NHL thermostat and Berendsen barostat, respectively [31]. Total simulation time of 100 ps with 100000 number of steps. The simulations were carried out at 298.15 K and 1 atm. Material studio (version 2016) were used for the geometry optimizations, molecular dynamics and solvation free energy calculations. 3. Results and discussion 3.1. Selection of biocompatible ILs Assessment of cytotoxicity of ILs is a very important preliminary test before utilization of the ILs for DNA extractions and storages. It is generally accepted that cations have a major role in the toxicity of ILs [32]. Longer cation side chains have more severe effect on living cells [5]. Generally, the toxicity of ILs can be reduced by reducing the hydrophobicity of the cation, by shortening long alkyl chain length and by introducing polar functional groups (such as ether, hydroxyl, or nitrile groups) into the cation alkyl chain spacer [33]. Moreover, the chemical structure of the cation head group have significant effect on the toxicity [34]. Amde and coworkers [35] summarized the relative toxicity of ILs (based on cationic head groups) as follows: choline < piperidinium < pyrrolidinium < morpholinium < pyridinium = imidazolium < ammonium < phosphonium. Based on these assessments, we selected ILs with choline, piperidinium, pyrrolidinium, morpholinium cation ahead, and also limited the alkyl chain length to four carbon ( C4). We selected 13 cations and coupled with 20 anions based on natural amino acids to model 260 biocompatible ILs. Amino acids are important biomolecules can be converted easily into anions and cations. Amino acids are also cheap and can be abundantly found in
8
nature. More importantly, the amino acid based anion can provide low toxicity ILs if combined with appropriate cations.
3.2. Ionic liquids and DNA nucleotides modelling In contrast to a classical solvent, ILs can be described as a mixture of ions (cations and anions) or either as a single compound [36]. The two descriptions reflect a different chemistry on the atomistic scale properties and for many experimental data the two descriptions affect the definition of the mole fraction. The use of electroneutral mixture is the most flexible description of ILs and successfully been applied for prediction of nucleotides in ILs [26, 36]. We applied the electroneutral mixture to model the ILs. Consequently, the mole fractions used in the activity coefficient calculations were different from the mole fraction normally used in the experiments, where the ILs are treated as one compound. Therefore, the properties of the nucleotides in the ternary system (nucleotide, cation and anion) were converted to binary mixtures (nucleotide and ILs) accordingly. The details of the calculation procedures of estimating properties of solutes in ILs using COSMO-RS can be found elsewhere [36]. It is not practical to perform quantum (DFT) calculation for DNA with practically infinite number of atoms. A practicable approach for DNA modelling is to choose representative part of the DNA chain that is small enough to allow for quantum chemical calculations and large enough to display characteristic features of the molecule. We have chosen four monomer nucleotides
(Deoxyadenosine
5'
monophosphate,
Deoxythymidine
5'
monophosphate,
Deoxycytidine 5' monophosphate, Deoxyguanosine 5' monophosphate) as the representative units for DNA modelling. Moreover, we modelled DNA as a combination of two nucleotides (dimers) since it permits us to study the mutual influence of neighbouring monomeric unit. In 9
this case, two subsequent nucleotides were used to model the DNA. The monomers and dimers are extracted from structure of calf-thymus DNA (Ct-DNA) which was obtained from RCSB Protein Data Bank [30]. Figure 1 shows the structure of Deoxyadenosine 5' monophosphate and Deoxycytidine 5' monophosphate and their dimer extracted from the calf-thymus DNA.
(a)
(b)
(c) Fig.1. Structures and COSMO-charge distribution for DNA nucleotides. (a) Deoxyadenosine 5' monophosphate (A); (b) Deoxycytidine 5' monophosphate (C); (c) A-C dimer. 3.3. Activity coefficient at infinite dilution Activity coefficient is a thermodynamic factor used in thermodynamics to account for deviations from ideal behaviour in a mixture of chemical substances [37]. Activity coefficient is highly dependent on the concentration of each component in the system. At infinite dilution, the solute is surrounded only by solvent molecules and the solute-solute interaction is negligible while solute-solvent interaction attains maximum values resulting in maximum activity coefficient which is commonly called infinite dilution activity coefficient (γ∞). Infinite dilution activity coefficient has very important theoretical and practical applications in chemical and environmental engineering. Infinite dilution activity coefficient can be used for characterizing the solute-solvent interaction [26] and qualitatively estimate the dissolving power of the solvents 10
[38].
The activity coefficient of solutes can also be related quantitively with the relative
solubility of the solute in solvents. Kahlen et al.[38] and Ana Casas et al.[39] successfully applied COSMO-RS predicted activity coefficient to predict the relative solubility complex polymeric materials such as lignin and cellulose in ILs. Since DNA is also is a polymer composed of four different nucleotides monomers we applied similar approach to predict the relative solubility of calf-thymus DNA in the ILs. The quantitative description of nucleoids solubility in ILs can be expressed by the following simplified equation [38].
(1)
where, xiL is the mole fraction of the dissolved component i in a saturated solution in equilibrium with the solid of i, ∆hm,i and Tim denote the enthalpy of melting and the melting temperature of component i, respectively. According equation (1), at given temperature and specific system (solute-solvent mixture), the exponential term depends only on the pure properties (melting point and heat of fusion) of pure solute (nucleotides in this case) which is a constant term. Therefore, the reciprocal of the activity coefficient can qualitatively show the relative solubility of the nucleotides in the ILs. That means, the lower activity coefficient of the nucleotide in ILs results in higher solubility the solute in the ILs. 3.3.1.Effect of DNA nucleotides on coefficient Fig. 2 shows a plot of a natural logarithm of the activity coefficients at infinite dilutions (lnγ∞) of DNA nucleotide monomers and dimers in 4-butyl-4-methylmorpholinium ILs with 20-amino acid based anions. The activity coefficients of the DNA nucleotides in the 4-butyl-4methylmorpholinium based ILs increase in the order of A-T < A-C < G-C < T < G < A < C. The activity coefficients of the monomer DNA nucleotides (A, C, G and T) are higher than their 11
corresponding dimers (A-C, A-T and G-C). Similar trends were observed for all ILs investigated in this work. The predicted activity coefficients of the nucleotides in the studied ILs are provided in supporting information (Table S1). [Gly] [Ala] [Lys] [Phe] [Val] [Ise] [Leu] [Met] [Pro] [Cys] [Trp] [His] [Tyr] [Arg] [Thr] [Gln] [Asg] [Ser] [Glu] [Asp]
-10
-15
ln(γ∞)
-20 -25 -30
-35 -40 A
C
G
T
A-C
A-T
G-C
Fig. 2. Activity coefficient at infinite dilution at 298.15 of DNA nucleotides and dimers in 4butyl-4-methylmorpholinium based ILs. 3.3.2. Effect of cations and anions on coefficient at infinite dilution Fig. 3 shows the activity coefficient at infinite dilution of T in the ILs with the studied cations with anion. The activity coefficient at infinite dilution of T in the choline based ILs are higher than that of 1-butyl-1-methylpiperidinium, 1-butyl-1-methylpyrrolidinium and 4-butyl-4methylmorpholinium based ILs. This could be due to the presence of cyclic head group in piperidinium, pyrrolidinium and morpholinium based ILs, and lack of the cyclic group in choline based ILs. The structural similarity between the ILs head group and the solutes (nucleotides) may enhance the solute-solvent interaction in piperidinium, pyrrolidinium and morpholinium based ILs. The four nucleotides in the DNA structure contain 5 and 6-cyclic structure which creates structural similarity with the cations of the ILs. Piperidinium and morpholinium based cation contain 6-cyclic structure while pyrrolidinium is the 5-cyclic cation. Introduction of 12
functional group in cation alkyl spacer increases the activity coefficient of the nucleotides (Fig.3). Introduction of nitrile, hydroxyl and ethoxy functional groups increases the activity coefficients of the nucleotides in the ILs. The effect of nitrile functional group on the activity coefficient is more pronounced than that of hydroxyl and ethoxy functional groups, that is, hydroxyl and ethoxy functional groups ILs show lower activity coefficient compared to nitrile functionalized ILs. Moreover, the hydroxyl and ethoxy functionalized piperidinium, pyrrolidinium and morpholinium based ILs show lower activity coefficient compared to choline based ILs. Therefore, the hydroxyl and ethoxy functionalized can be a potential candidate for extraction and storage DNA as they are also less toxic compared to ILs without functional groups in alkyl chains. 0
-5 -10
lnγ∞
-15 -20 -25 -30 -35 -40 -45
A
T
A-T
Figure 3. Activity coefficient at infinite dilution at 298.15 of A, T and A-T in the ILs with glycinate with anion. Fig. 4 shows the effect of anions on the activity coefficient at infinite dilution of T for 1-butyl-1-methyl-pyrrolidinium based ILs. Similar observations were made for all the studied ILs and DNA nucleotides. Amino acids contain amine (-NH2) and carboxyl (-COOH) functional 13
groups, along with a side chain (R group) which is specific to each amino acid (Fig.5). They can be classified as positively or negatively charge, polar or nonpolar amino acids amino acid based on the side chain [40]. Generally, anions based on hydrophobic amino acids such as [Gly], [Ala], [Phe], [Val], [Ise], [Leu] and [Pro] show lower activity coefficients compared to other anions (Fig. 4). ILs with non-polar anions [Cys], [Trp], [His], [Tyr] and [Thr] show intermediate activity coefficient for the DNA nucleotides. On the other hand, ILs with charged side chain amino acid anions such as [Asp], [Glu], [Asg] and [Ser] show higher activity coefficient. The only anion from this group that shows lower activity coefficient is [Lys]. This could be due to the long alkyl chain in lysine structure which may reduce the effect of the charge side chain on the polarity of the anion [40]. Similar trends were observed for all nucleotides and other ILs studied in this work. This suggests ILs with non-polar amino acid based anions interacts strongly with the DNA nucleotides and could be considered as potential candidate for extraction and storage of DNA. 0 -5 -10
lnγ∞
-15
-20 -25 -30 -35 -40
A
C
A-C
-45
Figure 4. Activity coefficient at infinite dilution at 298.15 K of A, C and A-C in 1-butyl-1methyl-pyrrolidinium based ILs.
14
side chain (alpha carbon) R
Amin group
O H2N OH
Caboxylic group
Fig. 5. Structure of an amino acid in its un-ionized form. 3.3.3. Excess enthalpy The excess enthalpy of the nucleotides-ILs mixture were predicted using COSMO-RS model to get insight into the nature of interaction of ILs and DNA nucleotides. The excess enthalpy allows the evaluation of the energetic contributions of all possible specific interactions established by each species and their contributions to the total excess enthalpy. The excess enthalpies can also be used to infer on the strength of ILs-DNA nucleotides interaction in the binary mixtures. In COSMO-RS model, the excess enthalpy of mixture (HEm) is sum of hydrogen bond interaction (HEHB), van der Waals force interaction (HEvdW), and electrostatic//misfit interactions (HEMF) as shown in equation 2.
(2) The excess enthalpy contributions and the total excess enthalpy of T and morpholinium cystinate based ILs at equimolar composition (x T = 0.5) at 298.15 K are depicted in Figure 6. The excess enthalpy of the remining morpholinium based ILs with cystinate anion and the DNA nucleotides over the entire composition is provided in supporting information (Table S2). The HEm for all the studied ILs and nucleotides moistures (both monomer and dimer) are negative indicating favourable energetic interactions between the ILs and nucleotides. A more negative HEm values were obtained for dimer DNA nucleotides than their corresponding monomer counterparts. The 15
more negative values for dimers implies stronger interaction between the ILs and the nucleotide dimer which is consistent with results obtained activity coefficients. Moreover, the misfit/ electrostatic, hydrogen bonding and van der Waals interactions are all negative for ILsnucleotides systems, but their contribution to the total excess enthalpy differ significantly. The hydrogen bond interaction contribution to exothermicity of the mixtures is higher in magnitudes than van der Waals force and electrostatic/misfit interactions for all the studied ILs-DNA nucleotide systems. This confirms that hydrogen bonding is the dominant interaction and determines the enthalpic nature of the mixtures whereas van der Waals force interactions have minor contribution to exothermicity of the mixture. Moreover, the HEm decreases in the order of [CNC1C1 mor] > [HOC3C1mor] > [C2O C1C1 mor] > [C4 C1 mor] for all studied anions. This shows [C4C1mor] based ILs strongly interacts with the DNA bases whereas [CNC 1C1pyr] based ILs are the less interacting ILs. This is in good agreement with the predicted activity coefficients as stated previously. Similar trends were observed for DNA nucleotides and all the studied ILs. 0
Excess Enthalpy (kJ/mol)
-5 -10
-15 -20 -25 -30 -35
HE,M
HE,HB
HE,MF
HE,VDW
-40 [C4 C1mor]
[C2O C1C1mor]
[HOC3C1mor]
[CNC1C1mor]
Figure 6. Excess enthalpy (HEm) of T-morpholinium cystinate based ILs binary mixture at 298.15 K predicted by COSMO-RS at (xH2O = 0. 5).
16
The HEm of T and 1-butyl-1-methylpyrrolidinium based ILs with three different anions (one from each group) is depicted in Figure 7. As it can be clearly seen, glycinate based ILs shows highe negative HEm compared to histidinate and aspiraginate baes ILs. This implies that ILs with non-polar amino acid based anions are favourable for energetic interactions with the DNA nucleotides; and ILs with charged amino acid anions are less favourable for the energetic interactions. All the hydrogen bonding, van der Waals force, and electrostatic/misfit interactions favour the energetic interaction but the major contribution arises from the hydrogen bond interaction for all studied ILs. This might be due to amino acid based anions which can form strong hydrogen bonding. 0 Excess Enthalpy (kJ/mol)
-5 -10 -15
-20 -25 -30 -35 -40
HE,M
HE,HB
HE,MF
HE,VDW
-45 [Gly]
[His]
[Asp]
Figure 6. Excess enthalpy (HEm) of T-1-butyl-1-methylpyrrolidinium based ILs binary mixture at 298.15 K predicted by COSMO-RS at (xH2O = 0. 5). 3.4. Solvation free energies (∆Gsolv) The solvation free energy plays a crucial role in understanding the chemical behaviour of molecules in liquid phases [41]. It provides a way to characterize preferential solvation in a
17
solvent mixture [42]. In this work, the solvation free energies of DNA nucleotides in ILs were calculated to investigate the effect of structural variations of amino acid based anions on solvation free energy of the DNA nucleotides in the ILs. The solvation free energies of monomer A and dimer A-C in 1-butyl-1-methyl pyrrolidinium based ILs is depicted in Fig.7. The computed results show that the free solvation energies of the DNA nucleotides in the ILs are negatives, showing that the ILs can interact with the DNA nucleotides. The results also show ILs with anions based on hydrophobic amino acids such as [Gly], [Ala], [Phe], [Val], [Ise], [Leu] and [Pro] show high negative free solvation energies compared to other ILs. On the other hand, anions based charged side chain amino acid anions such as [Asp], [Glu], [Asg] and [Ser] show low negative free solvation energies. Similar trends were observed both for the monomer A and dimer A-C DNA nucleotides. The solvation free energy of A in the 1-butyl-1-methyl pyrrolidinium based ILs varies from (-17.0 to -33.5) kcal mol-1. On the other hand, the solvation free energy of the dimer A-C DNA nucleotide in the 1-butyl-1-methyl pyrrolidinium based ILs are in the range of (-27.4 to -44.0) kcal mol-1. The solvation free energies of A-C are more negative compared to that of monomer A for corresponding ILs. This implies the interaction between the ILs and the DNA increases as the number of nucleotides increases in the DNA. This observation supports the observations obtained from activity coefficients and excess enthalpy of the systems. Finally, it is worth mentioning that the current work is based on COSMO-RS based activity coefficient and infinite dilution and excess enthalpy, and solvation free energies obtained from molecular simulation. The results of this study can help as a starting point for application of amino acid based ILs for DNA extraction/purification and storage.
18
∆G solv(kcal.mol-1)
0 -10 -20 -30
-40 -50
A
A-C
Figure 7. Solvation free energies of A and A-C in 1-butyl-1-methyl pyrrolidinium based ILs. 4. Conclusions In this work, the interactions between DNA nucleotides and bio-ILs were investigated to get insight into the effect of structural variations of the ILs on the ILs-DNA complex formations by using COSMO-RS model and molecular simulation. 260 bio-based ILs based on choline, piperidinium, pyrrolidinium,
morpholinium,
pyridinium, imidazolium, ammonium and
phosphonium cations and amino acid based anions were evaluated. The activity coefficients at infinite dilution of the DNA nucleotides in the ILs and excess enthalpy of mixing of the systems were predicted using COSMO-RS model. Solvation free energies of the DNA nucleotides in the ILs were estimated employing molecular dynamics simulations. The activity coefficients of the monomer nucleotide are higher for all the studied ILs, implying the interaction between the DNA nucleotides increases with DNA nucleotide chain length. The lower activity coefficient (higher interaction) shows higher solubility of longer DNA nucleotide chain length. Moreover, 19
piperidinium and pyrrolidinium based ILs show lower activity coefficients than choline and morpholinium based ILs. Furthermore, ILs based on anions with nonpolar side chain amino acids show lower activity coefficient than anions with polar side chains. This implies strong interaction between the nucleotides and ILs with anions with nonpolar side chain amino acids compared to anions with polar side chains. Moreover, ILs based on anions with nonpolar side chain show more negative excess enthalpy of mixing compared to anions based on amino acid with polar side chain. Further, the solvation free energies of the nucleotides in the studied ILs are negative. Solvation free energy is more negative for dimers compared to monomer nucleotides. ILs with anions containing nonpolar side chain show higher negative solvation free energies compared to those with polar side chains. Based on COSMO-RS model and molecular simulation studies ILs based piperidinium and pyrrolidinium cations and amino acid anions with nonpolar side chain are suitable candidate for DNA extraction and storage. AUTHOR INFORMATION Corresponding Author *Tel.: (60) 175667304. E-mail: [email protected]. ACKNOWLEDGEMENTS This work is supported by PRF Ionic liquid programme research grant scheme (PRF-0153ABA30) of Centre for ionic liquid research centre, Universiti Teknologi PETRONAS Reference [1] W. Sun, P. Qin, H. Gao, G. Li, K. Jiao, Electrochemical DNA biosensor based on chitosan/nano-V 2 O 5/MWCNTs composite film modified carbon ionic liquid electrode and its
20
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[9] R. Vijayaraghavan, A. Izgorodin, V. Ganesh, M. Surianarayanan, D.R. MacFarlane, Long‐Term Structural and Chemical Stability of DNA in Hydrated Ionic Liquids, Angewandte Chemie International Edition, 49 (2010) 1631-1633. [10] Y. Ding, L. Zhang, J. Xie, R. Guo, Binding characteristics and molecular mechanism of interaction between ionic liquid and DNA, The Journal of Physical Chemistry B, 114 (2010) 2033-2043. [11] H. Zhao, DNA stability in ionic liquids and deep eutectic solvents, Journal of Chemical Technology and Biotechnology, 90 (2015) 19-25. [12] G. Gonfa, M. Bustam, Z. Man, M. Abdul Mutalib, Unique structure and solute-solvent interaction in imidazolium based ionic liquids, Res. J. Chem. Environ, 16 (2012) 93-103. [13] K. Jumbri, H. Ahmad, E. Abdulmalek, M.B.A. Rahman, Binding energy and biophysical properties of ionic liquid-DNA complex: Understanding the role of hydrophobic interactions, Journal of Molecular Liquids, 223 (2016) 1197-1203. [14] A. Chandran, D. Ghoshdastidar, S. Senapati, Groove binding mechanism of ionic liquids: a key factor in long-term stability of DNA in hydrated ionic liquids?, Journal of the American Chemical Society, 134 (2012) 20330-20339. [15] S. Satpathi, A. Sengupta, V. Hridya, K. Gavvala, R.K. Koninti, B. Roy, P. Hazra, A green solvent Induced DNA package, Scientific Reports, 5 (2015). [16] K. Jumbri, M.A. Rahman, E. Abdulmalek, H. Ahmad, N. Micaelo, An insight into structure and stability of DNA in ionic liquids from molecular dynamics simulation and experimental studies, Physical Chemistry Chemical Physics, 16 (2014) 14036-14046.
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[17] L. Cardoso, N.M. Micaelo, DNA molecular solvation in neat ionic liquids, ChemPhysChem, 12 (2011) 275-277. [18] H. Tateishi-Karimata, N. Sugimoto, Structure, stability and behaviour of nucleic acids in ionic liquids, Nucleic acids research, (2014) gku499. [19] J. Hulsbosch, D.E. De Vos, K. Binnemans, R. Ameloot, Bio-based ionic liquids: solvents for a green processing industry?, ACS Sustainable Chemistry & Engineering, (2016). [20] A.M. Socha, R. Parthasarathi, J. Shi, S. Pattathil, D. Whyte, M. Bergeron, A. George, K. Tran, V. Stavila, S. Venkatachalam, Efficient biomass pretreatment using ionic liquids derived from lignin and hemicellulose, Proceedings of the National Academy of Sciences, 111 (2014) E3587-E3595. [21] A. Klamt, F. Eckert, TmoleX3.1, COSMOlogic GmbH & Co. KG: Leverkusen, Germany, in, 2011. [22] J.P. Perdew, Density-functional approximation for the correlation energy of the inhomogeneous electron gas, Phys. Rev. B, 33 (1986) 8822. [23] A. Schäfer, C. Huber, R. Ahlrichs, Fully optimized contracted Gaussian basis sets of triple zeta valence quality for atoms Li to Kr, J. Chem. Phys., 100 (1994) 5829-5835. [24] A. Klamt, F. Eckert, COSMOthermX A Graphical User Interface to the COSMOtherm Program, version C30_1201, 2011; COSMOlogic GmbH & Co. KG: Leverkusen, Germany, in, 2010. [25] M. Diedenhofen, A. Klamt, COSMO-RS as a tool for property prediction of IL mixtures-a review, Fluid Phase Equilib. , 294 (2010) 31-38.
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[26] G. Gonfa, M.A. Bustam, A.M. Sharif, N. Mohamad, S. Ullah, Tuning ionic liquids for natural gas dehydration using COSMO-RS methodology, Journal of Natural Gas Science and Engineering, 27 (2015) 1141-1148. [27] L.Y. Garcia-Chavez, A.J. Hermans, B. Schuur, A.B. de Haan, COSMO-RS assisted solvent screening for liquid–liquid extraction of mono ethylene glycol from aqueous streams, Separation and purification technology, 97 (2012) 2-10. [28] J. Palomar, M. Gonzalez-Miquel, J. Bedia, F. Rodriguez, J.J. Rodriguez, Task-specific ionic liquids for efficient ammonia absorption, Separation and purification technology, 82 (2011) 4352. [29] J. Bedia, J. Palomar, M. Gonzalez-Miquel, F. Rodriguez, J.J. Rodriguez, Screening ionic liquids as suitable ammonia absorbents on the basis of thermodynamic and kinetic analysis, Separation and purification technology, 95 (2012) 188-195. [30] H. Rozenberg, D. Rabinovich, F. Frolow, R.S. Hegde, Z. Shakked, Structural code for DNA recognition revealed in crystal structures of papillomavirus E2-DNA targets, Proceedings of the National Academy of Sciences, 95 (1998) 15194-15199. [31] H.J. Berendsen, J.v. Postma, W.F. van Gunsteren, A. DiNola, J. Haak, Molecular dynamics with coupling to an external bath, The Journal of chemical physics, 81 (1984) 3684-3690. [32] M. Petkovic, J.L. Ferguson, H.N. Gunaratne, R. Ferreira, M.C. Leitao, K.R. Seddon, L.P.N. Rebelo, C.S. Pereira, Novel biocompatible cholinium-based ionic liquids—toxicity and biodegradability, Green Chemistry, 12 (2010) 643-649.
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[33] S. Morrissey, B. Pegot, D. Coleman, M.T. Garcia, D. Ferguson, B. Quilty, N. Gathergood, Biodegradable, non-bactericidal oxygen-functionalised imidazolium esters: A step towards ‘greener’ionic liquids, Green Chemistry, 11 (2009) 475-483. [34] S. Stolte, M. Matzke, J. Arning, A. Böschen, W.-R. Pitner, U. Welz-Biermann, B. Jastorff, J. Ranke, Effects of different head groups and functionalised side chains on the aquatic toxicity of ionic liquids, Green Chemistry, 9 (2007) 1170-1179. [35] M. Amde, J.-F. Liu, L. Pang, Environmental application, fate, effects, and concerns of ionic liquids: a review, Environmental science & technology, 49 (2015) 12611-12627. [36] M. Diedenhofen, A. Klamt, COSMO-RS as a tool for property prediction of IL mixtures—a review, Fluid Phase Equilibria, 294 (2010) 31-38. [37] A.D. McNaught, A. Wilkinson, Compendium of chemical terminology. IUPAC recommendations, (1997). [38] J. Kahlen, K. Masuch, K. Leonhard, Modelling cellulose solubilities in ionic liquids using COSMO-RS, Green Chemistry, 12 (2010) 2172-2181. [39] A. Casas, J. Palomar, M.V. Alonso, M. Oliet, S. Omar, F. Rodriguez, Comparison of lignin and cellulose solubilities in ionic liquids by COSMO-RS analysis and experimental validation, Industrial Crops and Products, 37 (2012) 155-163. [40] N.V. Bhagavan, Medical biochemistry, Academic press, 2002. [41] M.S. Lee, M.A. Olson, Evaluation of Poisson solvation models using a hybrid explicit/implicit solvent method, The Journal of Physical Chemistry B, 109 (2005) 5223-5236. [42] R.L. Akkermans, Solvation Free Energy of Regular and Azeotropic Molecular Mixtures, The Journal of Physical Chemistry B, 121 (2017) 1675-1683. 25
Highlights
Interaction between DNA nucleotides biocompatible ILs were investigated.
Activity coefficient, excess enthalpy and solvation free energies were predicted
COSMO-RS and molecular simulation were applied to predict the mixture properties
Both the cation and the anions affects the properties of the binary system
ILs based on anions with nonpolar side chain show more affinity for DNA nucleotides
26
S1383-5866(17)31266-2 http://dx.doi.org/10.1016/j.seppur.2017.08.033 SEPPUR 13975
To appear in:
Separation and Purification Technology
Received Date: Revised Date: Accepted Date:
20 April 2017 28 July 2017 11 August 2017
Please cite this article as: G. Gonfa, N. Muhammad, M. Azmi Bustam, Probing the interactions between DNA nucleotides and biocompatible liquids: COSMO-RS and molecular simulation study, Separation and Purification Technology (2017), doi: http://dx.doi.org/10.1016/j.seppur.2017.08.033
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Probing
the
interactions
between
DNA
nucleotides
and
biocompatible liquids: COSMO-RS and molecular simulation study Girma Gonfa*a,b, Nawshad Muhammad c , Mohamad Azmi Bustamb a
College of Biological and Chemical Engineering, Addis Ababa Science and Technology
University, 16417 Addis Ababa, Ethiopia b
Chemical Engineering Department, Universiti Teknologi PETRONAS, Bandar Seri Iskandar,
31750 Tronoh, Perak, Malaysia c
Interdisciplinary Research Center in Biomedical Materials, COMSATS Institute of Information
Technology, Lahore, Pakistan.
*
Corresponding author:
Girma Gonfa Email: [email protected] Tel: +60175667304 1
Abstract Ionic liquid (ILs) have been attracting significant attention as an alternative solvent for DNA extraction/purification and stabilization/storage. In this work, we investigated the interaction between DNA nucleotides and bio-base ILs to get insight into the effect of structural variations of the ILs on the ILs-DNA complex formations. COSMO-RS based quantum calculations and molecular simulation were used to investigate the interaction between the bio-base ILs and DNA nucleotides. Deoxyadenosine 5' monophosphate (A), Deoxythymidyine 5' monophosphate (T), Deoxycytidine 5' monophosphate (C), Deoxyguanosine 5' monophosphate (G) and their dimers were used to model DNA. 260 ILs (13 cations and 20 amino acid based anions) were evaluated. Activity coefficients at infinite dilution of the DNA nucleotides and excess enthalpy of mixing of the systems were predicted using COSMO-RS model. Solvation free energies of the DNA nucleotides were estimated employing molecular dynamics simulations. The activity coefficients of DNA nucleotides decrease with increasing nucleotides chain length. This implies solubility of the nucleotides is higher for longer DNA nucleotide chain. Piperidinium and pyrrolidinium based ILs show lower activity coefficient than choline and morpholinium based ILs. ILs with anions containing nonpolar side chain amino acids show lower activity coefficient compared to those with polar side chains. This implies strong interaction between the nucleotides and ILs with anions containing nonpolar side chain amino acids compared to anions with polar side chains. Moreover, ILs based on anions with nonpolar side chain show higher negative excess enthalpy of mixing compared to those with polar side chain. Further, solvation free energies of DNA nucleotides in the ILs are negative. Solvation free energy is more negative for dimers compared to monomer nucleotides. ILs based on anions with nonpolar side chain show more negative solvation free energies compared to those with polar side chains.
2
Keywords: DNA nucleotide; Ionic liquid; COSMO-RS; Molecular dynamics
3
1. Introduction DNA is an important biomolecule containing the genetic information necessary for the viability of virtually every organism. Moreover, DNA can also be regarded as a kind of structurally precise nanomaterials. Today, DNA emerged as a fundamental and an intelligent molecule to assist construction and functionalization of nanodevices in the field of nanotechnology such as biosensor [1, 2], nanodevice construction [3, 4], drug delivery [4]. However, to find a medium (solvent) in which DNA is both soluble (for extraction) with long term stability (for storage) is a bottleneck in DNA technology [5]. Recently, ionic liquid (ILs) have been attracted significant attention as alternative solvent for DNA extraction/purification [6-8] and stabilization [9-11]. ILs are used for DNA extraction/purification and storage because of their many advantages, including the enhanced solubility and excellent stability of DNA in ILs [11] and wide temperature range for liquid phase [12]. More importantly, the properties of ILs can be finely tuned through the careful selection of cations and anions to adjust important properties for DNA extraction and storage [5]. Moreover, considerable effort has been devoted to understand the mechanism of DNA and its interactions with ILs and to develop new bio-ILs for dissolution of DNA [7, 10, 13-15].
For instance, Ding et al. [10] have shown that 1-butyl-3-
methylimidazolium chloride can bind to DNA to form IL-DNA complex through electrostatic interaction between the imidazolium cation head groups and DNA phosphates, and hydrophobic association between the cation hydrocarbon chains and the nucleotide of DNA. This shows that ILs-DNA binding cab involve both electrostatic and non-electrostatic interactions. Other experimental and molecular dynamics simulations works also showed the importance of electrostatic interactions occurred between ILs cation head and DNA phosphate groups and hydrophobic interactions between the cation alkyl chain length of the ILs and hydrophobic
4
moieties of DNA nucleotides [13, 16, 17]. These studies suggested that cations tend to move close to the DNA main chain due to the strong electrostatic interactions with the phosphate groups as well as hydrogen bonding and edge-to-face NH···?? interactions with the DNA bases, while anions mainly form hydrogen bonds with cytosine, adenine, thymine and guanine nitrogenous bases [17]. However, the effects of structural variations of ILs on DNA-ILs interactions and the chemistry behind the dissolution of DNA and stability of DNA in ILs were not systematically explored. The aim of the current work is to probe the interaction between some biocompatible ILs and DNA nucleotides to get insight into the effect of structural variations of the ILs on the ILs-DNA complex formations. We chose biocompatible ILs since they have attracted attention for extraction and storage of DNA due to their low toxicity and high biodegradability [9, 11, 18]. The biocompatible ILs were selected by combining biocompatible cations and anions [19, 20]. Quantum calculations and molecular simulation were used to contribute to a deeper insight into the interaction between these ILs and DNA nucleotides. Four DNA nucleotides (Deoxyadenosine 5' monophosphate, Deoxythymidyine 5' monophosphate, Deoxycytidine 5' monophosphate, Deoxyguanosine 5' monophosphate) were used as model molecule for DNA nucleotide. 260 ILs were selected for this study by combining 13 cations and 20 amino acid based anions. The nomenclature and abbreviations of the cations and anions of the studied ILs are shown in Table 1. The rationale for selection of the studied ILs will be presented in result and discussion (section 3.1). This study helps to understand the effect of structural variations of biocompatible ILs on their interaction with DNA nucleotides and to develop new bio-ILs for extraction and storage of DNA.
5
Table 1. Nomenclature and abbreviations of cations and anions if studied ILs. Cations
Anions
No Nomenclature
Acronym
No
Nomenclature
1.
Choline
[Ch]
1.
Cysteinate
[Cys]
2.
1-butyl-1-methylpiperidinium
[C4 C1im]
2.
Phenylalaninate
[Phe]
3.
1-(3-hydroxypropyl)-1-methylpiperidinium
[HOC3C1pip]
3.
Tryptophanate
[Trp]
4.
1-(ethoxymethyl)-1-methylpiperidinium
[C2O C1C1pip]
4.
Tyrosinate
[Tyr]
5.
1-(cyanomethyl)-1-methylpiperidinium
[CNC1C1pip]
5.
Alaninate
[Ala]
6.
1-butyl-1-methylpyrrolidinium
[C4 C1pyr]
6.
Argininate
[Arg]
7.
1-(3-hydroxypropyl)-1-methylpyrrolidinium [HOC3C1pyr]
7.
Asparaginate
[Asg]
8.
1-(ethoxymethyl)-1-methylpyrrolidinium
[C2O C1C1pyr]
8.
Aspartate
[Asp]
9.
1-(cyanomethyl)-1-methylpyrrolidinium
[CNC1C1pyr]
9.
Glutamate
[Glu]
[C4 C1mor]
10.
Glutaminate
[Gln]
11. 4-(3-hydroxypropyl)-4-methylmorpholinium [HOC3C1mor]
11.
Glycinate
[Gly]
12. 4-(ethoxymethyl)-4-methylmorpholinium
[C2O C1C1mor]
12.
Histidinate
[His]
13. 4-(cyanomethyl)-4-methylmorpholinium
[CNC1C1mor]
13.
Isoleucinate
[Ise]
14.
Leucinate
[Leu]
15.
Lysinate
[Lys]
16.
Methioninate
[Met]
17.
Prolinate
[Pro]
18.
Serinate
[Ser]
19.
Threoninate
[Thr]
20.
Valinate
[Val]
10. 4-butyl-4-methylmorpholinium
Acronym
2. Computational details 2.1. COSMO-RS calculation The COSMO-RS calculations were carried out following a multistep procedure. The geometries and the continuum solvation COSMO calculations for each DNA nucleotides, cations and anions of targeted ILs were optimized and COSMO-files were obtained using TURBOMOLE program 6
package [21] . Density functional theory (DFT) calculations were performed with BeckePerdew-86 (BP86) functional [22] using triple zeta valance potential (TZVP) basis set and resolution of identity standard (RI) approximation [23]. After geometries optimization, the COSMO-files were generated and were used for the estimation of activity coefficients at infinite dilutions and other related properties. COSMO-RS calculations were performed using COSMOthermX, Version C2.1 using the parameter file BP_TZVP_C20_0111 (COSMOlogic GmbH & Co KG, Leverkusen, Germany) [24]. Electroneutral molecular model was applied to simulate the ILs in the COSMO-RS calculation. In this approach, ILs are treated as an equimolar mixture of cations and anions [25]. The details of the calculation procedures of estimating activity coefficient of solutes in ILs using COSMO-RS can be found elsewhere [26-29]. 2.2. Solvation free energies The structures of the DNA nucleotides were extracted from calf-thymus DNA structure. The structure of calf-thymus DNA (Ct-DNA) was obtained from RCSB Protein Data Bank (RCSB PDB) with a PDB ID 425D [30]. The geometries of DNA nucleotides, cations and anions of the studied ILs were optimized using the DFT calculation with Generalized Gradient Approximations (GGA) and Perdew−Wang exchange and correlation functional (PW91) basis set. Initially cubic boxes (primitive cells) of 32 × 32 ×32 Å were created using Material studio visualizer. The DNA nucleotides were placed at the centre of the box and ILs were packed to the box using Amorphous cell module. The nucleotides were solvated with 100 ILs (100 cations and 100 anions) by packing the ILs into the cells. Geometry optimizations were performed to relax the cell and equally distribute the DNA nucleotides the ions. The COMPASS force field were adopted to represent the interaction potentials of nucleotides and ILs throughout the calculations. The energy minimizations were performed with the following convergence criteria: energy (10-4
7
kcal/mol), force (0.005 kcal/mol/Å) and displacement (5×10-5Å). The cells were further equilibrated using Molecular Dynamics (MD) with the constant-temperature (NVT) ensemble followed by Constant-pressure (NPT) ensemble for 100 ps with no position restraints applied. Temperature and pressure control were implemented using the NHL thermostat and Berendsen barostat, respectively [31]. Total simulation time of 100 ps with 100000 number of steps. The simulations were carried out at 298.15 K and 1 atm. Material studio (version 2016) were used for the geometry optimizations, molecular dynamics and solvation free energy calculations. 3. Results and discussion 3.1. Selection of biocompatible ILs Assessment of cytotoxicity of ILs is a very important preliminary test before utilization of the ILs for DNA extractions and storages. It is generally accepted that cations have a major role in the toxicity of ILs [32]. Longer cation side chains have more severe effect on living cells [5]. Generally, the toxicity of ILs can be reduced by reducing the hydrophobicity of the cation, by shortening long alkyl chain length and by introducing polar functional groups (such as ether, hydroxyl, or nitrile groups) into the cation alkyl chain spacer [33]. Moreover, the chemical structure of the cation head group have significant effect on the toxicity [34]. Amde and coworkers [35] summarized the relative toxicity of ILs (based on cationic head groups) as follows: choline < piperidinium < pyrrolidinium < morpholinium < pyridinium = imidazolium < ammonium < phosphonium. Based on these assessments, we selected ILs with choline, piperidinium, pyrrolidinium, morpholinium cation ahead, and also limited the alkyl chain length to four carbon ( C4). We selected 13 cations and coupled with 20 anions based on natural amino acids to model 260 biocompatible ILs. Amino acids are important biomolecules can be converted easily into anions and cations. Amino acids are also cheap and can be abundantly found in
8
nature. More importantly, the amino acid based anion can provide low toxicity ILs if combined with appropriate cations.
3.2. Ionic liquids and DNA nucleotides modelling In contrast to a classical solvent, ILs can be described as a mixture of ions (cations and anions) or either as a single compound [36]. The two descriptions reflect a different chemistry on the atomistic scale properties and for many experimental data the two descriptions affect the definition of the mole fraction. The use of electroneutral mixture is the most flexible description of ILs and successfully been applied for prediction of nucleotides in ILs [26, 36]. We applied the electroneutral mixture to model the ILs. Consequently, the mole fractions used in the activity coefficient calculations were different from the mole fraction normally used in the experiments, where the ILs are treated as one compound. Therefore, the properties of the nucleotides in the ternary system (nucleotide, cation and anion) were converted to binary mixtures (nucleotide and ILs) accordingly. The details of the calculation procedures of estimating properties of solutes in ILs using COSMO-RS can be found elsewhere [36]. It is not practical to perform quantum (DFT) calculation for DNA with practically infinite number of atoms. A practicable approach for DNA modelling is to choose representative part of the DNA chain that is small enough to allow for quantum chemical calculations and large enough to display characteristic features of the molecule. We have chosen four monomer nucleotides
(Deoxyadenosine
5'
monophosphate,
Deoxythymidine
5'
monophosphate,
Deoxycytidine 5' monophosphate, Deoxyguanosine 5' monophosphate) as the representative units for DNA modelling. Moreover, we modelled DNA as a combination of two nucleotides (dimers) since it permits us to study the mutual influence of neighbouring monomeric unit. In 9
this case, two subsequent nucleotides were used to model the DNA. The monomers and dimers are extracted from structure of calf-thymus DNA (Ct-DNA) which was obtained from RCSB Protein Data Bank [30]. Figure 1 shows the structure of Deoxyadenosine 5' monophosphate and Deoxycytidine 5' monophosphate and their dimer extracted from the calf-thymus DNA.
(a)
(b)
(c) Fig.1. Structures and COSMO-charge distribution for DNA nucleotides. (a) Deoxyadenosine 5' monophosphate (A); (b) Deoxycytidine 5' monophosphate (C); (c) A-C dimer. 3.3. Activity coefficient at infinite dilution Activity coefficient is a thermodynamic factor used in thermodynamics to account for deviations from ideal behaviour in a mixture of chemical substances [37]. Activity coefficient is highly dependent on the concentration of each component in the system. At infinite dilution, the solute is surrounded only by solvent molecules and the solute-solute interaction is negligible while solute-solvent interaction attains maximum values resulting in maximum activity coefficient which is commonly called infinite dilution activity coefficient (γ∞). Infinite dilution activity coefficient has very important theoretical and practical applications in chemical and environmental engineering. Infinite dilution activity coefficient can be used for characterizing the solute-solvent interaction [26] and qualitatively estimate the dissolving power of the solvents 10
[38].
The activity coefficient of solutes can also be related quantitively with the relative
solubility of the solute in solvents. Kahlen et al.[38] and Ana Casas et al.[39] successfully applied COSMO-RS predicted activity coefficient to predict the relative solubility complex polymeric materials such as lignin and cellulose in ILs. Since DNA is also is a polymer composed of four different nucleotides monomers we applied similar approach to predict the relative solubility of calf-thymus DNA in the ILs. The quantitative description of nucleoids solubility in ILs can be expressed by the following simplified equation [38].
(1)
where, xiL is the mole fraction of the dissolved component i in a saturated solution in equilibrium with the solid of i, ∆hm,i and Tim denote the enthalpy of melting and the melting temperature of component i, respectively. According equation (1), at given temperature and specific system (solute-solvent mixture), the exponential term depends only on the pure properties (melting point and heat of fusion) of pure solute (nucleotides in this case) which is a constant term. Therefore, the reciprocal of the activity coefficient can qualitatively show the relative solubility of the nucleotides in the ILs. That means, the lower activity coefficient of the nucleotide in ILs results in higher solubility the solute in the ILs. 3.3.1.Effect of DNA nucleotides on coefficient Fig. 2 shows a plot of a natural logarithm of the activity coefficients at infinite dilutions (lnγ∞) of DNA nucleotide monomers and dimers in 4-butyl-4-methylmorpholinium ILs with 20-amino acid based anions. The activity coefficients of the DNA nucleotides in the 4-butyl-4methylmorpholinium based ILs increase in the order of A-T < A-C < G-C < T < G < A < C. The activity coefficients of the monomer DNA nucleotides (A, C, G and T) are higher than their 11
corresponding dimers (A-C, A-T and G-C). Similar trends were observed for all ILs investigated in this work. The predicted activity coefficients of the nucleotides in the studied ILs are provided in supporting information (Table S1). [Gly] [Ala] [Lys] [Phe] [Val] [Ise] [Leu] [Met] [Pro] [Cys] [Trp] [His] [Tyr] [Arg] [Thr] [Gln] [Asg] [Ser] [Glu] [Asp]
-10
-15
ln(γ∞)
-20 -25 -30
-35 -40 A
C
G
T
A-C
A-T
G-C
Fig. 2. Activity coefficient at infinite dilution at 298.15 of DNA nucleotides and dimers in 4butyl-4-methylmorpholinium based ILs. 3.3.2. Effect of cations and anions on coefficient at infinite dilution Fig. 3 shows the activity coefficient at infinite dilution of T in the ILs with the studied cations with anion. The activity coefficient at infinite dilution of T in the choline based ILs are higher than that of 1-butyl-1-methylpiperidinium, 1-butyl-1-methylpyrrolidinium and 4-butyl-4methylmorpholinium based ILs. This could be due to the presence of cyclic head group in piperidinium, pyrrolidinium and morpholinium based ILs, and lack of the cyclic group in choline based ILs. The structural similarity between the ILs head group and the solutes (nucleotides) may enhance the solute-solvent interaction in piperidinium, pyrrolidinium and morpholinium based ILs. The four nucleotides in the DNA structure contain 5 and 6-cyclic structure which creates structural similarity with the cations of the ILs. Piperidinium and morpholinium based cation contain 6-cyclic structure while pyrrolidinium is the 5-cyclic cation. Introduction of 12
functional group in cation alkyl spacer increases the activity coefficient of the nucleotides (Fig.3). Introduction of nitrile, hydroxyl and ethoxy functional groups increases the activity coefficients of the nucleotides in the ILs. The effect of nitrile functional group on the activity coefficient is more pronounced than that of hydroxyl and ethoxy functional groups, that is, hydroxyl and ethoxy functional groups ILs show lower activity coefficient compared to nitrile functionalized ILs. Moreover, the hydroxyl and ethoxy functionalized piperidinium, pyrrolidinium and morpholinium based ILs show lower activity coefficient compared to choline based ILs. Therefore, the hydroxyl and ethoxy functionalized can be a potential candidate for extraction and storage DNA as they are also less toxic compared to ILs without functional groups in alkyl chains. 0
-5 -10
lnγ∞
-15 -20 -25 -30 -35 -40 -45
A
T
A-T
Figure 3. Activity coefficient at infinite dilution at 298.15 of A, T and A-T in the ILs with glycinate with anion. Fig. 4 shows the effect of anions on the activity coefficient at infinite dilution of T for 1-butyl-1-methyl-pyrrolidinium based ILs. Similar observations were made for all the studied ILs and DNA nucleotides. Amino acids contain amine (-NH2) and carboxyl (-COOH) functional 13
groups, along with a side chain (R group) which is specific to each amino acid (Fig.5). They can be classified as positively or negatively charge, polar or nonpolar amino acids amino acid based on the side chain [40]. Generally, anions based on hydrophobic amino acids such as [Gly], [Ala], [Phe], [Val], [Ise], [Leu] and [Pro] show lower activity coefficients compared to other anions (Fig. 4). ILs with non-polar anions [Cys], [Trp], [His], [Tyr] and [Thr] show intermediate activity coefficient for the DNA nucleotides. On the other hand, ILs with charged side chain amino acid anions such as [Asp], [Glu], [Asg] and [Ser] show higher activity coefficient. The only anion from this group that shows lower activity coefficient is [Lys]. This could be due to the long alkyl chain in lysine structure which may reduce the effect of the charge side chain on the polarity of the anion [40]. Similar trends were observed for all nucleotides and other ILs studied in this work. This suggests ILs with non-polar amino acid based anions interacts strongly with the DNA nucleotides and could be considered as potential candidate for extraction and storage of DNA. 0 -5 -10
lnγ∞
-15
-20 -25 -30 -35 -40
A
C
A-C
-45
Figure 4. Activity coefficient at infinite dilution at 298.15 K of A, C and A-C in 1-butyl-1methyl-pyrrolidinium based ILs.
14
side chain (alpha carbon) R
Amin group
O H2N OH
Caboxylic group
Fig. 5. Structure of an amino acid in its un-ionized form. 3.3.3. Excess enthalpy The excess enthalpy of the nucleotides-ILs mixture were predicted using COSMO-RS model to get insight into the nature of interaction of ILs and DNA nucleotides. The excess enthalpy allows the evaluation of the energetic contributions of all possible specific interactions established by each species and their contributions to the total excess enthalpy. The excess enthalpies can also be used to infer on the strength of ILs-DNA nucleotides interaction in the binary mixtures. In COSMO-RS model, the excess enthalpy of mixture (HEm) is sum of hydrogen bond interaction (HEHB), van der Waals force interaction (HEvdW), and electrostatic//misfit interactions (HEMF) as shown in equation 2.
(2) The excess enthalpy contributions and the total excess enthalpy of T and morpholinium cystinate based ILs at equimolar composition (x T = 0.5) at 298.15 K are depicted in Figure 6. The excess enthalpy of the remining morpholinium based ILs with cystinate anion and the DNA nucleotides over the entire composition is provided in supporting information (Table S2). The HEm for all the studied ILs and nucleotides moistures (both monomer and dimer) are negative indicating favourable energetic interactions between the ILs and nucleotides. A more negative HEm values were obtained for dimer DNA nucleotides than their corresponding monomer counterparts. The 15
more negative values for dimers implies stronger interaction between the ILs and the nucleotide dimer which is consistent with results obtained activity coefficients. Moreover, the misfit/ electrostatic, hydrogen bonding and van der Waals interactions are all negative for ILsnucleotides systems, but their contribution to the total excess enthalpy differ significantly. The hydrogen bond interaction contribution to exothermicity of the mixtures is higher in magnitudes than van der Waals force and electrostatic/misfit interactions for all the studied ILs-DNA nucleotide systems. This confirms that hydrogen bonding is the dominant interaction and determines the enthalpic nature of the mixtures whereas van der Waals force interactions have minor contribution to exothermicity of the mixture. Moreover, the HEm decreases in the order of [CNC1C1 mor] > [HOC3C1mor] > [C2O C1C1 mor] > [C4 C1 mor] for all studied anions. This shows [C4C1mor] based ILs strongly interacts with the DNA bases whereas [CNC 1C1pyr] based ILs are the less interacting ILs. This is in good agreement with the predicted activity coefficients as stated previously. Similar trends were observed for DNA nucleotides and all the studied ILs. 0
Excess Enthalpy (kJ/mol)
-5 -10
-15 -20 -25 -30 -35
HE,M
HE,HB
HE,MF
HE,VDW
-40 [C4 C1mor]
[C2O C1C1mor]
[HOC3C1mor]
[CNC1C1mor]
Figure 6. Excess enthalpy (HEm) of T-morpholinium cystinate based ILs binary mixture at 298.15 K predicted by COSMO-RS at (xH2O = 0. 5).
16
The HEm of T and 1-butyl-1-methylpyrrolidinium based ILs with three different anions (one from each group) is depicted in Figure 7. As it can be clearly seen, glycinate based ILs shows highe negative HEm compared to histidinate and aspiraginate baes ILs. This implies that ILs with non-polar amino acid based anions are favourable for energetic interactions with the DNA nucleotides; and ILs with charged amino acid anions are less favourable for the energetic interactions. All the hydrogen bonding, van der Waals force, and electrostatic/misfit interactions favour the energetic interaction but the major contribution arises from the hydrogen bond interaction for all studied ILs. This might be due to amino acid based anions which can form strong hydrogen bonding. 0 Excess Enthalpy (kJ/mol)
-5 -10 -15
-20 -25 -30 -35 -40
HE,M
HE,HB
HE,MF
HE,VDW
-45 [Gly]
[His]
[Asp]
Figure 6. Excess enthalpy (HEm) of T-1-butyl-1-methylpyrrolidinium based ILs binary mixture at 298.15 K predicted by COSMO-RS at (xH2O = 0. 5). 3.4. Solvation free energies (∆Gsolv) The solvation free energy plays a crucial role in understanding the chemical behaviour of molecules in liquid phases [41]. It provides a way to characterize preferential solvation in a
17
solvent mixture [42]. In this work, the solvation free energies of DNA nucleotides in ILs were calculated to investigate the effect of structural variations of amino acid based anions on solvation free energy of the DNA nucleotides in the ILs. The solvation free energies of monomer A and dimer A-C in 1-butyl-1-methyl pyrrolidinium based ILs is depicted in Fig.7. The computed results show that the free solvation energies of the DNA nucleotides in the ILs are negatives, showing that the ILs can interact with the DNA nucleotides. The results also show ILs with anions based on hydrophobic amino acids such as [Gly], [Ala], [Phe], [Val], [Ise], [Leu] and [Pro] show high negative free solvation energies compared to other ILs. On the other hand, anions based charged side chain amino acid anions such as [Asp], [Glu], [Asg] and [Ser] show low negative free solvation energies. Similar trends were observed both for the monomer A and dimer A-C DNA nucleotides. The solvation free energy of A in the 1-butyl-1-methyl pyrrolidinium based ILs varies from (-17.0 to -33.5) kcal mol-1. On the other hand, the solvation free energy of the dimer A-C DNA nucleotide in the 1-butyl-1-methyl pyrrolidinium based ILs are in the range of (-27.4 to -44.0) kcal mol-1. The solvation free energies of A-C are more negative compared to that of monomer A for corresponding ILs. This implies the interaction between the ILs and the DNA increases as the number of nucleotides increases in the DNA. This observation supports the observations obtained from activity coefficients and excess enthalpy of the systems. Finally, it is worth mentioning that the current work is based on COSMO-RS based activity coefficient and infinite dilution and excess enthalpy, and solvation free energies obtained from molecular simulation. The results of this study can help as a starting point for application of amino acid based ILs for DNA extraction/purification and storage.
18
∆G solv(kcal.mol-1)
0 -10 -20 -30
-40 -50
A
A-C
Figure 7. Solvation free energies of A and A-C in 1-butyl-1-methyl pyrrolidinium based ILs. 4. Conclusions In this work, the interactions between DNA nucleotides and bio-ILs were investigated to get insight into the effect of structural variations of the ILs on the ILs-DNA complex formations by using COSMO-RS model and molecular simulation. 260 bio-based ILs based on choline, piperidinium, pyrrolidinium,
morpholinium,
pyridinium, imidazolium, ammonium and
phosphonium cations and amino acid based anions were evaluated. The activity coefficients at infinite dilution of the DNA nucleotides in the ILs and excess enthalpy of mixing of the systems were predicted using COSMO-RS model. Solvation free energies of the DNA nucleotides in the ILs were estimated employing molecular dynamics simulations. The activity coefficients of the monomer nucleotide are higher for all the studied ILs, implying the interaction between the DNA nucleotides increases with DNA nucleotide chain length. The lower activity coefficient (higher interaction) shows higher solubility of longer DNA nucleotide chain length. Moreover, 19
piperidinium and pyrrolidinium based ILs show lower activity coefficients than choline and morpholinium based ILs. Furthermore, ILs based on anions with nonpolar side chain amino acids show lower activity coefficient than anions with polar side chains. This implies strong interaction between the nucleotides and ILs with anions with nonpolar side chain amino acids compared to anions with polar side chains. Moreover, ILs based on anions with nonpolar side chain show more negative excess enthalpy of mixing compared to anions based on amino acid with polar side chain. Further, the solvation free energies of the nucleotides in the studied ILs are negative. Solvation free energy is more negative for dimers compared to monomer nucleotides. ILs with anions containing nonpolar side chain show higher negative solvation free energies compared to those with polar side chains. Based on COSMO-RS model and molecular simulation studies ILs based piperidinium and pyrrolidinium cations and amino acid anions with nonpolar side chain are suitable candidate for DNA extraction and storage. AUTHOR INFORMATION Corresponding Author *Tel.: (60) 175667304. E-mail: [email protected]. ACKNOWLEDGEMENTS This work is supported by PRF Ionic liquid programme research grant scheme (PRF-0153ABA30) of Centre for ionic liquid research centre, Universiti Teknologi PETRONAS Reference [1] W. Sun, P. Qin, H. Gao, G. Li, K. Jiao, Electrochemical DNA biosensor based on chitosan/nano-V 2 O 5/MWCNTs composite film modified carbon ionic liquid electrode and its
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Highlights
Interaction between DNA nucleotides biocompatible ILs were investigated.
Activity coefficient, excess enthalpy and solvation free energies were predicted
COSMO-RS and molecular simulation were applied to predict the mixture properties
Both the cation and the anions affects the properties of the binary system
ILs based on anions with nonpolar side chain show more affinity for DNA nucleotides
26