Role of backbones on the interaction of metal ions with deoxyribonucleic acid and peptide nucleic acid: A DFT study

Journal Pre-proof Role of backbones on the interaction of metal ions with deoxyribonucleic acid and peptide nucleic acid: A DFT study Surjit Bhai, Bishwajit Ganguly PII:

S1093-3263(19)30292-X

DOI:

https://doi.org/10.1016/j.jmgm.2019.107445

Reference:

JMG 107445

To appear in:

Journal of Molecular Graphics and Modelling

Received Date: 21 April 2019 Revised Date:

28 August 2019

Accepted Date: 28 August 2019

Please cite this article as: S. Bhai, B. Ganguly, Role of backbones on the interaction of metal ions with deoxyribonucleic acid and peptide nucleic acid: A DFT study, Journal of Molecular Graphics and Modelling (2019), doi: https://doi.org/10.1016/j.jmgm.2019.107445. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 Published by Elsevier Inc.

Role of backbones on the interaction of metal ions with deoxyribonucleic acid and peptide nucleic acid: A DFT study Surjit Bhai†, and Bishwajit Ganguly*† †

Computation and Simulation Unit (Analytical and Environmental Science Division and Centralized Instrument Facility), CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar, Gujarat, India-364 002. *Corresponding Author. Fax: (+91)-278-2567562, E-mail: [email protected]; [email protected]

Graphical Abstract

Role of backbones on the interaction of metal ions with deoxyribonucleic acid and peptide nucleic acid: A DFT study Surjit Bhai†, and Bishwajit Ganguly*† †

Computation and Simulation Unit (Analytical and Environmental Science Division and Centralized Instrument Facility), CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar, Gujarat, India-364 002. *Corresponding Author. Fax: (+91)-278-2567562, E-mail: [email protected]; [email protected] Abstract Metal ion interaction with deoxyribonucleic acid and peptide nucleic acid were studied using B3LYP-D3/6-311++g(d,p)//B3LYP/6-31+G(d) level of theory in aqueous phase employing polarized continuum (PCM) model. This study reports the role of backbones on deoxyribonucleic acid and peptide nucleic acid for complexation with different metal ions. The systematic study performed with DFT calculations reveals that central binding (Type-4) shows the strongest binding compared to the other binding modes because of the involvement of the backbone as well as the nitrogenous bases. The charged backbone of DNA nucleotides contributes significantly towards binding with the metal ions. The deoxyguanosine monophosphate (dGMP) clearly indicates the strongest binding upon complexation with Mg2+ (-49.6 kcal/mol), Zn2+ (-45.3 kcal/mol) and Cu2+ (-148.4 kcal/mol), respectively. The

neutral backbone of PNA also assists to complex the metal ions with PNA nucleotides. The Mg2+ and Cu2+ prefer to bind with the PNA-Cytosine (-32.9 kcal/mol & -132.9 kcal/mol) in central binding mode (type-4). PNA-Adenine-Zn2+ (-29.1 kcal/mol) is the preferred binding mode (type-4) compared to other modes of interaction for this metal ion with PNA-Adenine nucleotide. The Cu2+ ion showed the superior complexation ability with deoxyribonucleic acid and peptide nucleic acid compared to Mg2+ and Zn2+ ions. The cation-π complexation 1

with the bases of nucleotides was also obtained with Cu2+ ion. The AIM (atoms in molecule) theory has been applied to examine the nature of the interaction of Mg2+, Zn2+, and Cu2+ ion to the deoxyribonucleic acid and peptide nucleic acid. The alkaline earth metal, Mg2+ ion shows electrostatic nature while interaction with deoxyribonucleic acid and peptide nucleic acid, however, the transition metal ions (Zn2+, Cu2+) showed partly covalent nature as well with deoxyribonucleic acid and peptide nucleic acid. The optical properties calculated for the binding of metal ions with deoxyribonucleic acid and peptide nucleic acid showed a diagnostic signature to ascertain the interaction of metal ions with such nucleotides. Cu2+ ion showed larger red shifts in the absorption spectrum values upon complexation with the DNAs and PNAs. The calculated results suggest that such metal ions would prefer to bind with the DNA compared to PNA in DNA-PNA duplexes. The preference for the binding of metal ions with DNA nucleotides is largely attributed to the contribution of charged backbones compared to the neutral PNA backbones. Keywords DNA, Peptide nucleic acid, TD-DFT, polarized continuum model, AIM Introduction Metal ions play a crucial role in biological phenomenon with the nucleotides such as transcription,

DNA

replication,

oxidation-reduction

reactions,

enzymatic cleavage,

carcinogenesis, DNA packing, and mutagenesis. The study of metal ions with biological molecules such as proteins and DNA have shown pathologic processes including metabolic imbalances and neuro-degenerative problems.[1–3] Many experimental and theoretical reports are available regarding the interaction of the metal ions with the nucleotides, nucleosides, and nucleobases of DNA, RNA, and PNA. [1–19] The peptide nucleic acid (PNA) is an analogue of DNA, which mimics the property of DNA and obey Watson-Crick rules. Peptide nucleic acids (PNA) have an excellent property to bind strongly to the 2

complementary DNA as well as RNA counterparts. The flexible backbone of PNA composed of N-(2-amino-ethyl) glycine unit to which the nitrogenous bases are linked through a methylene linkage offers high bio-stability that helps the PNA for in vivo applications.[20– 22] The alkali and alkaline earth metal ions are important cations in the living system and their role in biological processes is well discussed in the literature.[23,24] Alkali metal cations and alkaline earth metals (Na+, K+, Mg2+, and Ca2+) prefer to interact with the backbone of DNA resulting in the neutralizing of the negative charges and stabilize the βdouble helix of DNA. Transition metals like Zn2+ and Cu2+ have also played an important role in the biological systems. The zinc ion is generally involving in different cellular processes, comprising immunofunction, proliferation, reproduction, and defence against free radicals.[25–27] Zinc ion has the capability to influence the chromatin structure, DNA replication, transcription, and repair. The metal ions also influence the conformational changes in DNA structures. The temperature, pH, and concentration of metal ions can induce other DNA structures due to the involvement of metal ions such as Zn2+.[28] Copper has a role in the formation of the reactive oxygen species (ROS) in the biological systems, which can lead to DNA damage.[29–31] Further, some studies highlighted that the interaction of Cu2+ ion leads to the breakage of the single and double strand of DNA by the excess production of the hydroxyl radicals.[29,32,33] Such hydroxyl radicals are the main cause of the modified bases and sugars in DNA and DNA-protein cross-links.[34] Copper can produce active OH• and OOH• radicles which strongly reacts with sugar and polyol structures.[35,36] There is also a report using Cu2+ catalyst to for oxidative coupling of amines to produce imines cause the leaching of copper ion in the solution and hence can possibly lead to DNA damage.[37] It becomes noxious when the concentration of the copper rises above the optimum level in the mammalian cell.[29,32,33]

3

The binding of the metal ions with modified PNAs has been reported in the literature.[38,39] The interactions of metal ions (Mg2+, Zn2+, Ni2+, and Co2+) with thin films of PNA oligomer was studied using electrochemical impendence study (ESI).[21] The charge transfer resistance, RCT results suggest that the binding of such metal ions to the duplex of DNA, PNA, and DNA-PNA can presumably be identified. The specific binding sites for the metal ions with such duplexes is not trivial from these studies. The efforts to establish the interaction of metal ions with nucleic acids such as DNA and or PNA in duplex structures are scarce in the literature. In particular, the role of backbones in binding the metal ions with DNA and PNA is not well explored. In this article, we have examined the binding affinity of a few important metal ion ions i.e., Mg2+, Zn2+, and Cu2+ with the deoxyribonucleic acid and peptide nucleic acid. The importance of backbone i.e., charged one for DNA and the neutral for PNA in the binding of such metal ions will be ascertained. The binding energies computed using DFT calculations would suggest the possible binding sites of metal ions in DNA-DNA, PNA-PNA, and DNA-PNA duplexes. The interactions were modeled with individual nucleobases attached to the backbones of DNA and PNA (Scheme 1).

4

ADENINE NH2

N

N

N

N

NH2

N

N

N

N R

Type-1

Type-2

N

N

N

N

R

NH2

NH2 N

N

N

N

NH2

N

N

N

N

N

R

R

Type-2b

Type-2a

N

N

R

R

NH2

N

Type-4

Type-3

GUANINE O N N

O N

NH N

N

NH2

R

N

NH N

NH2

N

NH

N

R

N

NH2

O NH

N

NH2

N

R

R Type-2

Type-1

O

O

N

O N

NH

N

N

N

NH2

R

N

NH2

R Type-3

Type-2b

Type-2a

NH

Type-4

CYTOSINE NH2

NH2

NH2

NH2

N

N

N

N

N

O

N

R

N

O

N

R

R Type-2

Type-1

O

O

R

Type-3

Type-4

THYMINE

H3C

O NH N R Type-1

O

H3C

O NH N

H3C

O

O NH N

R

O

R

Type-2

Type-2a

H3C

O NH N

O

R Type-3

H3C

O NH N

O

R Type-4

Scheme 1: Different possible sites for the interaction of metal ions to deoxyribonucleic acids and peptide nucleic acids.

5

Computational Methods All the geometrical complexes of metal ions (Mg2+, Zn2+, and Cu2+) with DNA and PNA were optimized at B3LYP/6-31+G(d) level of theory in the aqueous phase.[40–43] The positive vibrational frequencies confirm that optimized structures are minima. We have carried out single point calculation at B3LYP/6-311++G(d,p) level of theory using B3LYP/631+G(d) optimized geometries. We have employed effective core potentials, such as LANL2DZ for transition metal ions, Zn2+ and Cu2+ ions.[44] Furthermore, the dispersion corrections have been considered with Grimme's dispersion correction (DFT-D3) to account London dispersion correction energy in aqueous phase using polarizable continuum models (PCM) solvation model.[45,46]

Open shell calculations were performed with Cu2+

complexes using spin unrestricted formalism. The calculations have been performed with a larger basis set to examine the relative trends observed with relatively lower basis sets. The computed results suggest that the trends are similar even with higher basis set also. The binding energies are calculated using equation 1. Binding Energy (∆E) = EComplex – (EDNA/PNA + EM2+)

(1)

Where EComplex refers to the energy of the complex of the PNA or DNA with metal ions, EDNA/PNA refers to the energy of the isolated PNA or DNA and EM2+ is the energy of the studied metal ions (Mg2+, Zn2+, and Cu2+). Time-dependent density functional theory (TDDFT) calculations were performed at the B3LYP/6-31+G(d) level of theory for simulating the absorption spectra of metal ion complexes with the deoxyribonucleic acid and peptide nucleic acid in aqueous solution using polarizable continuum models.[47,48] All calculations are performed with Gaussian 09 package.[43] AIM (atoms in molecules) analysis was performed using Multiwfn software with the wave functions generated at B3LYP/6-31+G(d) level of theory.[49] Bader’s AIM (atom in molecules) analysis is widely used to unravel the

6

behavior of the atom-atom interactions in covalent and non-covalent interaction in molecules, crystals, proteins, DNA base stacking, and DNA base pairing.[50] Charge transfer calculation was examined using Natural Bond Orbital (NBO) analysis at B3LYP/6-31+G(d) level of theory.[51,52] A large number of reports available in the literature on the use of B3LYP DFT functional for the interaction of metal ions with the nucleotide, nucleosides, and nucleobases.[4,6– 9,18,19,53–55] DFT with B3LYP functional has shown its reliability in complexation of metal ions with heteroatom systems in less computational cost in comparison to other quantum chemical methods such as MP2.[56,57] In this study, we have also employed B3LYP functional to examine metal ion interactions with deoxyribonucleic acids and peptide nucleic acids. Ab initio molecular dynamics calculations were also performed with density functional programme DMOL3 software (version 4.1) in Material Studio from Accelrys Inc. with the local spin density approximation and the Perdew-Wang correlation (LDA/PWC) using DND basis set using COSMO solvation model in aqueous phase.[58–62] The simulations were performed using canonical NVT ensemble and the temperature was kept at 300K using a Gaussian thermostat.[63] The ab initio molecular dynamics were carried out for 1 picosecond with the time step of 1femtosecond. Results The nucleobases with the respective backbones of DNA and PNA were taken from crystal structures of DNA-PNA (https://www.rcsb.org) PDB ID: 1NR8 CSD site. The segregated nucleobases of DNA and PNA were considered for the interaction study of metal ions Mg2+, Zn2+, and Cu2+. All the structures of metal ion nucleotide complexes are optimized using B3LYP/6-31+G(d) level of theory in the aqueous phase with polarized continuum solvation

7

(PCM) model. The possible sites of interaction of the metal ions to the deoxyribonucleic acid and peptide nucleic acid are shown in scheme 1. Type-1 represents the cation-π-interaction with the nucleotide, type-2, type-2a and type-2b represent the interaction of metal ions with the nucleobase, type-3 for the interaction with backbones of DNA and PNA, whereas type-4 is the site for the central binding where the nucleobases and backbone both involve in complexation process. The binding energies of the metal ions with the DNA and PNA have been reported with B3LYP-D3/6-311++g(d,p) level of theory using PCM solvation model. There are reports of metal ion interaction with DNAs in the gas phase and some reports are also available in solvent medium. [8],[53] We have performed the DFT calculations for the interaction of metal ions with deoxyribonucleic acid and peptide nucleic acid in the aqueous phase. The DNA nucleotides have been optimized at B3LYP/6-31+G(d) level of theory and the optimized structures were found to be similar to that of the crystal geometries taken for the study (Figure S1 & Table ST1). The implicit solvent model employed in this study, however, not significantly affected the optimized geometries compared to the observed crystal structures. Nonetheless, the protic explicit solvent molecule can influence the geometry of nucleotides (Figure S1 & Table ST1). The optimized complexes of Mg2+ ion with DNA nucleotide are shown in figure 1. The distances and binding energy of Mg2+ ion with the deoxyadenosine monophosphate (dAMP) deoxyguanosine monophosphate (dGMP), deoxycytidine monophosphate (dCMP), deoxythymidine monophosphate (dTMP) with Mg2+ are given in figure 1. The calculated binding energies at B3LYP-D3/6-311++g(d,p) level shows that the dAMP-Mg2+, type-3 (-32.0 kcal/mol) and type-4 (-32.7 kcal/mol) shows comparable stability as compared to other modes of interaction (Figure 1 & Figure S2A). The dGMP-Mg2+ complex shows the stronger binding of Mg2+ (type-4) i.e., to the central binding mode (-49.6 kcal/mol) where the oxygen of the phosphate backbone aligns to coordinate with the nucleobases in a bidentate manner (Figure 1 & Figure S2A). Further to mention that the

8

central binding mode of the dGMP-Mg2+ complex is strongest in terms of energy among all the DNA nucleotides studied here. Guanine possesses the large dipole moment and its orientation supports the type-4 interaction for complexation with metal ions.[15] The Mg2+ ion also interact with the guanine nucleobase in type-2, type-2a, type-2b & type-3, respectively (Figure S2A). The geometry of cation-π interaction (Type 1) of Mg2+ ion with the nucleobases was not obtained as the metal ion moved away from the π-site of these nucleobases. The cytosine nucleotide dCMP has lesser sites of interaction with Mg2+ ion (Scheme 1). The Mg2+ ion prefers to interact with the backbone of dCMP (Type-3) and the binding energy is 2.0 kcal/mol stronger compared to the binding energy calculated for Type-2 (Figure 1 & S2A). In the complex of dTMP-Mg2+, Mg2+ prefers to bind strongly (type-3), where Mg2+ binds with the backbone of the nucleotide in a bidentate manner (Figure 1 & S2A). In one of the earlier reports, on the binding of Mg2+ ion using semi-empirical PM3 method with DNA nucleotides suggest that the phosphate backbone attached to adenine base is energetically preferred compared to the other corresponding other bases. It is important to note that such calculations were carried out in the gas phase and the interactions of the metal ion with bases and the backbones were not observed.[5] The semi-empirical results mainly contributed towards the binding affinity of phosphate backbones only with the metal ions.

9

Figure 1: Best binding sites of DNA and PNA with Mg2+ calculated using B3LYP-D3/6311++g(d,p)//B3LYP/6-31+G(d) level of theory in the aqueous phase. Similar calculations were performed for the complexation of the metal ions with the PNAs. The optimized structures of peptide nucleic acids obtained from the PDB file are largely similar to that of their corresponding x-ray crystal structures (Figure S1). The dispersion corrected B3LYP-D3/6-311++g(d,p) calculated result shows that the PNA-Adenine-Mg2+ complex is comparable in binding energies in type-1, type-2, type-2a, type-2b and type-3, respectively (Figure 1 & Figure S2B). As observed in the case of DNA nucleotides, the cation-π interactions (type-1) are also not possible with PNAs in the aqueous phase. The interaction of Mg2+ ion with PNA in type-1 finally converged to the type-2a interaction mode and hence the energies are similar to the type-2a interaction of Mg2+ with this nucleobase. In PNA-Guanine-Mg2+ complex, the metal ion prefers to bind with the central binding (type-4), which is the strongest binding energy (-28.3 kcal/mol) observed (Figure 1 & Figure S2B). It is important to note that the neutral backbone of PNA, however, participates in binding with the metal ions in PNA-cytosine-Mg2+ complex (type-4). The smaller cytosine nucleobase is aligned with the backbone of PNA to coordinate the Mg2+ ion effectively and changes the 10

preference of binding compared to the DNA nucleotide (Figure 1 & Figure S2B). The PNAthymine-Mg2+ complex also showed remarkable preference in binding where the backbone of thymine is primarily involved in complexation with the metal ion (type-3, Figure 1). The binding energies calculated for the interaction of Mg2+ ion with the cytosine and thymine of peptide nucleic acids are similar in energy and these sites are energetically preferred compared to PNA-adenine and PNA-guanine complexes. Zn2+ Complexes with deoxyribonucleic acid and peptide nucleic acid The zinc ion is one of the crucial metal ions involved in diverse cellular processes like immunofunction, proliferation, reproduction, and protection against free radicals.[26,27,64] One of the important features of zinc ion is that it can alter the chromatin structure, DNA transcription, DNA repair, and replication.[65] The study was further extended with the interaction of Zn2+ ion with deoxyribonucleic acid and peptide nucleic acid (Figure 2, Figure S3A & Figure S3B). The calculated corrected binding energies at B3LYP-D3/6-311++g(d,p)//B3LYP/6-31+G(d) of dAMP-Zn2+ suggest that type-4 (-30.9 kcal/mol) interaction is energetically preferred compared to other modes of interaction. The dGMP-Zn2+ complex showed the strongest binding energy amongst all the DNA nucleotides studied here. The calculated binding energy using B3LYP-D3/6311++g(d,p) method for dGMP-Zn2+ complex is -45.3 kcal/mol (Figure 2 & Figure S3A). The coordination of the Zn2+ ion is in a bidentate manner between the guanine nucleobase and the phosphate backbone.

11

Figure 2: Best binding sites of DNA and PNA with Zn2+ calculated using B3LYP-D3/6311++g(d,p)//B3LYP/6-31+G(d) level of theory in the aqueous phase. The calculated binding energies for dCMP-Zn2+ complex (in type-1 & type-2) is energetically comparable, however, such modes are preferred sites as compared to other modes of interaction (Figure 2 & Figure S3A). The binding of Zn2+ ion with the thymine nucleotide i.e., dTMP-Zn2+ complex also showed the preferred interaction with the backbone (type-3) as shown in figure 2. The binding energy of Zn2+ ion with the nucleobase of dTMP is relatively weaker compared to the backbone interaction of this nucleotide (Figure S3A). The binding of Zn2+ with peptide nucleic acids was optimized using the same DFT level of theory. The sites of interaction of Zn2+ with PNA-adenine reveal that type-4 is energetically favored compared to the other sites of interaction (Figure 2 & Figure S3B). The binding of Zn2+ to PNAAdenine nucleobase (type-2, type-2a, and type-2b) shows comparable binding affinity toward the nucleobase. Type-2a is energetically favored binding site in the case of PNA-guanine Zn2+ complex (Figure 2 & figure S3B). In the case of PNA-cytosine-Zn2+ complex, type-2 shows the preferred binding site as compared to the other binding sites (Figure 2 and Figure S3B). Interestingly, the PNA-Thymine-Zn2+ complex showed a clear preference for the 12

binding of Zn2+ ion in the type-3 mode of interaction (Figure 2 & Figure S3B). The zinc ion (Zn2+) has fully occupied d-orbitals and interact weakly with the nucleotides whereas the Cu2+ ion has unoccupied d-orbitals which leads to the stronger binding to the nucleotide. Similar energy differences were also observed in previous studies.[66] Cu2+ complexes with deoxyribonucleic acid and peptide nucleic acid The binding energies of Cu2+ with DNA nucleotides are given in figure 3 and figure S4A. The calculated binding energies at B3LYP-D3/6-311++g(d,p)//B3LYP/6-31+G(d) level of theory shows that the Cu2+ ion can form a cation-π complex with dAMP (type-1), which otherwise was not observed with Mg2+ and Zn2+ ions (Figure 1-3, Figure S2A-S4B). Marino et al., have investigated the interaction of Cu2+ ion with DNA and RNA nucleobases where they confirmed that cation-π interaction with the pyrimidine nucleobases (uracil and thymine) are possible.[6] In our study, we have also observed that Cu2+ ion interacts with the π plane of nucleobases (Figure S4A & Figure S4B). The preferred interaction of Cu2+ ion with dAMP nucleotide is central interaction mode (type-4), where the backbone and nucleobase participate in complexation with Cu2+ ion (Figure 3 & Figure S4A). The interaction of Cu2+ ion in type-2 mode with dAMP optimized to central interaction mode (type-4). In dGMPCu2+ complex, the similar binding strength is observed in type-2, type-2a and type-4 showing the binding energy of -148.4 kcal/mol. The type-2 and type-2a geometries show that Cu2+ ion complexed in the central binding mode as in the case of type-4. The interaction of Cu2+ ion is relatively weaker with the backbone of dGMP and the calculated energy is -124.4 kcal/mol (Figure S4A). The dGMP-Cu2+ complex also showed the cation-π interaction, however, the binding energy is much lower compared to other binding modes obtained here (Figure S4A). In the complex of dCMP-Cu2+, Cu2+ ion prefers to bind comparable with the phosphate backbone of the DNA and with type-2 as well (Figure 3). Type-1 (cation-π) is showing the least binding energy as compared to the other interaction sites. Type-2 interaction showed the 13

binding energy of -110.8 kcal/mol (Figure-S4A). In the complex of dTMP-Cu2+, phosphate backbone is the energetically preferred binding site compared to the other modes of interaction (Figure 3 & Figure S4A). The dGMP nucleotide showed a clear preference for the binding with Cu2+ ion compared to the other nucleotides as observed with the Zn2+ and Mg2+ ions (Figure 1, 2 & 3). Andrushchenko et al., investigated the metal ion interaction to the deoxyguanosine monophosphate where Cu2+ shows the strongest binding to the phosphate backbone as well as to the nucleobases.[66] The continuum solvation model may lead to an overestimation in the binding energy of metal ions with the nucleobases. The comparison of free energy of hydration of these three metal ions with the available experimental values suggest that for Cu2+ ion the difference is as large as 30% (Table ST4). The interaction of metal ions with molecular and biomolecular systems in solution has been the subject of many experimental and computational studies.[67–70] The inclusion of accurate interaction of metal ions with biomolecules is aqueous phase is computationally very demanding and considering the number of systems examined here, the polarized continuum model was the choice for this study.[71] Such models have been used for the interaction of metal ions with nucleobases and presumably the errors borne out in all the calculated results would mutually cancel in this comparative study.[66,72–74]

14

Figure 3: Best binding sites of DNA and PNA with Cu2+ calculated using B3LYP-D3/6311++g(d,p)//B3LYP/6-31+G(d) level of theory in the aqueous phase. The interaction of Cu2+ ion with peptide nucleic acids show that the type-1 (cation-π) binding is feasible where no cation-π interaction was observed in the case of Mg2+ and Zn2+ (Figure S4B). The PNA-Adenine-Cu2+ complex shows comparable binding affinity to the type-2a and type-2b i.e., -114.0 kcal/mol as compared to other modes of interaction. The PNAguanine, PNA-cytosine, and PNA-thymine show the preferred binding of Cu2+ ion with the backbone and the nucleobases (Figure 3). PNA-cytosine showed a clear binding preference with the Cu2+ ion compared to the other PNAs as observed with the Mg2+ ion (Figure 1 & Figure 3). Importantly, the peptide nucleic acids do not show any preference for binding with Zn2+ ion (Figure 2). The interaction of Mg2+, Zn2+ and Cu2+ with DNA and PNA was examined with ab initio molecular dynamics simulations to confirm the interaction sites obtained with the DFT calculations. The best binding modes of such metal ions between DNA and PNA using B3LYP/6-31+G(d) was considered as initial guess for this study. The simulation results reveal that the interaction of these metal ions with DNA and PNA nucleobases are similar to 15

that observed with B3LYP-D3/6-311++g(d,p)//B3LYP/6-31+G(d) level of theory (Figure S8). The structures shown in (Figure S8) are the lowest in energy in the trajectory files. The dGMP-Zn2+ trajectory file converged within 2ps and the lowest energy structures were similar for 1ps and 2ps (Figure S8). The interactive distances between the metal ions and the sites of nucleobases have showed slight variation as compared to the DFT results. We have calculated atoms in molecules (AIM) at B3LYP/6-31+G(d) level of theory to reveal the binding nature of metal ion complexed with deoxyribonucleic acid and peptide nucleic acid. The critical points (CPs) are mentioned between the interaction of the metal ions (Mg2+, Zn2+, and Cu2+) to the DNAs and PNAs systems in table ST2 and figure S7. The existence of the (3, -1) CP gives the nature of bonding between the metal ions and the nucleotides. From

∆

the other topological properties like gradient (Laplacian) of the electron density ( 2r), the total energy (H(r)), potential energy (V(r)), and Lagrangian kinetic energy (G(r)), we can characterize the nature of the bonding of the metal complexes with DNAs and PNAs (Table ST2). When │V(r) │> G(r) and H(r) is negative, the interaction is said to be shared, but when │V(r)│< G(r) and H(r) is positive, the interaction is said to a closed shell. Larger the │V(r)│value, more negative the H(r) value, more shared the bonded interaction and hence the stabilization is greater of that particular structure.[75] When the ratio of the │V(r) │/ G(r) < 1, interaction is a closed shell, however, when the ratio of the │V(r) │/G(r) > 2, covalent nature will occur for such interactions. When the ratio falls between 1 and 2, an intermediate situation will occur.[76] From the calculated Laplacian and density of all electrons, the Cu2+ complexes clearly show the strongest binding to DNAs and PNAs (Table ST2). In DNA nucleotide, dGMP-Cu2+ shows the strongest binding whereas in PNAcytosine-Cu2+ complex shows the strongest binding nature as compared to the other metal ions (Mg2+ and Zn2+). The total energy (H(r)) is positive in the case of Mg2+ complexes suggest the electrostatic behavior of the Mg2+ to the DNAs and PNAs complexes shown in 16

table ST2. The total energy (H(r)) suggest that Cu2+ shows more electrostatic behavior compared to Zn2+ with DNAs and PNAs complexes.

DNA-Adenine-Parent DNA-Mg2+-Adenine-Type-4

35000

DNA-Guanine-Parent DNA-Mg2+-Guanine-type-4

178.8 nm

30000

196.6 nm 30000

25000

Intensity (a.u.)

Intensity (a.u.)

25000

201.9 nm 20000

178.6 nm

15000

252.4 nm 260.5 nm

203.9 nm

246.3 nm

20000

244.2 nm

15000

10000

10000

5000

5000

204.6 nm 0 150

200

250

300

350

0 150

400

200

250

Wavelength (nm)

DNA-Cytosine-parent DNA-Mg2+-Cytosine-Type-3

35000 30000

25000

191.2 nm 191.8 nm Intensity (a.u.)

Intensity (a.u.)

350

400

DNA-Thymine-parent DNA-Mg2+-Thymine-type-3

166.5 nm

20000

25000 20000 15000

226.9 nm) 227.3 nm 262.9 nm 262.6 nm

10000 5000 0 150

300

Wavelength (nm)

170.1 nm 15000

211.5 nm 211.2 nm 10000

259.6 nm 258.8 nm

5000

0 200

250

300

350

400

150

Wavelength (nm)

200

250

300

350

400

Wavelength (nm)

Figure 4: UV-Vis absorption spectra of DNA parent nucleotide and their most stable their Mg2+ complexes calculated using B3LYP/6-31+G(d) level of theory in the aqueous phase. To predict the optical properties of the studied complexes, we have investigated the ultraviolet (UV) absorption spectra of the best binding sites of metal ions to DNA and PNA. The absorption spectra of DNA-parent nucleotides and DNA-Mg2+ metal ion complex is given in figure 4. We have calculated the absorption spectra (λmax) of the stable complexes with metal ions molecules in PCM model using B3LYP/6-31+G(d) level of theory. The parent dAMP nucleotide showed an apparently single peak at 196.6 nm which however, on complexation with Mg2+ ion splits at 178.6 nm and 201.9 nm with reduced intensities. The other peak at 252.4 nm shifted slightly to 260.5 nm (8 nm) with reduction of intensity. In the case of dGMP, the parent peak at 178.8 nm is apparently disappeared and a small peak at 204.6 nm appeared with reduction in intensity upon complexation with Mg2+ ion. A smaller 17

blue shift (~2.1 nm) was observed with reduced intensity when the parent peak (246.3 nm) shifted slightly to 244.2 nm. In dCMP nucleotide, the parent peak appeared at 191.2 nm, 226.9 nm, and 262.9 nm, which however, doesn’t show significant changes in absorption pattern upon complexation with Mg2+ ion. In the case of dTMP nucleotide, the prominent peak at 170.1 nm shifted to 166.5 nm with enhancement intensity. The other two peaks at 211.5 nm and 258.8 nm showed no significant changes in the peak position upon complexation with Mg2+ ion (Figure 4). Experimental reports on the interaction of Mg2+ ion with DNA molecules using UV absorption and circular dichroism (CD) spectra reveal that this alkaline earth metal ion does not show a significant change in the spectral pattern as obtained in the computational UV absorption results. [77]

35000

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Figure 5: UV-Vis absorption spectra of DNA parent nucleotide and their most stable Zn2+ complexes calculated using B3LYP/6-31+G(d) level of theory in the aqueous phase. Furthermore, we have studied the ultraviolet absorption spectra of DNA-Zn2+complexes at the same level of theory (Figure 5). The UV absorption spectral changes while complexing 18

with Zn2+ ion is largely different in the case of dCMP nucleotide. In the case of dAMP, the prominent adenine parent peak at 196.6 nm splits into two peaks at 177.3 nm and 199.7 nm upon complexation with Zn2+ ion similar to that of observed with DNA-Mg2+-Adenine-type-4 complex. The dAMP with Zn2+ interaction shows a small red shift of the peak at 196.6 nm to 199.7 nm and the peak at 252.4 nm shifted to 255.7 nm with reduced intensity. The DNAGuanine parent nucleotide upon interaction with Zn2+ shows larger red shift 178.8 nm to 191.3 nm (12.5 nm) with reduced intensity, whereas another peak at 246.3 nm remains on the same position at 246.2 nm with lower intensity. The DNA-Cytosine prominent peak at 191.2 nm shifted to 181.5 nm upon complexation with reduced intensity, however, the other two peaks at 226.9 nm and 262.9 shows smaller blue shift to 212.3 nm and 259.9 nm with enhancement in intensity. The DNA-Thymine-parent nucleotide showed no changes in the UV-Vis spectrum upon interaction with Zn2+ ion. The DNA-Thymine parent peak at 170.1 slightly shifted to 169.9 nm, whereas the other two peaks shows no significant changes in the spectrum (Figure 5). We have also investigated the UV spectra of the DNA-Cu2+ complexes on the same level of theory. DNA with Cu2+ showed significant changes in the absorption bands compared to parent DNA nucleotides (Figure 6). In the DNA-adenine-Cu2+complex, larger red shift (45.7 nm) was observed as compared to the parent nucleotide with lower intensity. The parent peak at 196.6 nm disappear when complexed with Cu2+ ion. A tail peak at 469.2 nm appeared mainly because of d-d transition of Cu2+ ion. The dGMP nucleotide upon complexation with Cu2+ ion also showed a larger red shift as compared to the parent nucleotide (31.6 nm). The parent peak of dGMP at 178.8 nm disappeared when complexed with Cu2+ ion. The larger red shift is observed when another parent peak, 246.3 nm shifted to 277.9 nm. A tail peak is observed at 494.7 nm due to d-d transition of Cu2+ ion. In the case of dCMP, the parent peak at 191.2 nm disappeared when complexed with Cu2+ ion. The peak in parent dCMP shows at 19

262.9 nm remains at the same position upon complexation with Cu2+ ion. A tail peak is observed at 372.0 nm mainly due to d-d transition of Cu2+ ion. The dTMP-Cu2+ complex could not show any significant change in the absorption band (Figure 6). The Parent peaks at 170.1 nm and 211.5 nm completely disappeared upon complexation with Cu2+ ion. The other parent peak at 259.6 nm upon complexation with Cu2+ ion at appeared at 259.2 nm with reduced intensity. A tail peak is observed at 375.2 nm due to d-d transition. (Figure 6). The experimentally observed results also showed the bathochromic shift upon the complexation of Cu2+ ion with DNA, which is qualitatively in good agreement with our computed results. [77] The red shifts were observed with dAMP-Mg2+, dAMP-Cu2+ and dGMP-Cu2+ complexes using B3LYP-D3/6-311++g(d,p)//B3LYP/6-31+G(d) level of theory. The complexation of metal ions with these nucleobases is common in a way that the donor –NH2 group is close to the nitrogen center involved in the complexation process. Presumably, the donor –NH2 group raises the filled orbital energies in these cases and leads to the longer λmax shift in these cases. The blue shift of (~14 nm) was observed in the case of dCMP-Zn2+ complex.

20

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Figure 6: UV-Vis absorption spectra of DNA parent nucleotide and their most stable Cu2+ complexes calculated using B3LYP/6-31+G(d) level of theory in the aqueous phase.

The UV absorption spectra of peptide nucleic acids (PNAs) with Mg2+ ion have changed compared to their parent spectrum. The PNA-Adenine parent nucleotide upon interaction with Mg2+ showed smaller blue shift (~3 nm). The parent peak shows at 193.2 nm shifted to 190.3 nm upon complexation with Mg2+ ion with reduced intensity (Figure S5A). The PNACytosine parent nucleotide upon interaction with Mg2+ clearly showed a larger blue shift (~15.4 nm) in the absorption spectrum. The prominent peak at 192.0 nm blue shifted to 186.5 nm showed (5.5 nm) with reduced intensity, similarly other two peaks at 230.9 nm and 260.4 nm shifted to blue shift 221.8(9.1 nm) and 245.0 nm (15.4 nm) with increased intensity (Figure S5A). The absorption spectrum of PNA-guanine and PNA-thymine with Mg2+ ion showed smaller blue shift (~4.9 nm) compared to their corresponding parent systems (Figure S5A).

21

The PNA-Adenine parent peak at 193.2 nm shifted to 183.4 nm with increased intensity upon complexation with Zn2+ whereas the other peak shifted from 252.8 nm to 258.5 nm with increased intensity (Figure S6A). The PNA-Cytosine parent nucleotide with Zn2+ clearly shows blue shift in the spectrum. The prominent peak at 192.0 nm shifted to 182.2 nm showed blue shift (9.8 nm) with reduced intensity, whereas, other two peaks at 230.9 nm and 260.4 nm shifted to 219.8 nm and 255.7 nm, respectively, resulted to blue shift (11.1 nm) and (4.7 nm) with increased intensities (Figure S6A). The PNA-guanine and PNA-thymine (λmax) values are largely similar in both the parent and the complexed forms with Zn2+ ion showed no significant changes (Figure S6A). The PNA-Adenine parent nucleotide with Cu2+ showed that the prominent parent peak at 193.2 nm is disappeared. The blue shift (~4.0 nm) was observed in the UV-Vis spectra when the other parent peak at 252.8 nm shifted to 248.3 nm with lower intensity. A tail peak is observed at 552.0 nm due to d-d transition of Cu2+ ion (Figure S7A). The PNA-Guanine parent nucleotide upon interaction with Cu2+ showed larger red shift (42.6 nm) when parent peak at 247.4 nm shifted to 290.0 nm with reduction in intensity. The prominent peak at 190.5 nm disappeared after interaction with Cu2+ ion. A tail peak is observed at 374.5 nm due to d-d transition of Cu2+ ion (Figure S7A). A small red shift (~6 nm) is observed in the case of PNA-Cytosine-Cu2+ complex. The parent peak at 230.9 nm shifted to 236.6 nm after complexation with Cu2+ ion with higher intensity. A tail peak is observed at 632.7 nm due to d-d transition of Cu2+ ion. (Figure S7A). Larger blue shift (~12 nm) was observed in the UVVis spectra in PNA-Thymine-Cu2+ complex, when the parent peak 260.2 nm shifted to 248.2 nm with reduction in intensity. The principal excitation of the deoxyribonucleic acid and peptide nucleic acid with metal ions (Mg2+, Zn2+, and Cu2+) are represented in figure S9. Discussion

22

The calculated results suggest that the metal ions i.e., Mg2+, Zn2+, and Cu2+ interacts more strongly with the DNA nucleotides compared to the corresponding PNAs. The electrostatic interaction between the phosphate backbones of DNA and the metal ions is stronger compared to the neutral backbones of PNAs (Figure 1-3, and Table ST2). The results summarized in figure 1, 2 and 3 for the best binding modes of DNA and PNA with these metal ions show that the role of backbones is important for the complexation process. The experimental electrochemical studies performed with DNA-DNA, DNA-PNA and PNA-PNA with the metal ions reveal that the DNA nucleotides are the better binding sites compared to PNA.[21,78–81] The experimental studies show the viability of utilizing the interaction of metal ions to detect the nucleotide mismatches and can function as biosensors.[78,80] An electrochemical study performed for the interaction of Zn2+ and Mg2+ ions with DNA-DNA, DNA-PNA, and PNA-PNA shows that Zn2+ ion interacts favorably with both DNA and PNA duplexes.[21] However, the charge transfer resistance (RCT) results suggest that Mg2+ ion is not bound with the PNA duplexes. The computational binding energies show that the Mg2+ ion can as well bind with the peptide nucleic acids (Figure 1). The natural bond orbital (NBO) charge analysis of the metal ions with deoxyribonucleic acid and peptide nucleic acid suggest that the charge transfer is relatively higher to the metal ions from DNA compared to PNAs (Table ST3). Importantly, the charge transfer is maximum from the nucleotides to the Cu2+ ion. The reports also reveal that Cu2+ ion is known to form the complex with PNA molecules presumably involving coordination of the nucleobase.[22] The calculated structure of PNA-cytosine Cu2+ complex also showed that the nucleobase is involved in the coordination with the Cu2+ ion (Figure 3). The charge transfers resistance (RCT) results from the electrochemical study for the complexation of Mg2+ and Zn2+ ions with PNA duplexes is relatively weaker compared to DNA duplexes and hence the charge transfer would less in the former duplexes, which qualitatively supports the experimental observation (Table ST3).[21]

23

This result was borne out from the computational study that such metal ions bind weakly with PNA compared to the DNA. The binding affinity of Mg2+ with PNA-cytosine is slightly higher than the binding affinity of Zn2+ with PNA-adenine, nonetheless, the RCT is relatively higher in the latter case. It appears that besides the binding strength this situation presumably arises due to the relatively easier charge transfer from the higher filled orbital energy of PNA-adenine to Zn2+ ion than that of PNA-cytosine to Mg2+ ion. To note that Cu2+ ion only showed the cation-π complex formation with the nucleobases of DNA and PNA (Figure S4A & Figure S4B). It is presumably due to the strong interaction of Cu2+ ion with both deoxyribonucleic acid and peptide nucleic acid compared to Mg2+ and Zn2+ ions. [6] Conclusion In summary, this work examined the modes of interaction of metal ions (Mg2+, Zn2+, and Cu2+)

with

deoxyribonucleic

acid

and

peptide

nucleic

acid

at

B3LYP-D3/6-

311++g(d,p)//B3LYP/6-31+G(d) level of theory. The binding affinity of metal ions varies with the choice of deoxyribonucleic acid and peptide nucleic acid. The charged backbone of DNA showed superior binding with the metal ions compared to the corresponding neutral backbone of PNAs. The backbones of the deoxyribonucleic acid and peptide nucleic acid played an important role in the complexation of metal ions. The phosphate backbone of DNA coordinates to complex with the metal ions in a bidentate fashion. Therefore, the central binding mode (Type-4) is energetically more stable than the other binding modes studied here. The deoxyguanosine monophosphate (dGMP) showed the strongest binding energy with Mg2+ (-49.6 kcal/mol), Zn2+ (-45.3 kcal/mol) and Cu2+ (-148.4 kcal/mol) as compared to the corresponding nucleotides. The strength of binding of these metal ions follow the order: Cu2+ > Zn2+ > Mg2+. The cation-π interaction in the case of Cu2+ complexes has been observed. The cation-π complexation energies of DNA and PNA ranges from (~97.0 kcal/mol to ~103.0 kcal/mol, respectively). Ab-initio molecular dynamics simulations performed with 24

LDA/PWC/DND level of theory showed similar binding geometries to the calculated B3LYP-D3/6-311++g(d,p)//B3LYP/6-31+G(d) results. The TD-DFT calculations performed with such metal complexes to observe the changes in UV-absorption spectra reveal that the Cu2+ ion significantly influences the λmax around 30-46 nm shift compared to the other two metal ions. Tail peaks were appeared in the UV range due to d-d transition of Cu2+ ion. The AIM calculations performed to examine the nature of interactions in these metal complexes suggest that deoxyribonucleic acid and peptide nucleic acid have more electrostatic nature with Mg2+ ion, whereas, the transition metal ions possess partial covalent nature upon complexation with such nucleotides. The results suggest that these metal ions would prefer to bind DNA in DNA-PNA duplexes and the cytosine of PNAs are the preferable sites in PNAPNA duplexes. The preference for the binding of metal ions with DNA nucleotides is largely attributed to the contribution of charged backbones. The efforts are underway to design PNAs with modified backbones to influence the complexation of metal ions with DNA-PNA duplexes and would be reported in the future. Associated Content: Supporting Information (SI) SI contains optimised geometries of deoxyribonucleic acid and peptide nucleic acid, the torsional angle between PDB structure and deoxyribonucleic acid and peptide nucleic acids. Interaction sites of deoxyribonucleic acid and peptide nucleic acids with metal ions (Mg2+, Zn2+, and Cu2+) calculated using B3LYP-D3/6-311++g(d,p) level of theory. Absorption spectra of most stable binding complexes to Zn2+ and Cu2+complexes with PNA and DNA. Charge transfer of metal ions to the deoxyribonucleic acid and peptide nucleic acid by using NBO analysis. Optimized cartesian coordinates of complexes at B3LYP/6-31+G(d) level of theory.

25

Author Information: Surjit Bhai; Email: [email protected] Corresponding Author *Dr. Bishwajit Ganguly; Email: [email protected] Fax: (+91)-278-2567562. Telephone: +91-278-2567760, ext. 6770

Acknowledgment S.B. and B.G thanks DBT, New Delhi (Grant no. BT/PR12730/BID/7/523/2015) and DST for financial support. We thank the reviewer’s for their comments and suggestions that have helped us to improve the paper. References [1]

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Role of backbones on the interaction of metal ions with deoxyribonucleic acid and peptide nucleic acid: A DFT study Surjit Bhai†, and Bishwajit Ganguly*† †

Computation and Simulation Unit (Analytical and Environmental Science Division and Centralized Instrument Facility), CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar, Gujarat, India-364 002. *Corresponding Author. Fax: (+91)-278-2567562, E-mail: [email protected]; [email protected]

Highlights: 1. Metal ions (Mg2+, Zn2+, and Cu2+) interaction with DNA and PNA nucleotide using DFT methods. 2. The study of role of backbones of DNA and PNA nucleotides with their energetically preferred mode of interaction. 3. Central binding mode (Type-4) showed the strongest mode of interaction. 4. The optical property calculated using TD-DFT method showed a diagnostic signature to ascertain the interaction of metal ions with such nucleotides.