A DFT approach to the adsorption of the Levodopa anti-neurodegenerative drug on pristine and Al-doped boron nitride nanotubes as a drug delivery vehicle

The adsorption behavior of the anti-neurodegenerative drug Levodopa (LD) on pristine and aluminum-doped (Al-doped) boron nitride nanotubes (BNNTs) has been investigated in the current study using the density functional theory (DFT) approach at the B3LYP/6-31G** level of theory. The aim was to improve and expand boron nitride nanotubes drug carriers used in biomedical systems, i.e., drug delivery systems. The binding qualities of pure and doped BNNT complexes as adsorbents with LD were explored using the natural bond orbitals (NBO) analysis, density of state (DOS), electrical and structural characteristics, and atoms in molecules (AIM) properties. Due to doping heteroatoms in the adsorbent's molecular structure, the obtained data reveal a gradual shift in LD adsorption, with a significant rise in negative adsorption energy values. The electronic perturbation caused by doped atoms, particularly Al, improves boron nitride nanotube sensitivity to adsorbed Levodopa, and the electronic properties of the nanotubes are altered following Levodopa adsorption in the complex. As the frontier molecular orbital distributions were transferred from LD to BNNTs in the complex of BNNT–LD, it was also shown that LD drugs could be loaded on pristine and Al-doped BNNTs while remaining safe from interactions with other substances. Furthermore, AIM analysis based investigations revealed that O–Al interaction in LD adsorbed on Al-doped boron nitride nanotube and O–N interaction in the BNNT–LD complex are partially covalent. Finally, the findings showed that pristine and Al-doped BNNT could be used in drug delivery processes by controlling the loaded LD contribution to future interactions.


Introduction
Non-carbon and carbon nanomaterials differ in terms of their structure. Iijima and Ichihashi discovered carbon nanotubes (CNTs) in Soot from carbon discharged in a neon-rich media [1]. Because of their needle-like structure, CNTs may pass through cell membranes [2]. Given that characteristics of CNTs are determined by the chiral features and diameter of the nanotube, different efforts have been conducted since 1991 to find non-carbon materials.
Afterward, some researchers produced boron nitride nanotubes (BNNTs) in 1995 for the first time [3,4]. Because of the nanotube walls' strong sp3 bonding, these nanotubes have outstanding mechanical properties, similar to CNTs [5,6]. Electrical and mechanical properties of BNNTs encompass a vast band gap (3.5-5.5 eV) [7], high oxidation resistance [8,9], excellent piezoelectric characteristics, and high thermal and chemical stability [10]. Owing to their unique mechanical characteristics and high thermal conductivity, they can be applied to diagnose and treat diseases, and moreover, are useful in sensor-based applications [11]. Considering that BNNTs are water-insoluble, hydrophobic, and oxidation-resistant, they can be employed as drug carriers [12], are also non-toxic to cells, and do not impact DNA [13]. As a result, it is critical to learn more about BNNTs' drug delivery capabilities and how they might be used in medicine.

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In the last two decades, theoretical research on nanostructures in the density functional theory (DFT) framework has sparked a lot of interest. Bououden investigated the interactions of carbon and boron nitride nanotubes with the Crizotinib medicine in 2021 [14]. 5-Fluorouracil adsorption and sensing on Ni-doped boron nitride nanotube were investigated via DFT by Yuksel et al. [15]. The relationship between BNNTs and anticancer drug betulinic acid and its analogue 3-o-acetyl-betulinic acid has been studied by Poorsargol using DFT simulations [16]. Likewise, Nafiu et al. examined the structural and electrical characteristics of (5,5) armchair the outer and inner surfaces, curcumin molecule-interacting chirality single walls BNNTs via DFT [17]. Recently, the interaction between the sulfanilamide drug and B12N12 and Al12N12 Fullerenes was investigated by Azarakhshi et al. [18]. That boron nitride nanotubes have been vastly employed paves the way for more studies into similar structures in the future.
For Parkinsonism, a degenerative neurological condition, Levodopa (LD) has been the gold standard symptomatic replacement treatment over the last 40 years. Dyskinesia, a kind of motor dysfunction produced by the brain's discontinuous and intermittent supply of Levodopa, is a common complication of long-term therapy, leading to pulsatile activation of striatal dopamine receptors that is not physiological [19,20]. It was also found that upon 5 and 10 years of treatment with Levodopa (the honeymoon period), respectively, 40 and over 80% of patients with Parkinson's disease develop dyskinesia [21]. Given their controlled release properties, nanotubes make a great contribution to drug delivery, and it is for this reason that lowering dopaminergic neurons' pulsatile stimulation is expected to reduce dyskinesia caused by Levodopa [22].
DFT simulations were utilized to investigate the structure, energy, and electronic characteristics of Levodopa molecules that interacted with the BNNTs in this study. One method to enhance BNNTs' capacity for adsorption is substitutional doping. According to previous studies [23][24][25][26], Al-doping increased the adsorption energy of BNNT (also single wall carbon nanotube [27]). For this reason, Al-doped BNNT looks like a logical option to investigate. Aluminum atom was used to replace one of the boron atoms in the middle of the tube, and both the structure of the compound and its complex with Levodopa were fully optimized. Bader's quantum theory of atoms in molecules (AIM) was applied to understand more regarding the nature of the relationships and the electron concentrations at bond crucial areas [28]. Natural atomic orbital occupancies and charge transfer were also calculated using the natural bond orbital analysis (NBO) [29].

Computational methods
In this computational study, we selected (7,0) BNNTs including 24 Nitrogen, 24 Boron atoms and 12 Hydrogen. Geometry optimizations, electronic structure computations, density of states (DOS) analysis, and molecule electrostatic potential (MEP) analysis were all performed using the B3LYP approach for all of the systems under investigation [30][31][32] and 6-31G ** basis set using the Gaussian09 software [33]. The dopant atom (Al) in this study comes from the third group of the periodic table of elements. GaussView 5.0.8, a molecular visualization tool, was used to examine the optimized structures [34]. Vibrational frequencies at the B3LYP/6-31G ** level were exploited to indicate that the ensuing patterns fit the energy minima. Likewise, The findings on DOS and molecular orbital energies, Highest occupied molecular orbital (HOMO) and Lowest unoccupied molecular orbital (LUMO), came from the Gauss-Sum 2.2 program [35]. After full optimization of the considered structures, we evaluated the adsorption energy (E ad ) of adsorbate molecule according to the following equation: where E (BNNT−LD) denotes the total energy of the complex generated when one molecule of Levodopa is adsorbed on the surface of BNNTs, and E BNNT and E LD , respectively, represent BNNTs and Levodopa molecules' total energies. The exothermic adsorption process corresponds to negative E ad values by definition.
For the evaluated systems, electronic characteristics like molecular orbitals (MO) were calculated, e.g., and LUMO and HOMO. The energy gap in a system's energy levels (E g ) were estimated as The DFT method is used to calculate the global and local indices of reactivity, as well as electron affinity (A) and the ionization potential (I) [36]: Chemical hardness (η), chemical softness (S), electrophilicity (ω), and electronic chemical potential (μ) are all regarded as global descriptors, respectively. The tendency of electrons to exit equilibrium systems is referred to as chemical potential [37]: A system's hardness is a measurement of its resistance to electron transport; thus high hardness values suggest that the system is tougher, more stable, and less reactive [37,38]: Global softness is the inverse of hardness, meaning that high global softness values are indicative of less stability and a proclivity to react with other molecules [37]: Exchange of electrons is local electrophilicity (ω) [39]: The natural bond orbital analysis, on the other hand, was used to compute the second-order perturbation energy and investigate the stability of the complex formed by charge transfer. Further topological parameters including the electronic energy density (Hc) at the bond critical points (BCP), Fig. 1 The optimized structure and density of states (DOSs) of BNNTs using B3LYP/6-31G **  plus the electron density distribution (ρ c ) and Laplacian of electron density ( ∇ 2 C ), are significant and useful in classifying the nature of interactions. Thus, the AIM method was used to analyze the electron density and bonding characteristics of the systems [40].
At the bond critical point, H C is an excellent index for bonding interactions [41]: Electronic potential and electronic kinetic energy densities, respectively, are V C and K C . According to the virial theorem, the Laplacian of electronic density is proportional to the bond interaction energy and is defined as Overall, Laplacian of ∇ 2 C < 0 negative value at the bond critical point denotes the electron charge concentration in atoms-contacting nuclei, and moreover, indicates a covalent bond interaction. The electron charge is reduced between the atoms when ∇ 2 C > 0 and Hc > 0, suggesting an electrostatic (noncovalent) contact.
The LD molecule adsorption to the surface of a Al B , and b Al N -BNNTcomplex' optimized geometry

Optimized structures and binding energy analysis
The optimized structure and DOS plot of BNNTs using B3LYP and 6-31G ** basis set without any symmetry constraint is shown in Fig. 1. The energy gap (E g ) of the BNNTs [the energy difference between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO)] is about 4.911 eV, implying that it is a semiconductor.
Determination of the stable configurations of LD molecule adsorbed on the boron nitride nanotubes was used regarding the molecular electrostatic potential (MEP) plot of LD which is shown in Fig. 2.
The electron density of the O atoms of the Levodopa molecule is reactive sites (partial negative charge, red color) as shown by the MEP plot and structural parameters, allowing a Levodopa molecule to approach the BNNTs. As a result, the Levodopa molecule can approach the single-walled BNNTs in a variety of ways. Between the full optimized initial structures of BNNT-LD complex, one of them is more stable (E ad − 19.13 kcal/mol) and is the best candidates for the considered adsorption of Levodopa molecule onto BNNTs (Fig. 3).
Considering chemical structure of BNNTs, we chose to evaluate the effect of BNNTs structural change on the adsorption of Levodopa in comparison to its pure form.
To do such a doping, we replaced one of the B atoms and one of the N on the wall with aluminum dopant containing more metallic characteristic. Figure 4 presents the optimized outcomes.
The doped aluminum atom, as seen, moves away from ideal lattice site, causing the local distortion of the tube. This is the collective structural change. The existence of two types of B-N bonding in pure boron nitride nanotubes, one parallel to the tube axis and the other oblique to it, is widely known. The intrinsic boron nitride nanotube's B-N bond, which runs parallel to the tube axis, increases from 1.44˚A to 1.76˚A when a B atom of BNNTs is replaced by an Al atom (see Fig. 4a). The B-N bond is pulled away from the tube wall and its length dramatically increases to 2.039˚A when an Al atom replaces one of the N atoms. Furthermore, the adsorption energy (E ad ) of the pure BNNT-Levodopa, Al B -BNNT-Levodopa and Al N -BNNT-Levodopa are calculated to be about − 19.13, − 31.24, and − 8.96 kcal/mol, respectively. Thus, we concluded that the effect of a B atom is substituted by the aluminum atom on the geometrical and adsorption energy of pristine BNNTs is more significant than that of a N atom is substituted by Al atom.
More information that has been obtained upon our calculation about different configurations of Levodopa-BNNT and Levodopa-Al B -doped BNNT complexes such as total energy (E total ), and charge transfers (Q T ), is summarized in Table 1.
The most stable configuration is linked to the strong interaction of the Levodopa molecule with the Al B -doped nanotube, as shown in Table 1. The computed value of E ad for this configuration is − 31.24 kcal/mol.

Electronic properties
The values of LUMO and HOMO, and the discrepancies in the HOMO-LUMO gap (E g ), ionization potential (I), chemical potential (μ), electron affinity (A), chemical hardness (η), and electrophilicity (ω) are all provided in Table 2.
When the Levodopa molecule, which adhered to the nanotube, was absorbed, the difference of the HOMO and LUMO levels decreased in comparison to the same value for the pure nanotube. Moreover, as BNNTs and the Levodopa interacted, this difference experienced the greatest decrease, attributable to adsorption of energy by molecules at this site.
Al doping reduced the energy gap. When E g was reduced, the electrical conductivity improved, which increased the metal characteristics of the doped nanotube relative to the pure BNNTs.
The DOS plot were examined in order to more closely examine these changes within the electron configurations (Fig. 5). It indicates that the energy gap of molecular structures can be determined using DOS plot [42].
For all adsorptions, the values of the energy parameters provided in Table 2 agree with the DOS diagram. In comparison to Al B -BNNTs, the bulk of the alterations in the DOS plot were also found. In other words, the adsorption energies were directly proportional to changes in the electron structure. With regard to the amount of adsorption energy and the DOS plot patterns seen in all cases, it can be assumed that the Levodopa molecule adsorption onto the BNNTs and its Al B -doped derivatives was chemical.

Natural bond orbital analysis
To have a better grasp of charge transfer as well as the of electron density delocalization between empty, non-Lewis acceptor NBOs (Rydberg and antibonding) and filled, non-Lewis acceptor NBOs (lone pair or bonding), it was crucial to calculate the natural bonding orbitals (NBOs).
Also, second-order perturbation theory can be utilized to predict the interaction energy between full and empty orbitals [43]. The following equation, if used for each donor NBO(i) and acceptor NBO(j), can help compute the donor-acceptor stabilization energy E (2) , related to the electron delocalization i → j [44]: The diagonal elements (orbital energies) are denoted by εi and εj, the donor orbital occupancy is represented by ni, and the off diagonal NBO Fock matrix element is F (i,j).
It was also shown that as the interaction energy E (2) increased, so did the contact between electron-doning and electron-accepting elements. The NBO, for the most stable configuration, was analyzed at the B3LYP/6-31G ** level via the stability energies E (2) , occupational values, and electron density delocalization for lone pair oxygen atoms electrons (Lewis type).
The computed second-order perturbation interaction energy E (2) for the Levodopa/BNNT complex varied between 0.28 and 10.24 kcal/mol (Table 3). It was discovered that electron transfer was a critical element in aiding molecule adsorption on the adsorbent. Higher E (2) values for Levodopa adsorption onto BNNTs were also shown to result in increased interaction between the Levodopa and BNNT molecules. The obtained results indicated that the total energy for LP(1) O 79 → BD * (1) N 43 -B 44 is E (2) = 10.24 kcal/mol. Drug molecules, according to the E (2) energy levels in this scenario, acted as electron donors, whereas BNNTs operated as acceptors in general.

Atoms in molecules analysis
Bader's theory was employed to investigate bond critical points features and to acquire a straight forward understanding of the vigor and type of interactions. A bond route inside the equilibrium molecular structure is referred to as an interatomic interaction line. In fact, some parameters like electron density at the donor-acceptor BCP (ρ c ) and Table 3 Results of second-order perturbation theory analysis of the NBO for the most stable configuration of the BNNT-LD complex at the level of B3LYP/6-31G **

Donor NBO (i)
Acceptor NBO (j) E (2)   its ( ∇ 2 ρ c ) are helpful to explore associated bond energies and the nature of the interactions [45]. Figure 6, comprising the BNNT-LD complex the molecular graph, illustrates all critical sites as well as the bond routes between the acceptor and donor. The important parameters obtained from AIM analysis and the types of bond formed between BNNTs and LD drug are summarized in Table 4.
According to Table 4, the computed electron densities at the N 47 ···H 73 -O 72 , N 43 ···O 79 , and N 42 ·H 80 -O 79 bond critical points for the BNNT-LD complex are discovered to be about 0.0031, 0.0014, 0.0044 a.u., respectively. The value of ( ∇ 2 ρ c ) confirms that the foremost stable configuration is achieved when Levodopa interacts from its O site with the N site of the single-walled BNNTs. As also is apparent from Table 4, examining path N 42 ···H 80 -O 79 demonstrations that the interface has positive ( ∇ 2 ρ c ) value and negative H C value. These options are an instance of a partial covalent interaction. In summary, the single-walled BNNTs can concentrate electrons at the bond critical points that are sensitive to the interaction sites.

Conclusion
Density functional computations were performed to evaluate the adsorption of Levodopa molecules of varying directions to BNNTs and its Al-doped variants in this study. The DFT/ B3LYP approach was employed since it allows for more easy and accurate estimation of the electron density surface of a large molecule system. The DFT method highlights the major stability and reactivity properties of molecular structure. The same results were suggested by all the analyses as shown below: 1. Al atoms can be substituted by BNNTs atoms through chemical bonds, as a result of which the BN nanotubes' chemical, electrical, and mechanical structures are considerably altered. 2. Al-doped BNNT has a comparatively high adsorption energy than pure BNNTs derivatives. Since the contact in this case comprises chemical adsorption, this Al-doped boron nitride nanotube would be an ideal sensor solution. Fig. 6 Molecular graph of BNNT-LD complex. The graph was obtained at the B3LYP/6-31G ** level. Bond critical points is represented by big and small spheres small, respectively (red circle is bond critical points). The lines are bond paths 3. The Levodopa molecule's adsorption energy on BNNTs and Al-doped BNNT ranges from − 19.13 to − 31.24 kcal/mol, respectively. 4. LD adsorption on the surfaces of BNNTs and Al-doped BNNT changes the energy levels of HOMO and LUMO, as well as their E g . 5. The outcomes of the analysis of charge on the basis of NBO showed that a charge value of nearly 0.02|e| and 0.41|e| is transferred from the Levodopa molecule to the pristine and Al-doped BNNT. 6. Finally, AIM analysis indicated that the interaction of Levodopa molecule with single-walled BNNTs is more partially covalent in nature. Our findings indicate that BNNTs can be an efficient adsorbent in medication delivery when compared to the Levodopa molecule. It is hoped that the new nanotubes would be effective in treating Parkinson's disease.