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A first-principles study of the interaction of doxorubicin with graphene
Computational and Theoretical Chemistry 1115 (2017) 270–275
Contents lists available at ScienceDirect
Computational and Theoretical Chemistry journal homepage: www.elsevier.com/locate/comptc
A first-principles study of the interaction of doxorubicin with graphene Mariana Zancan Tonel a, Mirkos Ortiz Martins a, Ivana Zanella a, Renato Borges Pontes b, Solange Binotto Fagan a,⇑ a b
Centro Universitário Franciscano, ZIP 97010-032, Santa Maria, RS, Brazil Universidade Federal de Goiás, Campus Samambaia, ZIP 74690-900, Goiânia, GO, Brazil
a r t i c l e
i n f o
Article history: Received 17 February 2017 Received in revised form 5 July 2017 Accepted 6 July 2017 Available online 8 July 2017 Keywords: Graphene Doxorubicin Density functional theory Temperature Computational simulations
a b s t r a c t Graphene is a single layer of graphite whose carbon atoms are arranged in a hexagonal form. On the other side, doxorubicin (DOX) is a drug widely used for the treatment of various cancer diseases. In this work, we performed calculations within the Density Functional Theory (DFT) framework in order to obtain both structural and electronic properties of the graphene interacting with DOX. The results show that, in the most stable conformation, DOX interacting with pristine graphene has a binding energy of approximately 0.5 eV. Likewise, it was also verified that no major changes in the intrinsic electronic properties of graphene. Ab Initio Molecular Dynamics (AIMD) calculations show that, even at room temperature (300 K), there is a weak interaction between graphene and DOX. Ó 2017 Elsevier B.V. All rights reserved.
1. Introduction Since its isolation in 2004, graphene has attracted great interest from the scientific community due to its amazing structural and electronic properties [1]. Being a material with one atom thick, it offers a wide range of applications. Some potential graphene applications are, among other: display screens, electric circuits, solar cells, biomedical and chemical sensors [2]. Regarding the biological and biomedical applications, not only graphene, but also, carbon-based materials such as fullerenes and carbon nanotubes, due to its physical-chemical characteristics, have great potential for applications [3]. In recent years, these systems have been studied for drug delivery and biomedical images [4–6]. Besides, due to its strong absorbance in the infrared, they have been studied as photothermal agents for cancer treatment [7]. Graphene is a material with a thickness atom. 2D scale features, i.e., the electrons are free in two directions and confined in one direction, this fact makes it has a large surface area, which develops a variety of possible applications [8]. Also, has electrical and thermal conductivity and is transparent to visible light [9]. Due to its characteristics open the possibility of applications including for vitamins entrainment [10,11], and drugs for cancer therapy.
⇑ Corresponding author. E-mail addresses: [email protected] (M.Z. Tonel), [email protected] (M.O. Martins), [email protected] (I. Zanella), renatoborgespontes@gmail. com (R.B. Pontes), [email protected] (S.B. Fagan). http://dx.doi.org/10.1016/j.comptc.2017.07.004 2210-271X/Ó 2017 Elsevier B.V. All rights reserved.
On the other side, chemotherapy is one of the main forms of treatment for cancer. For this kind of treatment, some chemotherapeutic agents are used. The DOX, in particular, is one of the most effective chemotherapeutic agents for the treatment of cancer among them: breast, ovary, sarcomas, pediatric solid tumors, Hodgkin’s disease, multiple myeloma and non-Hodgkin’s lymphoma [12]. However, the undesirable side effects of the chemotherapeutic are due to their high toxicity, affecting mainly the cardiovascular system by causing hypotension, tachycardia, ventricular dilation and heart failure [13]. The combination of carbon nanomaterials with DOX has already been experimentally investigated [3,14,15]. Also, theoretical studies involving DOX and carbon nanotubes already exist in the literature [16] and the results show that there is a negligible charge transfer between the components of typical non-covalent interaction, being ideal for DOX molecules are easily released from the nanotube. All the points mentioned above raise questions about the interaction of graphene and DOX. The combination of graphene with DOX has a great potential for applications in medicine as an adjuvant agent in the treatment of cancer [17]. The evaluation of the physical properties resulting from this interaction is very important and interesting because it can be related to existing experimental data [18,19]. These experimental results show the behavior of the combination of DOX with carbon nanostructures, using photothermal therapy, which significantly decreases the adverse effects of the drug.
M.Z. Tonel et al. / Computational and Theoretical Chemistry 1115 (2017) 270–275
271
Nomenclature AIMD BSSE CP DFT DOX DZP GGA
Ab Initio Molecular Dynamics Basis Set Superposition Error Counter Poise approach Density Functional Theory Doxorubicin Double-Zeta plus Polarization Generalized Gradient Approximation
In this paper, by performing ab initio quantum-mechanical electronic structure and ab initio molecular dynamics (AIMD) calculation it is evaluated the structural and electronic properties of DOX interacting with pristine graphene monolayer with the aim to analyze the interaction between the systems.
2. Material and methods The interaction of the DOX with graphene was studied through first-principles calculations with the Density Functional Theory (DFT) framework as implemented in the SIESTA code [20]. In the first part of the work, it was considered double-f plus polarization function (DZP) for the basis set. The exchange-correlation potential was described as a generalized gradient approximation (GGA) as the parameterized by Perdew, Burke and Ernzerhof [21]. The charge density was represented using an energy cutoff of 200 Ry to the grid, in real space integration. The structural optimization was performed by a conjugate gradient method [20] All atoms were allowed to move until the residual forces were less than 0.05 eV/Å. Additionally, to carry out the simulations of graphene with DOX we used periodic boundary conditions, the cell had dimensions of (25.94 40.00 14.98) Å3, also called supercell method. Similar calculations procedures were used in recent works of our group [22,23].
HOMO LUMO SIESTA
Highest Occupied Molecular Orbital Lowest Unoccupied Molecular Orbital Spanish Initiative for Electronic Simulations with Thousands of Atoms.
The calculated binding energies (Ebin) were corrected for the basis set superposition error (BSSE) in all the systems, by using the Boys and Bernardi counterpoise correction (CP) scheme [24]. Following this procedure, the binding energy (Ebin) can be computed by the following expression:
Ebin ¼ fEsys ðrÞ ½Ebasys Eabsys g where Esys stands for the total energy of system DOX-graphene in a given conformation. The terms Eba-sys and Eab-sys were evaluated through a calculation with ghost orbital on parts a and b indicated in the superscript parenthesis, with zero nuclear charge and no electrons, but containing the basis functions of the respective part (a or b), with both parts being placed at the corresponding equilibrium geometry of the system. The values taken as reference for this work, when the binding energy is positive, means that the system is attractive. In the second part of this work, with the aim of studying the interaction of pristine graphene with DOX in different thermodynamic conditions, in particular temperature, it was performed Ab Initio Molecular Dynamics (AIMD) by using the SIESTA code [20]. The evolution of the system in time can be followed by solving a set of classical equations of motion for all particles in the system. Equations of motion were integrated using the velocity Verlet algorithm [25,26]. The simulations were initialized from relaxed (unit
Fig. 1. (a) Ball-and-stick representation of the isolated DOX. (b) Schematic representation of the electronic energy levels of the DOX molecule. Plots of the electronic charge density for: HOMO (c) and LUMO (d) Charge isosurface value is 0.001 eV/Bohr3.
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Fig. 2. (a) Most stable configurations of the DOX interacting with pristine graphene. (b) Electronic band structures for the pristine graphene, levels of isolated DOX and band structures of the DOX interacting with graphene. Electronic charge density plots for: (c) the valence band and (d) conduction band. Charge isosurface value is 0.00001 eV/ Bohr3.
Table 1 Values of distances, binding energies (Ebin), charge transfer (Dq) for the configurations studied. The + signal in the charge transfer indicates that the graphene is a charge donor. Configuration
Distance(Å)
Ebin(eV)
Dq(e)
Conf_1 Conf_2 Conf_3 Conf_4 Conf_5
2.54 2.81 2.87 2.49 2.50
0.40 0.17 0.13 0.19 0.49
+0.04 +0.04 0.02 +0.07 0.20
cell and atomic positions) configurations (forces and stress). The AIMD used a temperature controlled Nosé thermostat (T = 50 K, 100 K and 300 K and a generalized Nosé mass Q = 10 Ry.fs2) and a time step of 0.5 fs [27,28]. 3. Results and discussion The structural properties of graphene as a two-dimensional planar geometry show potential applications to adsorb molecules on its
surface [22]. The DOX is an interesting molecule that can be associated with graphene nanostructure in this context. In this way, initially it is analyzed the isolated DOX molecule [C27H29NO11]. In Fig. 1(a), we present a ball-and-stick view of the optimized structure of the DOX molecule. In Fig. 1(b–d), we show the density of states of the isolated molecule and electronic charge densities plots of the HOMO (Highest Occupied Molecular Orbital) and LUMO (Lowest Unoccupied Molecular Orbital). The GGA-PBE calculated difference between the HOMO and the LUMO was approximately 1.96 eV. Moreover, we verified that the HOMO is concentrated in the planar portion of the molecule as well as in the nitrogen atom, whereas the LUMO is in the planar portion and in the carbon atom, opposite to the nitrogen. Different configurations of DOX interacting with graphene (Fig. 2(a)) were analyzed based on the charge density of the molecule studied (Fig. 1(c,d)). The configuration that presented greater stability was when the planar part of the molecule interacted with the graphene. This can be justified by the p p type interactions that occur. The electronic band structures of the five configurations studied are shown in Fig. 2(b), the red dotted line represents the
M.Z. Tonel et al. / Computational and Theoretical Chemistry 1115 (2017) 270–275
273
Fig. 3. Average distance from DOX to single layer graphene obtained from AIMD calculations considering the temperatures: (a) 50 K, (b)100 K and (c) 300 K. The insets are ball-and-stick representations of the selected geometries along the respective simulation.
Fermi energy. Electronic energy bands show that the levels remain unchanged, indicating that there was a weak interaction between the systems, as physical adsorption. In Fig. 2(b), the charge density of the system more stable DOX parallel interacting with the graphene is shown (+ DOX configuration Graphene-5). In this case, the binding energy is 0.49 eV and the shortest distance between the graphene and DOX is 2.50 Å. As noted in Fig. 2(c,d), the charge distribution is evenly in both conduction and valence bands of graphene. In the Table 1, we show the respective binding energies, bond lengths and charge transfer for each configuration studied. Positive values of binding energy indicate that there is attraction between the DOX and graphene. Moreover, positive (negative) Dq indicates
that there is charge transfer from graphene (DOX) to DOX (graphene). The electronic band structures of the considered conformations are shown in Fig.2(b). The red dotted horizontal line indicates the Fermi energy. The results show no significant changes in the neighborhood of the Fermi level, indicating a weak interaction between the DOX molecule and a monolayer graphene, as observed on the energy values. In Fig. 2(b), the charge density of the most stable system with DOX parallel the graphene is shown (+ DOX configuration Graphene-5). In this case, the binding energy is about 0.5 eV and the shortest distance between the graphene and DOX is 2.50 Å. As noted in Fig. 2 (c,d), the concentrated charge is homogeneously
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evenly in both the conduction band and the valence band in the graphene. To perform ab initio molecular dynamics (AIMD) we considered only the most stable configuration, that is, when the aromatic rings of molecule are parallel to the single layer graphene. To this investigation, three different temperatures are considered as 50, 100 and 300 K. In the Fig.3 it is presented the average distance between the DOX and the monolayer graphene obtained from AIMD calculations considering the temperatures: (a)50 K, (b)100 K and (c) 300 K. The average distance, for each step, was obtained by calculating:
Av eragedistance ¼ f½dzðDOXÞ=NDOX ½dzðgrapheneÞ=Ngraphene g; where dz(DOX/graphene) stands for the sum of the z-component of all atoms from DOX molecule (or graphene) and N(DOX/graphene) is the number of the atoms from DOX molecule (or graphene). As a function of the increasing of the temperature, the average distance goes from 4.8 to 5.0 Å, indicating that the interaction between the DOX and graphene decrease as a function of the temperature. In Fig. 3, we can also verify that oscillations in the value of the average distance occur during the simulation. These oscillations were verified for all investigated temperatures. Since the AIMD simulations are performed at finite temperatures, as a function of the temperature, occurs an increasing of the atomic vibrations of both molecule and graphene. The DOX intermolecular vibrational normal modes induce an increasing in the distance between the DOX molecule and graphene. Regarding graphene, the atomic vibrations can generated a local corrugation (see insets in Fig. 3), due to out-ofplane normal modes, also contributing to the increasing the molecule-graphene distance, as a function of the temperature. We also verified that the calculations of AIMD agree with the experiment performed by Zhang et al. [18]. They observed that as a function of the temperature occurred a withdrawal of the DOX molecule from the graphene, indicating a drug releasing. These results agree with experimental studies showing the withdrawal of DOX with the temperature. 4. Final remarks In this work we performed first-principles calculations, based on DFT framework, as implemented in SIESTA code, to analyze the structural and electronic properties of a system composed by pristine graphene and DOX molecule. The results show that pristine graphene interacts with DOX by a physical adsorption with a binding energy of 0.49 eV. The shortest distance between the atoms of the graphene DOX was 2.50 Å. Moreover, the calculations indicate that the most stable configuration is when the DOX molecule is parallel to the graphene. There are no significant changes in the band structures of the pristine graphene indicating a physical adsorption (interaction) of graphene and DOX molecule. The results of the AIMD show that with the increase in temperature, a withdrawal of DOX indicates a weak interaction. The physical adsorption, without electronic and chemical structural modifications, and the decrease of the interaction as a function of the temperature between the DOX molecule and the pristine graphene can be suggested as an indicative as drug releasing with temperature control. Acknowledgements The authors are grateful to CNPq-Brazil and CAPES-Brazil for financial support and fellowships and the CENAPAD-SP for the computational support.
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Contents lists available at ScienceDirect
Computational and Theoretical Chemistry journal homepage: www.elsevier.com/locate/comptc
A first-principles study of the interaction of doxorubicin with graphene Mariana Zancan Tonel a, Mirkos Ortiz Martins a, Ivana Zanella a, Renato Borges Pontes b, Solange Binotto Fagan a,⇑ a b
Centro Universitário Franciscano, ZIP 97010-032, Santa Maria, RS, Brazil Universidade Federal de Goiás, Campus Samambaia, ZIP 74690-900, Goiânia, GO, Brazil
a r t i c l e
i n f o
Article history: Received 17 February 2017 Received in revised form 5 July 2017 Accepted 6 July 2017 Available online 8 July 2017 Keywords: Graphene Doxorubicin Density functional theory Temperature Computational simulations
a b s t r a c t Graphene is a single layer of graphite whose carbon atoms are arranged in a hexagonal form. On the other side, doxorubicin (DOX) is a drug widely used for the treatment of various cancer diseases. In this work, we performed calculations within the Density Functional Theory (DFT) framework in order to obtain both structural and electronic properties of the graphene interacting with DOX. The results show that, in the most stable conformation, DOX interacting with pristine graphene has a binding energy of approximately 0.5 eV. Likewise, it was also verified that no major changes in the intrinsic electronic properties of graphene. Ab Initio Molecular Dynamics (AIMD) calculations show that, even at room temperature (300 K), there is a weak interaction between graphene and DOX. Ó 2017 Elsevier B.V. All rights reserved.
1. Introduction Since its isolation in 2004, graphene has attracted great interest from the scientific community due to its amazing structural and electronic properties [1]. Being a material with one atom thick, it offers a wide range of applications. Some potential graphene applications are, among other: display screens, electric circuits, solar cells, biomedical and chemical sensors [2]. Regarding the biological and biomedical applications, not only graphene, but also, carbon-based materials such as fullerenes and carbon nanotubes, due to its physical-chemical characteristics, have great potential for applications [3]. In recent years, these systems have been studied for drug delivery and biomedical images [4–6]. Besides, due to its strong absorbance in the infrared, they have been studied as photothermal agents for cancer treatment [7]. Graphene is a material with a thickness atom. 2D scale features, i.e., the electrons are free in two directions and confined in one direction, this fact makes it has a large surface area, which develops a variety of possible applications [8]. Also, has electrical and thermal conductivity and is transparent to visible light [9]. Due to its characteristics open the possibility of applications including for vitamins entrainment [10,11], and drugs for cancer therapy.
⇑ Corresponding author. E-mail addresses: [email protected] (M.Z. Tonel), [email protected] (M.O. Martins), [email protected] (I. Zanella), renatoborgespontes@gmail. com (R.B. Pontes), [email protected] (S.B. Fagan). http://dx.doi.org/10.1016/j.comptc.2017.07.004 2210-271X/Ó 2017 Elsevier B.V. All rights reserved.
On the other side, chemotherapy is one of the main forms of treatment for cancer. For this kind of treatment, some chemotherapeutic agents are used. The DOX, in particular, is one of the most effective chemotherapeutic agents for the treatment of cancer among them: breast, ovary, sarcomas, pediatric solid tumors, Hodgkin’s disease, multiple myeloma and non-Hodgkin’s lymphoma [12]. However, the undesirable side effects of the chemotherapeutic are due to their high toxicity, affecting mainly the cardiovascular system by causing hypotension, tachycardia, ventricular dilation and heart failure [13]. The combination of carbon nanomaterials with DOX has already been experimentally investigated [3,14,15]. Also, theoretical studies involving DOX and carbon nanotubes already exist in the literature [16] and the results show that there is a negligible charge transfer between the components of typical non-covalent interaction, being ideal for DOX molecules are easily released from the nanotube. All the points mentioned above raise questions about the interaction of graphene and DOX. The combination of graphene with DOX has a great potential for applications in medicine as an adjuvant agent in the treatment of cancer [17]. The evaluation of the physical properties resulting from this interaction is very important and interesting because it can be related to existing experimental data [18,19]. These experimental results show the behavior of the combination of DOX with carbon nanostructures, using photothermal therapy, which significantly decreases the adverse effects of the drug.
M.Z. Tonel et al. / Computational and Theoretical Chemistry 1115 (2017) 270–275
271
Nomenclature AIMD BSSE CP DFT DOX DZP GGA
Ab Initio Molecular Dynamics Basis Set Superposition Error Counter Poise approach Density Functional Theory Doxorubicin Double-Zeta plus Polarization Generalized Gradient Approximation
In this paper, by performing ab initio quantum-mechanical electronic structure and ab initio molecular dynamics (AIMD) calculation it is evaluated the structural and electronic properties of DOX interacting with pristine graphene monolayer with the aim to analyze the interaction between the systems.
2. Material and methods The interaction of the DOX with graphene was studied through first-principles calculations with the Density Functional Theory (DFT) framework as implemented in the SIESTA code [20]. In the first part of the work, it was considered double-f plus polarization function (DZP) for the basis set. The exchange-correlation potential was described as a generalized gradient approximation (GGA) as the parameterized by Perdew, Burke and Ernzerhof [21]. The charge density was represented using an energy cutoff of 200 Ry to the grid, in real space integration. The structural optimization was performed by a conjugate gradient method [20] All atoms were allowed to move until the residual forces were less than 0.05 eV/Å. Additionally, to carry out the simulations of graphene with DOX we used periodic boundary conditions, the cell had dimensions of (25.94 40.00 14.98) Å3, also called supercell method. Similar calculations procedures were used in recent works of our group [22,23].
HOMO LUMO SIESTA
Highest Occupied Molecular Orbital Lowest Unoccupied Molecular Orbital Spanish Initiative for Electronic Simulations with Thousands of Atoms.
The calculated binding energies (Ebin) were corrected for the basis set superposition error (BSSE) in all the systems, by using the Boys and Bernardi counterpoise correction (CP) scheme [24]. Following this procedure, the binding energy (Ebin) can be computed by the following expression:
Ebin ¼ fEsys ðrÞ ½Ebasys Eabsys g where Esys stands for the total energy of system DOX-graphene in a given conformation. The terms Eba-sys and Eab-sys were evaluated through a calculation with ghost orbital on parts a and b indicated in the superscript parenthesis, with zero nuclear charge and no electrons, but containing the basis functions of the respective part (a or b), with both parts being placed at the corresponding equilibrium geometry of the system. The values taken as reference for this work, when the binding energy is positive, means that the system is attractive. In the second part of this work, with the aim of studying the interaction of pristine graphene with DOX in different thermodynamic conditions, in particular temperature, it was performed Ab Initio Molecular Dynamics (AIMD) by using the SIESTA code [20]. The evolution of the system in time can be followed by solving a set of classical equations of motion for all particles in the system. Equations of motion were integrated using the velocity Verlet algorithm [25,26]. The simulations were initialized from relaxed (unit
Fig. 1. (a) Ball-and-stick representation of the isolated DOX. (b) Schematic representation of the electronic energy levels of the DOX molecule. Plots of the electronic charge density for: HOMO (c) and LUMO (d) Charge isosurface value is 0.001 eV/Bohr3.
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Fig. 2. (a) Most stable configurations of the DOX interacting with pristine graphene. (b) Electronic band structures for the pristine graphene, levels of isolated DOX and band structures of the DOX interacting with graphene. Electronic charge density plots for: (c) the valence band and (d) conduction band. Charge isosurface value is 0.00001 eV/ Bohr3.
Table 1 Values of distances, binding energies (Ebin), charge transfer (Dq) for the configurations studied. The + signal in the charge transfer indicates that the graphene is a charge donor. Configuration
Distance(Å)
Ebin(eV)
Dq(e)
Conf_1 Conf_2 Conf_3 Conf_4 Conf_5
2.54 2.81 2.87 2.49 2.50
0.40 0.17 0.13 0.19 0.49
+0.04 +0.04 0.02 +0.07 0.20
cell and atomic positions) configurations (forces and stress). The AIMD used a temperature controlled Nosé thermostat (T = 50 K, 100 K and 300 K and a generalized Nosé mass Q = 10 Ry.fs2) and a time step of 0.5 fs [27,28]. 3. Results and discussion The structural properties of graphene as a two-dimensional planar geometry show potential applications to adsorb molecules on its
surface [22]. The DOX is an interesting molecule that can be associated with graphene nanostructure in this context. In this way, initially it is analyzed the isolated DOX molecule [C27H29NO11]. In Fig. 1(a), we present a ball-and-stick view of the optimized structure of the DOX molecule. In Fig. 1(b–d), we show the density of states of the isolated molecule and electronic charge densities plots of the HOMO (Highest Occupied Molecular Orbital) and LUMO (Lowest Unoccupied Molecular Orbital). The GGA-PBE calculated difference between the HOMO and the LUMO was approximately 1.96 eV. Moreover, we verified that the HOMO is concentrated in the planar portion of the molecule as well as in the nitrogen atom, whereas the LUMO is in the planar portion and in the carbon atom, opposite to the nitrogen. Different configurations of DOX interacting with graphene (Fig. 2(a)) were analyzed based on the charge density of the molecule studied (Fig. 1(c,d)). The configuration that presented greater stability was when the planar part of the molecule interacted with the graphene. This can be justified by the p p type interactions that occur. The electronic band structures of the five configurations studied are shown in Fig. 2(b), the red dotted line represents the
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Fig. 3. Average distance from DOX to single layer graphene obtained from AIMD calculations considering the temperatures: (a) 50 K, (b)100 K and (c) 300 K. The insets are ball-and-stick representations of the selected geometries along the respective simulation.
Fermi energy. Electronic energy bands show that the levels remain unchanged, indicating that there was a weak interaction between the systems, as physical adsorption. In Fig. 2(b), the charge density of the system more stable DOX parallel interacting with the graphene is shown (+ DOX configuration Graphene-5). In this case, the binding energy is 0.49 eV and the shortest distance between the graphene and DOX is 2.50 Å. As noted in Fig. 2(c,d), the charge distribution is evenly in both conduction and valence bands of graphene. In the Table 1, we show the respective binding energies, bond lengths and charge transfer for each configuration studied. Positive values of binding energy indicate that there is attraction between the DOX and graphene. Moreover, positive (negative) Dq indicates
that there is charge transfer from graphene (DOX) to DOX (graphene). The electronic band structures of the considered conformations are shown in Fig.2(b). The red dotted horizontal line indicates the Fermi energy. The results show no significant changes in the neighborhood of the Fermi level, indicating a weak interaction between the DOX molecule and a monolayer graphene, as observed on the energy values. In Fig. 2(b), the charge density of the most stable system with DOX parallel the graphene is shown (+ DOX configuration Graphene-5). In this case, the binding energy is about 0.5 eV and the shortest distance between the graphene and DOX is 2.50 Å. As noted in Fig. 2 (c,d), the concentrated charge is homogeneously
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evenly in both the conduction band and the valence band in the graphene. To perform ab initio molecular dynamics (AIMD) we considered only the most stable configuration, that is, when the aromatic rings of molecule are parallel to the single layer graphene. To this investigation, three different temperatures are considered as 50, 100 and 300 K. In the Fig.3 it is presented the average distance between the DOX and the monolayer graphene obtained from AIMD calculations considering the temperatures: (a)50 K, (b)100 K and (c) 300 K. The average distance, for each step, was obtained by calculating:
Av eragedistance ¼ f½dzðDOXÞ=NDOX ½dzðgrapheneÞ=Ngraphene g; where dz(DOX/graphene) stands for the sum of the z-component of all atoms from DOX molecule (or graphene) and N(DOX/graphene) is the number of the atoms from DOX molecule (or graphene). As a function of the increasing of the temperature, the average distance goes from 4.8 to 5.0 Å, indicating that the interaction between the DOX and graphene decrease as a function of the temperature. In Fig. 3, we can also verify that oscillations in the value of the average distance occur during the simulation. These oscillations were verified for all investigated temperatures. Since the AIMD simulations are performed at finite temperatures, as a function of the temperature, occurs an increasing of the atomic vibrations of both molecule and graphene. The DOX intermolecular vibrational normal modes induce an increasing in the distance between the DOX molecule and graphene. Regarding graphene, the atomic vibrations can generated a local corrugation (see insets in Fig. 3), due to out-ofplane normal modes, also contributing to the increasing the molecule-graphene distance, as a function of the temperature. We also verified that the calculations of AIMD agree with the experiment performed by Zhang et al. [18]. They observed that as a function of the temperature occurred a withdrawal of the DOX molecule from the graphene, indicating a drug releasing. These results agree with experimental studies showing the withdrawal of DOX with the temperature. 4. Final remarks In this work we performed first-principles calculations, based on DFT framework, as implemented in SIESTA code, to analyze the structural and electronic properties of a system composed by pristine graphene and DOX molecule. The results show that pristine graphene interacts with DOX by a physical adsorption with a binding energy of 0.49 eV. The shortest distance between the atoms of the graphene DOX was 2.50 Å. Moreover, the calculations indicate that the most stable configuration is when the DOX molecule is parallel to the graphene. There are no significant changes in the band structures of the pristine graphene indicating a physical adsorption (interaction) of graphene and DOX molecule. The results of the AIMD show that with the increase in temperature, a withdrawal of DOX indicates a weak interaction. The physical adsorption, without electronic and chemical structural modifications, and the decrease of the interaction as a function of the temperature between the DOX molecule and the pristine graphene can be suggested as an indicative as drug releasing with temperature control. Acknowledgements The authors are grateful to CNPq-Brazil and CAPES-Brazil for financial support and fellowships and the CENAPAD-SP for the computational support.
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