Classical and Quantum Mechanical Calculations of the Stacking

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B: Biophysics; Physical Chemistry of Biological Systems and Biomolecules

Classical and Quantum Mechanical Calculations of the Stacking Interaction of Nd Complexes with Regular and Mismatched DNA Sequences III

María Joaquina Beltrán Leiva, Isabel Fuenzalida-Valdivia, Plinio Cantero-López, Ana Bulhoes Figueira, Jans H. Alzate-Morales, Dayán Paéz-Hernandéz, and Ramiro Arratia-Pérez J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.9b00703 • Publication Date (Web): 29 Mar 2019 Downloaded from http://pubs.acs.org on March 29, 2019

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The Journal of Physical Chemistry

Classical and Quantum Mechanical Calculations of the Stacking Interaction of NdIII Complexes with Regular and Mismatched DNA Sequences María J. Beltrán-Leiva,a Isabel Fuenzalida-Valdivia, b Plinio Cantero-López,a,c Ana Bulhoes‐Figueira,e Jans Alzate-Morales,d Dayán Páez-Hernández,a,c* and Ramiro Arratia-Pérez a,c* a

Relativistic Molecular Physics Group, Universidad Andres Bello, República 275, Santiago, Chile. bFacultad de Ciencias Biológicas, Centro de Biotecnología Vegetal, Santiago 8370146, Universidad Andres Bello, Santiago, Chile. cCenter for Applied Nanosciences (CANS), Facultad de Ciencias Exactas, Universidad Andres Bello, Av. República 275, Santiago, 8370146, Chile. dCentro de Bioinformática y Simulación Molecular (CBSM), Facultad de Ingeniería, Universidad de Talca, 1 Poniente 1141, Talca, Chile. eCentro Universitário Estácio de Ribeir o Preto, Rua Abrah o Issa Halach, 980 Ribeir nia, Ribeir o Preto, Sao Paulo 14096-160, Brazil. ABSTRACT: The design of organometallic complexes used as selective intercalators to bind and react at DNA mismatch sites has concentrated efforts the last years. In this context, lanthanides have received attention to be employed as active optical centers due to their spectroscopic properties. Despite there are several experimental data about synthesis and DNA binding of these compounds, theoretical analyses describing their interaction with DNA are scarce. To understand the binding to regular and mismatched DNA sequences, as well as, to determine the effect of the intercalation on the spectroscopic properties of the complexes, a complete theoretical study going from classical to relativistic quantum mechanics calculations has been performed on some lanthanide complexes with phenanthroline derivatives synthesized and characterized herein, viz. [Nd(NO3)3(H2O)(dppz-R)] with R=H, NO2-, CN- and their [Nd(NO3)3(H2O)(dpq)] analogue which was computationally modelled. The results were in correct agreement with the available experimental data showing that dppz complexes have higher binding affinities to DNA than dpq one and supporting the idea that these complexes are not selective to mismatch sites in the sampled time scale. Finally, the spectroscopic analysis evidences an intercalative binding mode and made possible the elucidation of the emission mechanism of these systems. This approach is proposed as a benchmark study to extend this methodology on similar systems and constitutes the first theoretical insight in the interaction between DNA and lanthanide complexes.

INTRODUCTION Cancer is one of the most common causes of mortality today, hence the development of new therapeutic agents has become an important aspect of current cancer research.1 Many of the approved chemotherapeutic drugs work by binding DNA, but there are still many difficulties with their design and application. Usually, these drugs act over generic DNA structures present in both healthy and cancerous cells. Therefore, a “collateral damage” is also produced on healthy tissue which can result in severe side-effects.2,3 Thus, it is essential to find new targets mostly located in cancerous cells. During the last decades, the focus has been placed on one special target: DNA base pair mismatches.3 Mismatches arise as result of errors in the replication process and are usually corrected by the mismatch repair (MMR) mechanism. However, in many solid tumors, mutations in MMR proteins severely down-regulate or completely inactivate this repair machinery. In consequence, some forms of cancer contain a relatively higher abundance of mismatch sites compared to healthy cells, which according to Barton et al.3 turn

the mismatches into “potential biomarkers” for selective cancer treatments.4 In this context, the design of intercalator complexes that bind and react at these specific sequences of DNA has become a hot area, since the understanding of how to target DNA mismatch sites with specificity may shed light on the design of new complexes to be employed as anticancer drugs and theranostic agents for the cancer treatment. Intercalators are small molecules containing a planar aromatic heterocyclic part which can stack between the base pairs of double-helical DNA.5-9 Thus, increasing the surface area for intercalative stacking may lead to a substantial increment in the intercalative binding affinity, which can provide immensely powerful tools to probe nucleic acids. Since the discovery of the DNA intercalation process, thousands of organic and inorganic compounds have been developed for the cancer treatment.8,9 However, the last ones have been mostly studied because the inclusion of an optically active metal center makes them extremely valuable as probes of biological systems. Actually, the Barton’s group has led the research in this field, reporting the most complete studies about

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binding of metallointercalators to DNA and their role as lightswitches for mismatch sites.10-17 They have synthesized several rhodium and ruthenium compounds, trying to attain mismatch specificity through ancillary ligands modifications. For example, in 201614 they reported the [Ru(Me4phen)2dppz]2+ complex which is selective to mismatch sites. This characteristic was attributed to a higher binding affinity toward mismatched DNA and a longer excited state emission lifetime when bound to these sites.14 Regarding the chemical structure of metallointercalators, most of them have a symmetrical structure and have been synthesized employing transition metals. However, in the last years, trivalent lanthanide (LnIII) ions have also received special attention in the field of theranostic medicines.18–23 Lanthanides are interesting from the spectroscopic point of view, because they have long radiative lifetimes, but low extinction coefficients owing to their parity-forbidden 4f-4f transitions.24,25 Therefore, in these elements the luminescence is mainly governed by a sensitization process called “antenna effect”.26 In this mechanism, a ligand (or antenna) absorbs light and transfers energy from their excited level to the resonant level of the lanthanide, which can emit light or decay non-radiatively.42 Because many of these ligands are also intercalators, lanthanide-based complexes have become suitable for their application in detection of mismatch sites. The exploration of these kind of molecules and the elucidation of their properties was initially carried out on singlestranded DNA through the construction of lanthanide-based binary probes.27,28 However, the double-stranded DNA have been the most interesting target for lanthanide-based compound designers, because it has a more rigid structure which offers an opportunity for sensing or recognition through ways such as groove binding or intercalation. Furthermore, these characteristics confer to the lanthanide compound a favorable environment, because it is protected from interactions with solvent molecules that could non-radiatively deactivate the lanthanide-localized emission. In this respect, it could be said that these complexes act as “switches” because, as reported by some authors,18,21,29 the complexes only luminesce when are bounded to the DNA structure. The growing interest to contribute in this field has led several research groups around the world to synthesize lanthanide-based compounds and analyze their binding to DNA. Initial works were performed by the Parker’s group in the early 2000s.30–34 They synthesized a family of strongly luminescent probes of DNA, based on nine-coordinate lanthanide

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(EuIII, TbIII) complexes employing dipyridoquinoxaline (dpq) and dipyridophenazine (dppz) as antenna-intercalator units. No significant spectroscopic changes were observed upon their interaction with DNA and charge-transfer interactions were detected between the base pairs and both antennas, thus supporting an intercalative binding mode. In 2010, Chakravarty et al. reported the photoinduced DNA cleavage activity for a series of LaIII and GdIII complexes with phenanthroline derivatives (among them, dppz) and terpyridine bases as photosensitizers, which exhibited significant photocytotoxic effects in HeLa cancer cells.35,42 Finally, since 2015 to the present, the Patra’s group have reported studies of several lanthanide complexes with phenanthrolines and terpyridines as antenna ligands. They have observed that these ligands sensitize properly all the lanthanide ions and, in addition, exhibit groove binding with partial intercalation to DNA.29,36-40 As observed, there are many studies addressing this issue and most of them have a common factor: the ligand used as antenna-intercalator unit. Phenanthroline derivatives, particularly dppz and dpq, are known as good antenna-intercalator agents due to their ability transferring energy to the lanthanide ion and their high DNAbinding affinity. Regarding their intercalator role, these ligands have a rigid structure with aromatic units that allow them to introduce between the base pairs of DNA and gain stabilization mainly through π-π stacking interactions.5-9,18 Many authors place the dppz as a better intercalator than dpq, due to the extra ring in their structure and for this reason it has been most widely employed in this kind of studies.29.30 Now, in relation to their role as antenna, these ligands have the ability to generate photoinduced 3(n → π*) and/or 3(π → π*) states which can properly sensitize lanthanides such as europium or terbium and, in addition, generate reactive oxygen species (ROS) which can be employed in photodynamic therapy (PDT).42 Because it has been reported that the mismatch specificity is reached having good intercalators and appropriate ancillary ligands, both dppz and dpq are currently considered as optimal candidates to constitute an organometallic complex to be selective to mismatches. As noted earlier, many experimental works about lanthanidebased intercalators can be found. Nevertheless, theoretical studies are scarce probably due to the inherent complexity in the computational treatment of these elements. We recently reported a theoretical protocol and some methodological considerations to understand the energy transfer mechanism in these type of complexes.41,42

Scheme 1. Neodymium complexes and DNA models. C= Cytosine and G= Guanine. a) Nd(NO3)3(dppz-R) where R = H, CNor NO2- b) Nd(NO3)3(dpq) c) 12-mer DNA d) Non-extruded CC mismatched 12-mer DNA e) Extruded CC mismatched 12mer DNA f) Non-extruded GG mismatched 12-mer DNA g) Extruded GG mismatched 12-mer DNA. From these complexes and DNA models, 10 different systems were theoretically designed: (1) DNA-Nd(NO3)3(dppz), (2) DNA-Nd(NO3)3(dpq), (3) DNA-Nd(NO3)3(dppz-CN), (4) DNA-Nd(NO3)3(dppz-NO2), (5) DNA MUT CC-Nd(NO3)3(dppz), (6) DNA MUT CCNd(NO3)3(dpq), (7) DNA MUT GG-Nd(NO3)3(dppz), (8) DNA MUT GG-Nd(NO3)3(dpq), (9) DNA MUT CC- Nd(NO3)3(dppz) with CC extruded from the double helix and (10) DNA MUT GG- Nd(NO3)3(dppz) with GG extruded from the double helix.

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Scheme 2. Structural formulas for the dppz and dpq ligands and [Nd(NO3)3(dppz-R)] and [Nd(NO3)3(dpq)] complexes.

starting points, to obtain a general perspective on the key intermolecular interactions between the intercalator systems and the DNA (12-mer and mismatched 12-mer) along with the recovery of the most stable configurations. Second, a systematic ab initio approach based on a multireference SO-CASSCF/NEVPT2 technique and the use of TDDFT, was employed to analyze the spectroscopic properties of these intercalator-DNA configurations and to set a comparison between the bounded and isolated complexes, in order to evaluate how the binding to the DNA affects the neodymium sensitization.

METHODS Computational Details Force Field Based Calculations

Thus, employing multiconfigurational ab initio methods along with the scalar relativistic time-dependent DFT (SRTDDFT) we proposed a fragmentation scheme to elucidate the most probable transfer pathways between both the antenna and lanthanide fragments. However, despite the relevance of these studies, it is essential to expand the scope of the research and gain more insight into the interaction between these compounds and the DNA to be able to answer questions such as: How these complexes interact with DNA? How is this interaction affected by determined mismatches? How is the performance of the dppz ligand relative to dpq? Therefore, to contribute and generate further molecular and mechanistic insights about this subject, we propose a theoretical approach integrating classical and quantum mechanics calculations. The first objective is to understand the interaction between some lanthanide-based compounds with phenanthroline ligands and regular and mismatched sequences of DNA. The second one is to analyze how these interactions affect the spectroscopic properties of these compounds. Therefore, some complexes synthesized and characterized herein, viz. [Nd(NO3)3(H2O)(dppz - R)] with R= H, NO2-, CN-, as well as, their [Nd(NO3)3(H2O)(dpq)] analogue which was also computationally modelled (see Scheme 1 and 2) were chosen as model systems . The methodology employed can be explained in two steps. First, molecular dynamics (MD) simulations and free binding energy (ΔGbind) using Molecular Mechanical/Generalized Born Surface Area (MM-GBSA) calculations were carried out as

In a first step, the analysis of the intercalator role of dpq and dppz ligands was performed. Thus, the interactions between both [Nd(NO3)3(dppz)] and [Nd(NO3)3(dpq)] systems with regular and mismatched DNA (mutations were applied based on the available literature) were studied. In a second step, a deeper insight was achieved in the study of dppz systems through the inclusion of the substituted ones.

Parametrization of the NdIII Complexes Ligands were parametrized based on quantum calculations using the MCPB.py43 parameter builder released with Ambertools16.44 The bonded model approach was used in order to obtain the force constants that are required for generation of bond and angle parameters as described by Seminario et al.45 The atomic charges were calculated through the restrained electrostatic potential (RESP) fitting scheme46 and the neodymium VDW parameters were taken from Li et al.47 Geometry optimizations for all neodymium complexes, evaluation of the Hessian matrix and electrostatic potential data using the Merz-SinghKollman (MK)48 method were computed at the B3LYP49,50/SDD51,52 level with Gaussian 09 software (See Table S4).53

Molecular Dynamics simulations and Free Binding Energy calculations The 12-mer DNA duplex d(GCATCGATTGGC)2 was retrieved from the Protein Data Bank (PDB ID: 5UZD) and it was employed for the intercalation of the complexes.54 The construction of the DNA-Nd(NO3)3(dppz) intercalation adduct was made by superimposing the crystal structure of [Ru(bpy)2(dppz)]2+ bound to DNA (PDB ID: 4E1U)55 with our DNA oligomer (details can be reviewed in Section 1.1, ESI†). Based on these resultant coordinates, the DNA-Nd(NO3)3(dpq), DNA-Nd(NO3)3(dppz-CN) and the DNA-Nd(NO3)3(dppz-NO2)

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models were built by removing and adding the relevant atoms from the neodymium complex. The Nd(NO3)3(dppz) and Nd(NO3)3(dpq) structures bounded to mismatched 12-mer DNA where built by replacement of the G20 nucleotide by a C and C5 nucleotide by a G in order to obtain the CC and GG mismatches, respectively, from initial DNA-Nd(NO3)3(dppz) and DNA-Nd(NO3)3(dpq) molecular models. These mutations were chosen based on the luminescence study performed by the Barton’s group in 2016.14 They analyzed the interaction between the [Ru(Me4phen)2dppz]2+ complex and several DNA mismatches, and discovered that the CC and GG ones were the most and less influential, respectively, on the emission of the complex. Furthermore, and because the encouraging initial results, two additional models of Nd(NO3)3(dppz) bound to mismatched DNA were constructed, but this time with the CC and GG mismatched nucleotides extruded from the double helix with the aim to simulate the insertion of these neodymium complexes (see details in Section 1.1, ESI†). In total, 10 different molecular systems were constructed (see Scheme 1): 4 of regular 12-mer DNA bound to Nd(NO3)3(dppz) (1), Nd(NO3)3(dpq) (2), Nd(NO3)3(dppz-CN) (3) and Nd(NO3)3(dppz-NO2) (4); 2 with a CC mismatched 12-mer DNA bound to Nd(NO3)3(dppz) (5) and Nd(NO3)3(dpq) (6); 2 with a GG mismatched 12-mer DNA bound to Nd(NO3)3(dppz) (7) and Nd(NO3)3(dpq) (8): 1 with the mismatched CC base pair extruded from the double helix bound to Nd(NO3)3(dppz) (9); and 1 with the mismatched GG base pair extruded from the double helix bound to Nd(NO3)3(dppz) (10). The structural parameters are presented in the Section 2.1, ESI†. All the systems were submitted to MD simulations in explicit water solvent. For the oligonucleotides the ff99 with the bsc0 correction (ff99bsc0)56,57 was used. Each system was inserted in a rectangular box using the TIP3P58 water model and imposing a buffer distance of 10 Å over all sides of the DNA molecule. 22 Na+ counterions were added for system neutralization. To remove steric clashes and optimizing the structures, 6 minimization stages were carried out, all of them performing 1000 minimization cycles switching from steepest descent to conjugated gradient after 500 steps. The first stage employed a very strong positional restraint of 500 kcal mol-1 Å-2 over the heavy atoms of the solute to adjust the water molecules and the hydrogens. Then, the next 5 minimizations stages used a restraint force going down from 50 to 10 kcal mol-1 angstrom-2 over the solute. A short MD simulation at NVT ensemble heating up the system from 100 K to 300 K was performed with a weak restraint of 0.5 kcal mol-1 Å-2 on the neodymium complex and the nucleotides around it. Finally, a production MD simulation of 100 ns for each system was carried out with no restraints in a NPT ensemble and periodic boundary conditions, to obtain an appropriate structure to perform the subsequent electronic analysis. Temperature and pressure were kept constant at 300 K and 1.013 bar using the Langevin thermostat with a collision frequency of 2.0 ps-1 and the Berendsen barostat,59 respectively. The SHAKE algorithm60 was used for bond length constraints involving hydrogen atoms and Particle Mesh Ewald (PME)61,62 for the long-range electrostatic interactions with a cutoff of 8.0 Å. All the MD simulations were performed with Amber14.63

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The preparation of the systems and their structural analysis were carried out using the leap and cpptraj modules from AmberTools16.44 Formally, the complexes have two water molecules bound to the NdIII center, but these were not included in the final systems in order to avoid exceeding the maximum coordination number per atom of leap. Visualization and images were obtained made using VMD 1.964 and Maestro 11 visualization tool.65 Free binding energy (ΔGbind) calculations, through MMGBSA approach, were performed using the “single trajectory” scheme. A total of 500 snapshots taken evenly from each of MD simulations were submitted to MM-GBSA calculations using the MMPBSA.py python script.66 Two GB models were used, the Hawkins, Cramer, Truhlar67–69 pairwise generalized Born model (igb=1) and the GB model developed by Onufriev, Bashford and Case70,71 (igb=5). Default values for surface tension and non-polar free energy correction were applied. Additionally, the linear algorithm to calculate the surface area for the nonpolar solvation term (Linear Combination of Pairwise Overlaps), and a probe molecule radius of 1.4 Å to determine the molecular surface were kept as default.

Quantum Mechanical Calculations In a first step, an attempt to get a deeper insight on the interaction between the complexes and the different models of DNA was made. Thus, the more stable snapshots were recovered from the MM-GBSA calculations to obtain the geometries for all systems, except the last two (9 and 10), in order to limit the analysis. A simplification of the molecular systems was performed to ease their quantum mechanical treatment, keeping only the base pairs that directly interact with the neodymium complex. The phosphate groups were also removed to avoid the problem of including counterions. All the structures were optimized using the ORCA 4.4 program, including the dispersion corrections by the Grimme approach (as explained below).72 The scalar relativistic effects were incorporated via the Douglas-Kroll-Hess approximation at second order (DKH2). 73 The BP86 generalized gradient approximation exchange-correlation functional was used.74 Both ligands and base pairs were described with the def2-SVP basis set while the neodymium was treated using the improved segmented all-electron relativistically contracted SARC2-DKH-QZV basis set.75–77 Once this process was completed, the Amsterdam Density Functional (ADF) package78 was employed to apply the decomposition of the total bonding energy (ΔEint) according to the Morokuma-Ziegler energy partition scheme at BP86/TZ2P level of theory.79 The scalar relativistic effects were incorporated by means of the two-component Hamiltonian with the zeroth-order regular approximation (ZORA).80 This analysis allows to explore the nature of the interactions produced between the NdIII complex and the base pairs, through the separation of the total interaction energy in different terms:

ΔEint =ΔEPauli + ΔEElec + ΔEOrb + ΔEdisp

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These four components describe the Pauli repulsion, electrostatic interaction, orbital mixing and dispersion energy, respectively. The dispersion correction was included via the Grimme pairwise scheme,81 in order to properly account for weak interactions. An extensive discussion about the physical meaning of all those terms used in the present analysis is given in the work of Bickelhaupt and Baerends. 81 To get more insight on the noncovalent interactions between the complexes and DNA, the NCI (Non Covalent Interaction) index was used, employing the wavefunction of the optimized structures which was obtained with an all-electron basis-set.82 The NCI method is a theoretical tool employed to visualize the non-covalent interactions based on the topological analysis of the electron density and of its reduced gradient as proposed by Yang et al.83 To study the noncovalent attractive or repulsive interactions, the sign of the second eigenvalue (λ2) in the electronic Hessian is utilized, which give information about the type of binding force: attractive forces, such as hydrogen bonds (λ20). The second step in the methodology consisted in the analysis of the effects caused by the DNA intercalation on the spectroscopic properties of the NdIII complexes. Thus, a comparison between both the isolated and intercalated complexes was made in order to understand, even in part, the role of the DNA. The calculation of the absorption spectra and characterization of the main bands for the isolated and intercalated NdIII complexes were performed through the scalar relativistic time-dependent density functional theory (SR-TDDFT) with the Coulomb-attenuated hybrid exchange-correlation functional (CAMB3LYP),84 which was designed to properly predict molecular transitions where charge transfer could take place.41 Before these calculations, geometry optimizations for the isolated complexes were carried out following the level of theory described in the paragraph above. Finally, the efforts were directed to analyze, in a rigorous way, the sensitization pathways that take place from the antenna to the neodymium, in the isolated and intercalated complexes. A fragmentation scheme, proposed in recent works,41,42 was employed in order to simplify the treatment of the systems. It was possible because in all of these, the absorption is ligand-localized and the emission lanthanide-centered, thus fulfilling the condition required for the application of this approach. The isolated NdIII complexes were splited as: [Nd(NO3)3] and [dppzR]/[dpq], where R=H, CN-, NO2- for dppz and dpq systems respectively; On the other hand, the intercalated NdIII complexes were split as: [Nd(NO3)3] and [(dppz-R)-DNA], where R=H, CN-, NO2-, for all the DNA models described for the systems (1) to (8) (see Section 2.1). Due to the heavy nature of the lanthanide elements, it is necessary to consider some factors to properly describe its electronic states. Relativistic effects (scalar and spin-orbit coupling), electronic correlation and ligand field are the main effects that should be taken into account in the theoretical treatment of these ions.24,41,42 Therefore, an ab initio multiconfigurational approach based on the SOC-CASSCF/NEVPT2 methodology was employed to analyze the last part of this work. All these calculations were performed employing the ORCA 4.4

program.72 The scalar relativistic effects and the basis sets employed were the same as those used in the optimization process. The spin-orbit coupling (SOC) effects were treated using quasidegenerate perturbation theory (QDPT). The dynamic correlation was included at the second order of perturbation theory employing the NEVPT2 method.85 For the neodymium fragments, a minimal active space (only 4f orbitals) was chosen to perform the CASSCF calculations, that is, a CAS(3,7)SCF which include 3 electrons in the 4f-shell. The isolated and intercalated antennas were treated at the same level of theory, using an active space selected in order to properly describe their electronic transitions (see ESI† for a more detailed description).

Experimental Details Lanthanide (III) complexes, were prepared using a general synthetic procedure by reacting an ethanolic solution of [Nd(NO3)3].6H2O (1 mmol) with the corresponding dypiridophenazine derivatives (2 mmol) dissolved in a 2:1 mixture of CHCl3 /CHCl2 (18mL). Ethanolic solution (2mL) was added dropwise to the ligand solution and stirred for 60 min. The precipitate was removed by filtration, dried, and washed with ethanol. All the complexes were isolated in good yields and characterized by elemental analysis (Section 3 in Supporting Information), FT-IR, UV-visible spectra and ESI-MS. Because of the poor solubility of the samples, crystal structures could not be obtained, and only X-ray powder diffraction measurements were made.

RESULTS All the studied neodymium complexes were modeled based on experimental reports of similar compounds (see structures a and b in Scheme 1) and their structural parameters are shown in Section 1.2.1 of ESI. In the case of dppz-containing systems, additional evidence was provided by our own experimental data. Therefore, the purpose of the first part of the results is to corroborate some well-established facts in relation to lanthanide complexes with phenanthroline derivatives as antenna ligands and their interaction as intercalators with DNA. Consequently, in the second part the idea is to get a deeper insight on the dppz systems (intercalated and isolated) describing their spectroscopic properties and the neodymium sensitization pathways. Due to limitations in the treatment of the eight-coordinated neodymium (III), the water molecules were removed (see Computational Details Section).

Force Field Calculations Molecular Dynamics Simulations Nuclear Magnetic Resonance (NMR) studies indicate that both dpq and dppz ligands bind to DNA mainly through the minor and major groove, respectively.86–88 However, in the case of dppz, there is experimental and computational evidence showing that the intercalation can also be produced in the minor groove.89–91 Thus, to simplify the discussion of results, the construction of the systems was made positioning the complexes within the DNA minor groove. The molecular superposition between our C5G20/G6C19 intercalation site for Nd(NO3)3(dppz) and the C11G2/G12C1 for

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[Ru(bpy)2(dppz)]2+ reported in 5UZD and 4E1U PDB structures, respectively; was performed for the 12-mer DNA systems (1, 2, 3, 4) and for those with mismatch, but bounded to the nonextruded DNA (5, 6, 7, 8) (See Computational Details Section). After the minimization process, a good structural agreement between the X-ray crystal and our model was observed, with a RMSD of 1.1424 Å (see Figure S4, ESI†). Due to a rotation of one nucleotide located at the mismatch site, that was noted at 80 ns of MD simulation, the superposition of our oligomer was also made with the X-ray crystal with PDB ID: 2O1I, because this structure reproduces properly the extruded base pair. The detailed description of this step is given in the Section 1.1 of ESI. After the minimization process, a RMSD of 2.6035 Å was obtained. Despite this value is greater than the previous one, a good positioning of the neodymium(III) complex between the DNA base pairs was achieved, and the correct rotation of those mutated nucleotides was allowed (see Figure S5, ESI†). Figure 1. Molecular conformations of the Nd(NO3)3(dppzNO2) complex at the DNA intercalation site. These conformations were obtained from a total of 5000 snapshots distributed over 100 ns of MD simulations.

The RMSF values along the MD trajectory showed multiple fraying events from the terminal base-pairs at both ends of the DNA. These events are naturally occurring and have been previously observed in MD simulations with DNA. 92-94. In case of the first strand, these nucleotides are 1, 2, 11 and 12, while in the second one these correspond to 13, 14, 23 and 24. In the 12mer DNA systems, specifically at the C5G20/G6C19 intercalation site, the increase in the RMSF value was slight, which could indicates that the site remains stable for both dppz and dpq complexes, despite the intercalation process (see Figure S6). Regarding the neodymium complexes, higher RMSF values were noted for the DNA-Nd(NO3)3(dpq) (blue) and DNANd(NO3)3(dppz-NO2) (red). This variation was attributed to the movement of the dppz and dpq ligands within the intercalation site keeping its parallel position with respect to the DNA base pairs, as observed in Figure 1. On the other hand, for the mismatched 12-mer DNA systems a similar result was obtained, but in this case a more pronounced variation was noted on the base pairs located at the intercalation site, particularly for the DNA MUT GG-Nd(NO3)3(dpq) (green) and DNA MUT GGNd(NO3)3(dppz) (red) systems. Regarding the RMSD values, an evident variation was detected throughout 100 ns of dynamics. This was specially marked in the mismatched 12-mer DNA systems (see Figure

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S7, ESI†), which can be attributed to the aforementioned fraying events. Therefore, the RMSD values were also calculated excluding those nucleotides. As observed in the Figure S8, the global structure of intercalator-DNA complexes, and the intercalation site of the systems, show a more stable structural behavior after this consideration was taken into account for the RMSD calculation. With the aim to perform a deep analysis about potential changes that could take place at the intercalation sites, the RMSDs were also obtained only considering the neodymium complexes and the DNA base pairs that directly interact with them. Figure S9 shows that the intercalation site of the non-mismatched systems remained stable along the MD trajectory for both dppz and dpq complexes, in agreement with the RMSF results. In case of the mismatched ones, large variations were noted specifically in the DNA MUT GG-Nd(NO3)3(dppz) (7) and DNA MUT GGNd(NO3)3(dpq) (8). According to the RMSF analysis, these fluctuations were produced in the residues 5 and 6 for (7), and in 5 and 20 for (8). The RMSD values for the intercalation adduct in (7) showed that a significant change occurred in the range of 87 to 97 ns, where the RMSD increased from 1.75 Å to ca. 3.5 Å, but returned to its initial value (1.75 Å) at the end of the simulation. This event was attributed to the larger movement of the G5 residue, which established an “edge to face” ππ stacking interaction with the dppz ligand. As observed in Figure S10, the hydrogen bond between G5 and G20 was kept, thus retaining the former nucleotide in the double helix of DNA until it returned to its initial position. In case of the system (8), the RMSD increased after 80 ns of simulation from 1.75 Å to ca. 3 Å, but unlike the previous case, this value was not restored. Figure S11 shows that this variation was produced at the G5 nucleotide (mutated) which moved from the stacking position and lost the interaction with G20. Therefore, in this simulation the G5 nucleotide was expelled out from the double helix structure by the neodymium complex.

Free Binding Energy Calculations The MM-GBSA calculations were performed employing two GB models: the Onufriev, Bashford and Case (igb=5), which has shown a good performance in the study of nucleic acids, 95– 97 and the Hawkins, Cramer and Truhlar (igb=1) which has been the most widely used in these kind of molecules and, according to many authors, the most robust in comparison to other GB models.98,99

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Figure 2. MM-GBSA Energies for the studied systems excluding those with the extruded base pairs.

Despite the standard deviation values are high, in both models the observed ΔGbind values indicate that the neodymium complexes (regular and mismatched) containing dppz (1) (3) (4) (5) (7) bind more effectively to DNA than those containing dpq (2) (6) (8), which can be attributed to the extra ring present in the dppz structure (see Figure 2). Experimental studies support

the obtained ΔGbind trend in systems containing these ligands.36,100,101 If a comparison is made in terms of ΔGbind values between the substituted 3 and 4) and the non-substituted (1) complexes in the regular systems, it is found that no substantial variations in their affinity against DNA are noted along the frames taken from MD simulations. This can be attributed to the fact that the CN- and NO2- substituent groups are located at the end of the dppz structure, towards the major groove. Therefore, it can be argued that the method is not sensitive enough to detect some energetic contributions from these substituents. Nonetheless, it cannot be ruled out that longer MD simulations, and a more robust free binding energy estimation approach may account for more evident contributions from these substituent groups. Regarding the mismatched systems (5)(6)(7)(8), a more favorable interaction between the NdIII complexes and the GG mismatched site (7)(8) was noted when compared to the CC one (5)(6). As pointed earlier, the RMSF and RMSD analyses showed that the most marked variations were produced in the GG mismatched systems. It could be interpreted as this mutation generates a greater destabilization of the neodymium compounds. However, this fact disagrees with ΔGbind results, which show the GG mismatch as the most promising from the energetic point

Table 1. Energy contributions[a] to the interaction energies from EDA at scalar relativistic level. All the values are given in kcal mol-1. ∆

System

∆

∆

∆

∆

DNA-La(NO3)3(dppz) (1) DNA-La(NO3)3(dpq) (2)

38.21 25.91

-18.40 -14.70

-10.25 -8.39

-51.21 -37.81

-41.65 -34.97

DNA-La(NO3)3(dppz-CN) (3)

38.02

-17.18

-10.92

-51.44

-41.52

DNA-La(NO3)3(dppz-NO2) (4)

37.99

-17.33

-11.08

-51.49

-41.91

DNA MUT CC-La(NO3)3(dppz) (5)

48.81

-21.83

-14.50

-49.30

-36.82

DNA MUT CC-La(NO3)3(dpq) (6)

38.68

-15.82

-11.49

-44.08

-32.72

DNA MUT GG-La(NO3)3(dppz) (7)

53.66

-29.27

-14.72

-53.89

-44.22

DNA MUT GG-La(NO3)3(dpq) (8)

42.87

-22.58

-13.24

-43.59

-36.53

[a]ΔE

Pauli:

Pauli repulsion; ΔEelec: electrostatic interaction; ΔEorb: orbital interaction; ΔEdisp: dispersive energy; ΔEint: interaction energy.

of view. A possible explanation for this discrepancy can be found in the fact that MD simulations for these systems were started with the GG base pair in “stacking” position (within the double helix). Therefore, because of the purine-purine interaction, the steric-hindrance increases which probably produced the marked flexibility of the complexes throughout the simulation until a more favorable position was reached. Furthermore, the extra ring contributed by the second guanine, relative to the cytosine, confers a larger surface of interaction, which finally should favor the free binding energies. With the aim to visualize more clearly this last point, the Figures S12 and S13 show the ΔGbind and RMSD values for the DNA MUT GG-

Nd(NO3)3(dpq) (8) system. It can be noted that ΔGbind variation from 80 ns of MD matches with the marked change in the RMSD value, which corresponds to the event where the mutated G5 nucleotide moves from the “stacking” position, losing the interaction with the G20, to the “edge to face” π-π stacking interaction with the dppz. To corroborate if these energetic and structural changes are maintained, the MD simulation for (8) was extended to 160 ns. As observed in Figures S14 and S15, these changes were conserved and after the movement of the G5 nucleotide, the RMSD values of the interaction site reached a stability that was not ob-

7



served in the first part of MD simulation. This was also supported by the comparison of the RMSF values (see Figure S16, ESI†), where a trend showing a decrease from 80 to 160 ns was observed. If a comparison between the first and last 80 ns of MD simulation is made, a favorable energetic difference of ca. -6 kcal/mol is obtained (see Figure S17, ESI†). In this part of the work, the presented MD simulations have started with the neodymium complex intercalated within the DNA structure and the mismatched base pairs in stacking position. Nevertheless, as pointed earlier, in case of the system (8) one of the nucleotides in the GG mismatched site left from the double helix. To achieve a better understanding of this phenomenon, new molecular dynamics were performed for the GG and CC mismatched systems, but this time with the base pairs extruded from the double helix. All details of this procedure can be found in the Section 1.2 of ESI, but from a general point of view, slight energy differences favoring the extruded systems were observed. However, considering the standard deviations, these cannot be assumed as conclusive. Until now, these classical mechanics analyses in the sampled time scale show a similar stability for 12-mer and mismatched 12-mer DNA systems, which indicate a lack of selectivity in neodymium complexes towards mismatched sites. Furthermore, the dppz ligand exhibits a higher DNA binding affinity than dpq, supporting experimental observations. Thus, to get a better understanding of the results obtained at this point, relativistic quantum methods were applied in the second part of this work (vide infra).

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intercalation of phenanthroline derivatives.104-106 On the other hand, the ∆E term account for the polarization observed from the DNA base pairs to the dppz and dpq ligands, in agreement with the results obtained by Galliot et al102 and Parker et al.30 Figure 3. NCI analysis. DNA-dppz and DNA-dpq fragments obtained from the DNA-Nd(NO3)3(dppz) (1) and DNANd(NO3)3(dpq) (2) systems, respectively. Both isosurfaces were mapped with an isovalue of 0.430.

NdIII complex - DNA Bonding Interactions The free binding energy calculations have shown three marked trends: (i) the dppz complexes are more stable than those with dpq (ii) no substantial variations were observed between the substituted (dppz-CN and dppz-NO2) and unsubstituted dppz systems (iii) regarding the complexes bounded to mismatched DNA base pairs, those with the GG mutation are more stable than the CC ones. In order to get more insight on these trends and to gain a better understanding on the nature of interactions between the DNA base pairs and the complexes, an energy decomposition analysis (EDA) was performed (see Computational Details Section). For this purpose, two fragments were defined taking the cut structures obtained from the MM-GBSA calculations: one corresponding to the lanthanide complex, and one corresponding to the four nucleotides surrounding it (see Figure 1). Because of limitations in the treatment of open-shell molecules, in these calculations the neodymium(III) was replaced by lanthanum(III). As expected, the dispersive component has a predominant contribution on the interaction for all cases (see Table 1) and it is in the range reported by Galliot et al.102 for similar systems. In this context, it is wellknown that the π-π stacking is a dominant interaction between DNA base pairs5-9,18 and intercalators and, according to Grimme,103 the governing factor for this interaction is a more favourable dispersive component, which supports our results. and However, it cannot be ruled out the contribution of ∆E ∆E for the final value of ∆E . The first one accounts for roughly 1/3 of the stabilizing forces, which has been also observed in previous works that addressed the role of electrostatics in stacked DNA base pairs and in other studies related to the

Regarding the aforementioned trends, the following can be observed: (i) in agreement with ΔGbind results, the dppz complexes, bounded to 12-mer and mismatched 12-mer DNA, are more stabilized than their dpq analogues. Despite this difference is not clear enough from ΔEint values, it is apparent from ΔEdisp ones which was expected because of the extra ring in the dppz structure. As pointed out by some authors,37 this ring confers to the dppz a greater interaction surface with the DNA base pairs thus favoring the binding energy. This fact is also supported by the non-covalent interaction (NCI) index, which was employed to visualize the regions where non-covalent forces arise. As shown in Figure 3, the NCI plot evidences the existence of interactions between the ligands and DNA base pairs, being more noticeable in case of the dppz (ii) as in ΔGbind trends, no marked differences were noted between the substituted and unsubstituted systems, supporting the results obtained in our previous work30 where, in addition, these electron-withdrawing groups did not affected the spectroscopic properties of the complexes (iii) there is not a marked trend for stabilization of 12mer DNA systems over mismatched ones or vice versa; in fact, a slight discordance is observed regarding the ΔGbind values, because from a ΔEdisp point of view, the 12-mer DNA systems are more stabilized than those CC mismatched (for both dppz and dpq), but the contrary occurs in case of the GG mismatched ones. This last observation has been reported before for the [Ru(Me4phen)2dppz]2+ complex and it makes sense considering

8


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that the GG mismatch has an extra ring which confers a larger interaction surface on which the ligands can be “accommodated”. However, in case of the ruthenium complex, it presented selectivity to mismatched DNA sites exhibiting a pronounced stability over regular DNA ones. According to Barton et al.14 and as mentioned before, this selectivity was attributed in part to the ancillary ligand modifications to disfavor binding to regular sites as result of steric clashing between these ligands and the DNA backbone. Therefore, at this point it could be concluded, in agreement with the force field and free binding energy calculations, that these neodymium complexes will not be selective to DNA mismatches, thus being necessary to improve the design of the systems by modification of the nitrate ligands. Until now, an analysis of the interaction between the complexes and the DNA base pairs has been made. Nevertheless, it is also necessary to study the spectroscopic properties of both isolated and intercalated complexes to predict and understand,

even in part, the role of the DNA over the emission of these systems. Therefore, the remaining part of the present work will be devoted to discussing and analyze this issue.

Spectroscopic Properties of Intercalated and Isolated Complexes The UV-visible absorption spectra of the synthesized Nd(NO3)3(dppz-R) complexes where R= H, CN- and NO2-, are shown in Figure S21, and two main bands are observed at ca. 348 - 365 nm. According to the experimental data, these bands can be ascribed mainly to n→π* and π→π* transitions in the dppz-R ligand, which absorbs within an energy range of 325400 nm. This is indicative of a sensitization process from the ligand to the neodymium. To reproduce, extend and analyze these experimental results, SR-TDDFT calculations were employed to deter-

Figure 4. Absorption spectra obtained from SR-TDDFT calculations. a) Intercalated Nd(NO3)3(dppz-R) complexes b) Intercalated Nd(NO3)3(dpq) complexes c) Isolated Nd(NO3)3(dppz-R) complexes d) Isolated Nd(NO3)3(dpq) complex

mine the spectroscopic properties of all the studied systems. For the isolated systems (Figure 4c and 4d) the transitions were characterized as n→π* and π→π* (see Section 2.2, ESI). As observed in Figure 4c, these calculations reproduce properly the most important transitions in correct agreement with our experimental reports and no significant changes were observed between the substituted and unsubstituted complexes. Now, regarding the dpq analogue, the spectrum showed in Figure 4d agrees with the experimentally reported by Patra et al. in 201637

for the same molecule. In relation to the DNA-bounded complexes (see Figure 4a and 4b), no shifts in the wavelengths were observed in comparison to the isolated ones. However, a marked hypochromism and polarizations from the DNA base pairs towards the neodymium complexes were observed in the most intense bands of the first ones. These features support an intercalative binding mode, as reported by Parker et al. in 2002.30

9



Page 10 of 15

The experimental emission spectra of the isolated Nd(NO3)3(dppz-R) complexes are shown in Figure S22 and exhibit an emission band at ca. 1437 nm which was characterized as a 4F3/2→4I15/2 transition in the NdIII center. According to the experimental work of Patra et al,37 in case of the Nd(NO3)3(dpq) complex it was not observed a NdIII centered emission, which was explained in our recent work.42 Because of that, the remaining analyses will be focused only on the dppz systems. At this point, the ligand localized absorption and the lanthanide localized emission have been well-established. Therefore, it is possible to employ a fragmentation scheme, proposed in previous works,41,42 to describe the sensitization pathways and emission of both isolated and intercalated systems. As detailed in the Computational Details section, the fragments were defined as follows: [Nd(NO3)3] and [dppz-R] for the isolated NdIII complexes and [Nd(NO3)3] and [(dppz-R)-DNA], where R=H, CN-, NO2-, for all the intercalated models described for the systems.

in correct agreement with that experimentally reported in a couple of works107,108 at ca. 11300 cm-1 (884 nm). Several authors have observed that the largest quantum yields occur when the triplet state of the ligand is close to resonant levels of the lanthanide ion (Ln*), and a “safe” energy difference has been established between 2500 and 3500 cm-1. Other factor that should be considered is the energy difference between these resonant states and the emissive one in the lanthanide center, because if this gap is too large other non-radiative deactivation mechanisms could take place. It is well-known that fulfil these conditions is complicated in case of NdIII systems due to the amount of nearby energy levels, which facilitates the quenching produced by high-energy vibrations. For example, in this case, the triplet in the dppz-CN and dppz-NO2 ligands was determined at ca. 26667 cm-1 being approximately 15000 cm-1 higher than the emissive 4F3/2 which could explain the experimental difficulties measuring the radiative lifetimes.

Electronic States of the Isolated and Intercalated Ligands

Figure 5 shows the energy diagram for the possible sensitization pathways for isolated and intercalated complexes. Regarding the isolated complexes, and according to CASSCF/NEVPT2 calculations, it can be observed that based on theoretical oscillator strengths a ligand-centered excitation leads to the S3 state in all systems. In case of the unsubstituted dppz, this state is located at ca. 33713 cm-1, while in the substituted dppz-CN and dppz-NO2 it is located at ca. 30000 cm-1. All these values are in good agreement with experimental excitation energies obtained in this work and reported by other authors.36,42 After this initial absorption, an internal conversion (IC) mechanism is proposed to reach the lowest singlet state (S1), which in case of dppz complex appears at ca. 28773 cm-1 and in case of dppz-CN and dppz-NO2 at ca. 26980 cm-1. Intersystem crossing (ISC) from S1 can lead to T1 which, as previously said, was determined in almost perfect agreement with experimental results. At this point, excitation energy is transferred to the neodymium from T1. Based on the aforementioned “safe” energy gap, the most probable pathway is in all cases T1→4G9/2, which has a theoretical gap (ΔE1) of ca. 3000 cm-1. After this process, the emissive state 4F3/2 is reached from which the emission to 4IJ states should be produced. However, the path to reach this emissive level is long in both substituted and unsubstituted dppz ligands. For example, in case of these last ones ∆ / is ca. 15000 / -1 cm which probably is not appropriated to observe a good emission. This fact may account for experimental difficulties ob) of the served in the measurement of radiative lifetimes ( synthesized complexes, because despite a characteristic band of the neodymium (4F3/2→4I15/2) was detected (see Figure S22), could not be obtained. Now, regarding the intercalated complexes, no substantial differences are observed in relation to the isolated ones. As mentioned above, the triplet states of the ligands were kept unchanged after the intercalation, supporting experimental reports.30 Thus, it could be thought that the role of the DNA is mainly to protect the lanthanide complex from its interactions with solvent molecules, to avoid non-radiative deactivations produced by high-energy vibrations. Figure 5. General scheme for the most probable energy transfer pathways in substituted [Nd(NO3)(dppz-R)] for

TDDFT calculations were employed to describe S0→Sn transitions. However, the state responsible for the energy transfer process is the lowest excited triplet state (T1). The localization of this state is a key step to analyze properly the sensitization pathways in lanthanide complexes. In previous works,30,42 T1 was experimentally determined at ca. 26667 cm-1 (~374 nm) for the dppz-CN and dppz-NO2 fragments, while for the unsubstituted dppz it was established at ca. 24000 cm-1 (~416 nm). These states were determined theoretically through CAS(10,10)SCF/PT2 calculations too, with an error of ca. 10 nm (~238 cm-1) relative to experimental values, which evidenced the good performance of the selected active space and also in good agreement with other reported theoretical studies.42 The effects of the DNA structure over the location of this state have been approached from experimental studies. In 2002 Parker et al.30 analyzed the interaction of europium and terbium complexes coordinated to dppz with DNA, and measured T1 at ca. 24000 cm-1 (416 nm). They also noted that this value was kept unchanged after DNA binding. To analyze theoretically the effect of the DNA base pairs over the location of T1 in the dppz ligand, CAS(10,10)SCF/PT2 calculations were repeated in all the intercalated systems with an active space carefully selected by looking for orbitals mainly located over the dppz. As result, the T1 states were kept almost unchanged in relation to the isolated complexes, supporting the findings reported by Parker et al.30

Electronic States of the NdIII Fragment To get more insight about the electronic states of the neodymium fragment, higher-level calculations are necessary owing to their particular electronic structure. In this context, multiconfigurational methods were used to determine the location of the energy levels in the fragments under study. First, according to the Russell-Saunders scheme, the predicted ground spin-free (SF) ion term for NdIII is 4I9/2, which was reproduced properly employing a minimal active space CAS(3,7)SCF (three electrons in seven 4f orbitals). Second, the emissive state (4F3/2) of neodymium was located at ca. 12326 cm-1 (811 nm), which is

Energy Transfer Pathways

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R=CN-, NO2-. Because of the similarity between both the isolated and intercalated systems, the scheme is presented for both.

CONCLUSIONS A rigorous study going from molecular mechanic to relativistic quantum chemical methods has been performed successfully to study the binding of NdIII complexes to DNA, its spectroscopic properties and sensitization pathways. Modelling of metal ion-containing systems pose a major challenge in molecular mechanic studies. Due to some particular characteristics of these elements, such as complicated electronic structures and multiple coordination numbers, parametrization of their structures requires a careful strategy. Here, the use of a metal center parameter builder based on quantum calculations55 enabled an adequate modelling of the NdIII complexes. Thus, despite the inherent difficulties in the treatment of lanthanides, both MD simulations and free binding energy calculations showed a correct performance, reproducing the main trends expected from the available experimental data and exhibiting a good correspondence with the quantum mechanical results. To start, MD simulations and MM-GBSA calculations allowed positioning the neodymium complexes between the DNA base pairs in order to get the most appropriate configurations to introduce the quantum mechanical study. In this context, the EDA analysis corroborated the main trends obtained from MM-GBSA calculations: (i) dppz complexes have a higher binding affinity to DNA than dpq ones and (ii) the CC mismatch is more destabilized than the GG. Furthermore, no marked differences were observed between the 12-mer and mismatched 12-mer systems. Therefore, it could be thought that these complexes are not selective to mismatch sites. Now regarding the role of DNA on the spectroscopic properties and sensitization pathways of these neodymium complexes, some effects which support the experimental reports of Parker et al.19 were observed: At TDDFT level, polarizations between the DNA base pairs and the antenna ligands were identified, which supports an intercalative binding mode. In addition, a hypochromism was noted in the intercalated complexes respect to the isolated ones. On the other hand, at SO-CASSCF/NEVPT2 level, T1 was determined as unchanged when the complexes are isolated or intercalated. Thus, based on these results, it seems

that the main role of the DNA is protect the complex from interactions with solvent molecules, preventing a possible quenching produced by high-energy vibrations as reported in works of Barton and Patra.5,18,25-29 Regrettably, because of theoretical limitations in the study of the emission in lanthanide complexes, this fact could not be analyzed. However, it should not be ruled out that the implementation of a method that allow to study the emission in these kinds of complexes, may account for the increase of the emission intensity experimentally observed for some authors when some of these systems are bounded to DNA. In fact, as the methodology is available for implementation, it could be possible to explain and predict the selectivity of some complexes to mismatched sites In the last step, SO-CASSCF/NEVPT2 methodology allowed us to elucidate the sensitization pathways of the studied complexes. Thus, based on experimental energy gaps defined as optimal to get a good energy transfer process, poor conditions were found for the neodymium sensitization. In fact, the path to reach the 4F3/2 emissive state in the NdIII center is very long which constitutes a disadvantage to get a good emission. Therefore, this could be an explanation for the complications exhibited experimentally to measure the radiative lifetimes in these complexes. In this context, a modification of the first coordination sphere employing bulky ligands could improve the emission of these NdIII complexes and confer them selectivity for mismatched sites. Finally, in this article a study integrating classical and quantum mechanical methods was carried out allowing to describe accurately, from a general to a particular point of view, the interactions between our NdIII complexes and DNA. The obtained results were in agreement with the available experimental data, corroborating well-established facts observed in this issue. Therefore, this work is proposed as a benchmark study to extend this methodology to similar compounds which can be selective or not to mismatch sites.

ASSOCIATED CONTENT Supporting Information. All structural information, TDDFT calculations and experimental details (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]. Tel/Fax: +56-2-2770-3352 (D.P. H). *E-mail: [email protected] (R.A.-P)

ORCID María J. Beltrán-Leiva: 0000-0003-3221-3118 Isabel Fuenzalida-Valdivia: 0000-0003-0797-1670 Plinio Cantero-López: 0000-0003-4090-9879 Jans Alzate-Morales: 0000-0001-9624-7849 Dayán Páez-Hernández: 0000-0003-2747-9982 Ramiro Arratia-Pérez: 0000-0001-6140-2116

ACKNOWLEDGMENTS

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This work has been supported by FONDECYT Grants N°: 1150629 and 1180017. M.J.B.-L. and I.F.-V. acknowledge CONICYT/Doctorado Nacional 2015/21151553 and 2018/21181106 for their Ph.D. fellowship. P.C.-L. acknowledges CONICYT for his postdoctoral Project FONDECYT/Postdoctorado-2018 No. 3180449.

REFERENCES (1) Cronin, K. A.; Lake, A. J.; Scott, S.; Sherman, R. L.; Noone, A.-M.; Howlader, N.; Henley, S. J.; Anderson, R. N.; Firth, A. U.; Ma, J.; et al. Annual Report to the Nation on the Status of Cancer, Part I: National Cancer Statistics. Cancer 2018, 124, 2785–2800. (2) Qin, S.-Y.; Zhang, A.-Q.; Cheng, S.-X.; Rong, L.; Zhang, X.-Z. Drug Self-Delivery Systems for Cancer Therapy. Biomaterials 2017, 112, 234–247. (3) Boyle, K. M.; Barton, J. K. A Family of Rhodium Complexes with Selective Toxicity toward Mismatch Repair-Deficient Cancers. J. Am. Chem. Soc. 2018, 140, 5612–5624. (4) Nano, A.; Boynton, A. N.; Barton, J. K. A Rhodium-Cyanine Fluorescent Probe: Detection and Signaling of Mismatches in DNA. J. Am. Chem. Soc. 2017, 139, 17301–17304. (5) Erkkila, K. E.; Odom, D. T.; Barton, J. K. Recognition and Reaction of Metallointercalators with DNA. Chem. Rev. 1999, 99, 2777–2796. (6) Hurley, H. H.; DNA and it’s Associated Processes as Targets for Cancer Therapy. Nat. Rev. Cancer. 2002, 2, 188-200. (7) Gill, R. M.; Harun, S. N.; Halder, S.; Boghozian, R. A.; Ramadan, K.; Ahmad, H.; Vallis, K. A. A Ruthenium Polypyridyl Intercalator Stalls DNA Replication Forks, Radiosensitizes Human Cancer Cells and is Enhanced by Chk1 Inhibition. Sci. Rep. 2016, 6, 31973. (8) Cheng, L.; Yang, K.; Chen, Q.; Zhuang, L. Organic Stealth Nanoparticles for Highly Effective in Vivo Near-Infrared Photothermal Therapy of Cancer. ACS Nano, 2012, 6, 5605-5613. (9) Ndagi, U.; Mhlongo, N.; Soliman, M. Metal Complexes in Cancer Therapy - An Update from Drug Design Perspective. Drug Des., Dev. Ther., 2017, 11, 599-616. (10) Liu, H.-K.; Sadler, P. J. Metal Complexes as DNA Intercalators. Acc. Chem. Res. 2011, 44, 349–359. (11) McConell, A. J.; Song, H.; Barton, J. K.; Luminescence of [Ru(bpy)2(dppz)]2+ Bound to RNA Mismatches. Inorg. Chem. 2013, 52, 10131-10136. (12) Weidmann, A. G.; Komor, A. C.; Barton, J. K. Targeted Chemotherapy with Metal Complexes. Comments Mod. Chem. A Comments Inorg. Chem. 2014, 34, 114-123. (13) Boyle, K. M.; Barton, J. K. Targeting DNA Mismatches with Rhodium Metalloinsertors. Inorg. Chim. Acta. 2016, 452, 3-11. (14) Boynton, A. N.; Marcélis, L.; Barton, J. K. [Ru(Me4phen)2dppz]2+, a Light Switch for DNA Mismatches. J. Am. Chem. Soc. 2016, 138, 5020-5023. (15) Boynton, A. N.; Marcélis, L.; McConnell, A. J.; Barton, J. K. A Ruthenium (II) Complex as a Luminescent Probe for DNA Mismatches and Abasic Sites. Inorg. Chem. 2017, 56, 8381-8389. (16) Nano, A.; Boynton, A. N.; Barton, J. K. A Rhodium-Cyanine Fluorescent Probe: Detection and Signaling of Mismatches in DNA. J. Am. Chem. Soc. 2017, 139, 17301-17304. (17) Boyle, K. M.; Barton, J. K. A Family of Rhodium Complexes with Selective Toxicity toward Mismatch Repair-Deficient Cancers. J. Am. Chem. Soc. 2018, 140, 5612-5624. (18) Hussain, A.; Chakravarty, A. R. Photocytotoxic Lanthanide Complexes. J. Chem. Sci. 2012, 124, 1327–1342. (19) Bünzli, J.-C. G. Lanthanide Light for Biology and Medical Diagnosis. J. Lumin. 2016, 170, 866–878. (20) Teo, R. D.; Termini, J.; Gray, H. B. Lanthanides: Applications in Cancer Diagnosis and Therapy. J. Med. Chem. 2016, 59, 6012– 6024.

Page 12 of 15

(21) Zhao, C.; Sun, Y.; Ren, J.; Qu, X. Recent Progress in Lanthanide Complexes for DNA Sensing and Targeting Specific DNA Structures. Inorg. Chim. Acta 2016, 452, 50–61. (22) Zhang, D.; Wen, L.; Huang, R.; Wang, H.; Hu, X.; Xing, D. Mitochondrial Specific Photodynamic Therapy by Rare-Earth Nanoparticles Mediated near-Infrared Graphene Quantum Dots. Biomaterials 2018, 153, 14–26. (23) Lu, L.; Tu, D.; Liu, Y.; Zhou, S.; Zheng, W.; Chen, X. Ultrasensitive Detection of Cancer Biomarker microRNA by Amplification of Fluorescence of Lanthanide Nanoprobes. Nano Res. 2018, 11, 264–273. (24) Hänninen, P.; Härmä, H. Lanthanide Luminescence. Photophysical, Analytical and Biological Aspects.; Springer Berlin Heidelberg: Turku, Finland, 2011. (25) Eliseeva, S. V.; Bünzli, J.-C. G. Lanthanide Luminescence for Functional Materials and Bio-Sciences. Chem. Soc. Rev. 2010, 39, 189–227. (26) Weissman, S. I. Intramolecular Energy Transfer, The Fluorescence of Complexes of Europium. J. Chem. Phys. 1942, 10, 214– 217. (27) Kolpashchikov, D. M. Binary Probes for Nucleic Acid Analysis. Chem. Rev. 2010, 110, 4709–4723. (28) Carr, R.; Evans, N. H.; Parker, D. Lanthanide Complexes as Chiral Probes Exploiting Circularly Polarized Luminescence. Chem. Soc. Rev. 2012, 41, 7673–7686. (29) Dasari, S.; Singh, S.; Sivakumar, S.; Patra, A. K. DualSensitized Luminescent Europium(ΙΙΙ) and Terbium(ΙΙΙ) Complexes as Bioimaging and Light-Responsive Therapeutic Agents. Dalt. Trans. 2016, 22, 17387–17396. (30) Bobba, G.; Frias, J. C.; Parker, D. Highly Emissive NineCoordinate Enantiopure Lanthanide Complexes Incorporating Tetraazatriphenylenes as Probes for DNA. Chem. Commun. 2002, 890– 891. (31) Law, G. L.; Man, C.; Parker, D.; Walton, J. W. Observation of the Selective Staining of Chromosomal DNA in Dividing Cells Using a Luminescent Terbium(iii) Complex. Chem. Commun. 2010, 46, 2391–2393. (32) Bobba, G.; Bretonnière, Y.; Frias, J. C.; Parker, D. Enantiopure Lanthanide Complexes Incorporating a Tetraazatriphenylene Sensitiser and Three Naphthyl Groups: Exciton Coupling, Intramolecular Energy Transfer, Efficient Singlet Oxygen Formation and Perturbation by DNA Binding. Org. Biomol. Chem. 2003, 1, 1870–1872. (33) Bobba, G.; Kean, S. D.; Parker, D.; Beeby, A.; Baker, G. DNA Binding Studies of Cationic Lanthanide Complexes Bearing a Phenanthridinium Group. J. Chem. Soc. Perkin Trans. 2 2001, 1738– 1741. (34) Mathieu, E.; Maupin, C. L.; Parker, D.; Riehl, J. P. Stereodifferentiation and Base-Pair Selectivity in the Binding of D and L Cationic Lanthanide Complexes to [( CG ) 6 ] 2 , [( AT ) 6 ] 2 and CT-DNA. Chem. Comm. 1999, 32, 1699–1700. (35) Hussain, A.; Lahiri, D.; Begum, M. S. A.; Saha, S.; Majumdar, R.; Dighe, R. R.; Chakravarty, A. R. Photocytotoxic Lanthanum (III) and Gadolinium (III) Complexes of Phenanthroline Bases Showing Light-Induced DNA Cleavage Activity. Inorg. Chem. 2010, 49, 4036–4045. (36) Dasari, S.; Abbas, Z.; Kumara, P.; Patra, A. K. Photosensitized samarium(III) and erbium(III) Complexes of Planar N,N-Donor Heterocyclic Bases: Crystal Structures and Evaluation of Biological Activity. Cryst. Eng. Comm. 2016, 18, 4313–4322. (37) Singh, K.; Srivastava, P.; Patra, A. K. Binding Interactions with Biological Targets and DNA Photocleavage Activity of Pr (III) and Nd (III) Complexes of Dipyridoquinoxaline. Inorg. Chim. Acta 2016, 451, 73–81. (38) Singh, K.; Singh, S.; Srivastava, P.; Sivakumar, S.; Patra, A. K. Lanthanoplatins: Emissive Eu(III) and Tb(III) Complexes Staining

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Page 13 of 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Nucleoli Targeted through Pt-DNA Crosslinking. Chem. Commun. 2017, 53, 6144–6147. (39) Chandra, A.; Singh, K.; Singh, S.; Sivakumar, S.; Patra, A. K. A Luminescent europium(III)-platinum(II) Heterometallic Complex as a Theranostic Agent: A Proof-of-Concept Study. Dalton Trans. 2015, 45, 494–497. (40) Gupta, K.; Patra, A. K. A Luminescent pH-Responsive Ternary Eu3+ Complex of β-Diketonate and Terpyridine Derivative as Sensitizing Antenae: Photophysical Aspects, Anion Sensing and Biological Interactions. Eur. J. Inorg. Chem. 2018, 1882–1890. (41) Beltrán-Leiva, M. J.; Páez-Hernández, D.; Arratia-Pérez, R. Theoretical Determination of Energy Transfer Processes and Influence of Symmetry in Lanthanide(III) Complexes: Methodological Considerations. Inorg. Chem. 2018, 57, 5120–5132. (42) Beltrán-Leiva, M. J.; Cantero-López, P.; Zúñiga, C.; Bulhões-Figueira, A.; Páez-Hernández, D.; Arratia-Pérez, R. Theoretical Method for an Accurate Elucidation of Energy Transfer Pathways in Europium(III) Complexes with Dipyridophenazine (Dppz) Ligand: One More Step in the Study of the Molecular Antenna Effect. Inorg. Chem. 2017, 56, 9200–9208. (43) Li, P.; Merz, K. A Python Based Metal Center Parameter Builder. J. Chem. Inf. Model. 2016, 56, 599–604. (44) Case, D. A.; Betz, R. M.; Cerutti, D. S.; Cheatham, T. E.; Darden, T. A.; Duke, R. E.; Giese, T. J.; Gohlke, H.; Goetz, A. W.; Homeyer, N.; et al. AMBER 2016. Univ. California, San Fr. 2016. (45) Seminario, J. Calculation of Intramolecular Force Fields from Second-Derivative Tensors. Int. J. Quantum Chem. 1996, 60, 1271–1277. (46) Bayly, C.; Cieplak, P.; Cornell, W.; Kollman, P. A WellBehaved Electrostatic Potential Based Method Using Charge Restraints for Deriving Atomic Charges: The RESP Model. J. Phys. Chem. 1993, 97, 10269–10280. (47) Li, P.; Song, L.; Merz, K. Parametrization of Highly Charged Metal Ions Using the 12-6-4-LJ-Type Nonbonded Model in Explicit Water. J. Phys. Chem. B 2014, 119, 883–895. (48) Besler, B.; Merz, K.; Kollman, P. Atomic Charges Derived from Semiempirical Methods. J. Comp. Chem. 1990, 11, 431–439. (49) Becke, A. Density-Functional thermochemistry.III. The Role of Exact Exchange. J. Chem. Phys. 1993, 98, 5648–5652. (50) Lee, C.; Yang, W.; Parr, R. Development of the ColleSalvetti Correlation-Energy Formula into a Functional of the Electron Density. Phys. Rev. B. 1988, 37, 785–789. (51) Dunning, T. Gaussian Basis Sets for the Atoms Gallium through Krypton. J. Chem. Phys 1977, 66, 1382–1383. (52) Fuentealba, P.; Preuss, H.; Stoll, H.; Szentpály, L. A Proper Account of Core-Polarization with Pseudopotentials: Single ValenceElectron Alkali Compounds. Chem. Phys. Lett. 1982, 89, 418–422. (53) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; et al. Gaussian 09, Revision E.01. Gaussian Inc. Wallingford CT 2009. (54) Sathyamoorthy, B.; Shi, H.; Zhou, H.; Xue, Y.; Rangadurai, A.; Merriman, D.; Al-Hashimi, H. Insights into Watson & Crick/Hoogsteen Breathing Dynamics and Damage Repair from the Solution Structure and Dynamic Ensemble of DNA Duplexes Containing m1A. Nucleic Acids Res. 2017, 45, 5586–5601. (55) Song, H.; Kaiser, J.; Barton, J. Crystal Structure of Δ[Ru(bpy)2dppz]2+ Bound to Mismatched DNA Reveals Side-by-Side Metalloinsertion and Intercalation. Nat. Chem. 2012, 4, 520–615. (56) Pérez, A.; Marchán, I.; Svozil, D.; Sponer, J.; Cheatam, T.; Laughton, C.; Orozco, M. Refinement of the AMBER Force Field for Nucleic Acids: Improving the Description of α/γ Conformers. Biophys. J. 2007, 92, 3817–3829. (57) Yildirim, I.; Stern, H. A.; Kennedy, S. D.; Tubbs, J. D.; Turner, D. H. Reparameterization of RNA χ Torsion Parameters for the

AMBER Force Field and Comparison to NMR Spectra for Cytidine and Uridine. J. Chem. Theory Comput. 2010, 6, 1520–1531. (58) Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. Comparison of Simple Potential Functions for Simulating Liquid Water. J. Chem. Phys. 1983, 79, 926–935. (59) Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F.; DiNola, A.; Haak, J. R. Molecular Dynamics with Coupling to an External Bath. J. Chem. Phys. 1984, 81, 3684–3690. (60) Ryckaert, J.-P.; Ciccotti, G.; Berendsen, H. J. C. Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of N-Alkanes. J. Comput. Phys. 1977, 23, 327–341. (61) Darden, T.; York, D.; Pedersen, L. Particle Mesh Ewald: An N⋅log(N) Method for Ewald Sums in Large Systems. J. Chem. Phys. 1993, 98, 10089–10092. (62) Essmann, U.; Perera, L.; Berkowitz, M. L.; Darden, T.; Lee, H.; Pedersen, L. G. A Smooth Particle Mesh Ewald Method. J. Chem. Phys. 1995, 103, 8577–8593. (63) Case, D. A.; Berryman, J. T.; Betz, R. M.; Cerutti, D. S.; Cheatham, T. E.; Darden, T. A.; Duke, R. E.; Giese, T. J.; Gohlke, H.; Goetz, A. W.; et al. AMBER 2015. Univ. California, San Fr. 2015. (64) Humphrey, W.; Dalke, A.; Schulten, K. VMD: Visual Molecular Dynamics. J. Molec. Graphics 1996, 14, 33-38. (65) Schrödinger Release 2017-4: Maestro, Schrödinger. LLC, New York, NY, 2017 2017. (66) Miller, B.; McGee, T.; Swails, J.; Homeyer, N.; Gohlke, H.; Roitberg, A. MMPBSA.py: An Efficient Program for End-State Free Energy Calulations. J. Chem. Theory Comput., 2012, 8, 3314-3321. (67) Hawkins, G. D.; Cramer, C. J.; Truhlar, D. G. Pairwise Solute Descreening of Solute Charges from a Dielectric Medium. Chem. Phys. Lett. 1995, 246, 122–129. (68) Hawkins, G. D.; Cramer, C. J.; Truhlar, D. G. Parametrized Models of Aqueous Free Energies of Solvation Based on Pairwise Descreening of Solute Atomic Charges from a Dielectric Medium. J. Phys. Chem. 1996, 100, 19824–19839. (69) Tsui, V.; Case, D. Theory and Applications of the Generalized Born Solvation Model in Macromolecular Simulations. Biopolymers 2001, 56, 275-291. (70) Onufriev, A.; Bashford, D.; Case, D. A. Modification of the Generalized Born Model Suitable for Macromolecules. J. Phys. Chem. B 2000, 104, 3712–3720. (71) Alexey, O.; Donald, B.; A., C. D. Exploring Protein Native States and Large scale Conformational Changes with a Modified Generalized Born Model. Proteins: Struct., Funct., Bioinf. 2004, 55, 383–394. (72) Neese, F. The ORCA Program System. Wiley Interdiscip. Rev. Comput. Mol. Sci. 2012, 2, 73–78. (73) Hess, B. A. Relativistic Electronic-Structure Calculations Employing a Two-Component No-Pair Formalism with External-Field Projection Operators. Phys. Rev. A 1986, 33, 3742. (74) Perdew, J. P.; Yue, W. Accurate and Simple Density Functional for the Electronic Exchange Energy: Generalized Gradient Approximation. Phys. Rev. B: Condens. Matter Mater. Phys. 1986, 33, 8800. (75) Pantazis, D. A.; Neese, F. All-Electron Scalar Relativistic Basis Sets for the Actinides. J. Chem. Theory Comput. 2011, 7, 677– 684. (76) Weigend, F.; Ahlrichs, R. Balanced Basis Sets of Split Valence, Triple Zeta Valence and Quadruple Zeta Valence Quality for H to Rn: Design and Assessment of Accuracy. Phys. Chem. Chem. Phys. 2005, 7, 3297–3305. (77) Eichkorn, K.; Weigend, F.; Treutler, O.; Ahlrichs, R. Auxiliary Basis Sets for Main Row Atoms and Transition Metals and Their Use to Approximate Coulomb Potentials. Theor. Chem. Accounts Theory, Comput. Model. (Theoretica Chim. Acta) 1997, 97, 119–124.

13



(78) E. J. Baerends, T. Ziegler, J. Autschbach, D. Bashford, A. Bérces, F. M. Bickelhaupt, C. Bo, P. M.; Boerrigter, L. Cavallo, D. P. Chong, L. et al. Amsterdam Density Functional, SCM, Theoretical Chemistry. Vrije Univ. Amsterdam, Netherlands http//www.scm.com 2012. (79) Kitaura, K.; Morokuma, K. A New Energy Decomposition Scheme for Molecular Interactions within the Hartree-Fock Approximation Pes. Int. J. Quantum Chem. 1976, 10, 325–340. (80) van Lenthe, E.; Baerends, E. J.; Snijders, J. G. Relativistic Regular Two component Hamiltonians. J. Chem. Phys. 1993, 99, 4597–4610 (81) Bickelhaupt, F. M.; Baerends, E. J. Kohn-Sham Density Functional Theory: Predicting and Understanding Chemistry. Rev. Comput. Chem. 2000, 15, 1–86. (82) Contreras-garcía, J.; Johnson, E. R.; Keinan, S.; Chaudret, R.; Piquemal, J.; Beratan, D. N.; Yang, W. NCIPLOT : A Program for Plotting Noncovalent Interaction Regions. J. Chem. Theory Comput. 2011, 7, 625–632. (83) Johnson, E.; Keinan, S.; Mori-Sánchez, P.; Contreras-García, J.; Cohen, A.; Yang, W. Revealing Noncovalent Interactions, J. Am. Chem. Soc., 2010, 132, 6498-6506.. (84) Yanai, T.; Tew, D. P.; Handy, N. C. A New Hybrid Exchange–correlation Functional Using the Coulomb-Attenuating Method (CAM-B3LYP). Chem. Phys. Lett. 2004, 393, 51–57. (85) Angeli, C.; Cimiraglia, R.; Malrieu, J. P. N-Electron Valence State Perturbation Theory: A Spinless Formulation and an Efficient Implementation of the Strongly Contracted and of the Partially Contracted Variants. J. Chem. Phys 2002, 117, 9138–9153. (86) Greguric, I.; Aldrich-Wright, J.; Collins, J. A 1H NMR Study of the Binding of Δ [Ru(phen)2DPQ]2+ to the Hexanucleotide d(GTCGAC)2. Evidence for Intercalation from the Minor Groove. J. Am. Chem. Soc. 1997, 119, 3621–3622. (87) Collins, J.; Sleeman, A.; Aldrich-Wright, J.; Greguric, I.; Hambley, T. A 1H NMR Study of the DNA Binding of Ruthenium(II) Polypyridyl Complexes. Inorg. Chem. 1998, 37, 3133–3141. (88) Wu, Y.; Chen, H.; Yang, P.; Xiong, Z. Racemic D,l[Co(phen)2dpq]3+ DNA Interactions: Investigation into the Basis for Minor-Groove Binding and Recognition. J. Inorg. Biochem. 2005, 99, 1126–1134. (89) Song, H.; Kaiser, J.; Barton, J. Crystal Structure of Δ[Ru(bpy)2dppz]2+ Bound to Mismatched DNA Reveals Side-by-Side Metalloinsertion and Intercalation. Nat. Chem. 2012, 4, 520–615. (90) Greguric, A.; Greguric, I.; Hambley, T.; Aldrich-Wright, J.; Collins, J. Minor Groove Intercalation of Δ-[Ru(Me2phen)2dppz]2+ to the Hexanucleotide d(GTCGAC)2. J. Chem. Soc., Dalt. Trans. 2002, 849–855. (91) Haq, I.; Lincoln, P.; Suh, D.; Norden, B.; Chowdhry, B.; Chaires, J. Interaction of .DELTA.- and .LAMBDA.[Ru(phen)2DPPZ]2+ with DNA: A Calorimetric and Equilibrium Binding Study. J. Am. Chem. Soc. 1995, 117, 4788–4796. (92) Vargiu, A.; Magistrato, A. Detecting DNA Mismatches with Metallo-Insertors: A Molecular Simulation Study. Inorg. Chem. 2012, 51, 2046–2057. (93) Komeiji, Y.; Uebayasi, M. Change in Conformation by DNA-Peptide Association: Molecular Dynamics of the HinRecombinase- hixL Complex. Biophys. J. 1999, 77, 123–138. (94) Jumbri, K.; Abdul, R.; Abdulmalek, E.; Ahmad, H.; Micaelo, N. An Insight into Structure and Stability of DNA in Ionic

Page 14 of 15

Liquids from Molecular Dynamics Simulation and Experimental Studies. Phys. Chem. Chem. Phys. 2014, 16, 14036–14046. (95) Bowerman, S.; Wereszczynski, J. An Insight into Structure and Stability of DNA in Ionic Liquids from Molecular Dynamics Simulation and Experimental Studies. Biophys. J. 2016, 110, 327–337. (96) Kormos, B.; Benitex, Y.; Baranger, A.; Beveridge, D. Affinity and Specificity of Protein U1A-RNA Complex Formation Based on an Additive Component Free Energy Model. J. Mod. Biol. 2007, 371, 1405–1419. (97) Ruscio, J.; Onufriev, A. A Computational Study of Nucleosomal DNA Flexibility. Biophys. J. 2006, 91, 4121–4132. (98) Gaillard, T.; Case, D. A Computational Study of Nucleosomal DNA Flexibility. J. Chem. Theory Comput. 2011, 7, 3181–3198. (99) S., H.; Cucinotta, F. Computational Studies on Full-Length Ku70 with DNA Duplexes: Base Interactions and a Helical Path. J. Mod. Model. 2011, 18, 1935–1949. (100) Lakshmipraba, J.; Arunachalam, S.; Vijay Solomon, R.; Venuvanalingam, P. Synthesis, DNA Binding and Docking Studies of copper(II) Complexes Containing Modified Phenanthroline Ligands. J. Coord. Chem. 2015, 68, 1374–1386. (101) Patra, A.; Bhowmick, T.; Ramakumar, S.; Nethaji, M.; Chakravarty, A. DNA Cleavage in Red Light Promoted by Copper(ii) Complexes of α-Amino Acids and Photoactive Phenanthroline Bases. Dalton. Trans. 2008, 6966. (102) Galliot, A.; Gil, A.; Calhorda, M. J. Effects of Oxygenation on the Intercalation of 1,10-Phenanthroline-5,6/4,7-Dione between DNA Base Pairs: A Computational Study. Phys. Chem. Chem. Phys. 2017, 19, 16638–16649. (103) Grimme, S. Do Special Noncovalent π-π Stacking Interactions Really Exist? Angew. Chemie - Int. Ed. 2008, 47, 3430– 3434. (104) Hill, G.; Forde, G.; Hill, N.; Lester, W. A.; Sokalski, W. A.; Leszczynski, J. Interaction Energies in Stacked DNA Bases? How Important Are Electrostatics? Chem. Phys. Lett. 2003, 381, 729–732. (105) Gil, A.; Melle-Franco, M.; Branchadell, V.; Calhorda, M. J. How the Intercalation of Phenanthroline Affects the Structure, Energetics, and Bond Properties of DNA Base Pairs: Theoretical Study Applied to Adenine–Thymine and Guanine–Cytosine Tetramers. J. Chem. Theory Comput. 2015, 11, 2714–2728. (106) Gil, A.; Branchadell, V.; Calhorda, M. J. A Theoretical Study of Methylation and CH/π Interactions in DNA Intercalation: Methylated 1,10-Phenanthroline in Adenine-Thymine Base Pairs. RSC Adv. 2016, 6, 85891–85902. (107) Bünzli, J.-C. G. Lanthanide Luminescence: From a Mystery to Rationalization, Understanding, and Applications. Handb. Phys. Chem. Rare Earths 2016, 50, 141–176.

(108) Chan, E. M. Combinatorial Approaches for Developing Upconverting Nanomaterials: High-Throughput Screening, Modeling, and Applications. Chem. Soc. Rev. 2015, 44, 1653–1679 .

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Classical and Quantum Mechanical Calculations of the Stacking

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