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Molecular dynamics study on loading mechanism of chitosan into boron nitride nanotubes
MOLLIQ-111753; No of Pages 7 Journal of Molecular Liquids xxx (xxxx) xxx
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Molecular dynamics study on loading mechanism of chitosan into boron nitride nanotubes Jiachen Li a, Chen Chen a, Jin Zhang a, Li Zhang a, ∗, Lijun Liang b, Zhe Kong c, ∗∗, Shen Jia-Wei d, Yunxia Xu a, Xinping Wang a, Wei Zhang a a
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, 310018, People's Republic of China College of Life Information Science and Instrument Engineering, Hangzhou Dianzi University, Hangzhou, 310018, People's Republic of China College of Material & Environmental Engineering Science Hangzhou Dianzi University, Hangzhou, 310018, People's Republic of China d School of Medicine, Hangzhou Normal University, Hangzhou, 310016, People's Republic of China b c
a r t i c l e
i n f o
Article history: Received 28 June 2019 Received in revised form 10 September 2019 Accepted 14 September 2019 Available online xxxx Keywords: Molecular dynamics simulation Drug delivery systems Chitosan Loading mechanism Boron nitride nanotubes
a b s t r a c t Boron nitride nanotubes (BNNTs) have been considered as one of the most promising materials in drug delivery systems. It is important to understand the interaction mechanism between chitosan and BNNTs from atomic level. Herein, molecular dynamics (MD) simulation were employed to investigate the interaction mechanism and loading mechanism of chitosan into/onto BNNTs. The effect of functional group in chitosan and the diameter of BNNTs on the interaction mechanism between BNNTs and chitosan were discussed. It is found that chitosan can only absorb on the outer surface of BNNT (12,12) owing to the size of chitosan and its solvent layer. The loading process of chitosan with –NH2 group (CS_A10) into the BNNT (14,14) is much easier than that for –NH+ 3 group system (CS_B10). The different loading dynamics for CS_A10/CS_B10 were explained from Gibbs free energy as well as the solvation behavior of chitosan chains. © 2019 Elsevier B.V. All rights reserved.
1. Introduction Boron nitride nanotubes (BNNTs) have been considered as one of the most promising materials in drug delivery systems owing to their unique physical and chemical properties [1–4]. As one kind analogues of carbon nanotubes (CNTs), BNNTs show better biocompatibility and lower cytotoxicity compared with CNTs [5–8]. For instance, Li et al. reported that the proliferation of human primary mammary fibroblasts and the transformed mammary cell line could be improved by film constructed by BNNTs [7]. Chen et al. revealed that BNNTs could deliver DNA oligomers to the interior of cells due to the noncytocompatibility of BNNTs in high concentration (100 μg/mL) [8]. All these researches indicate the broad prospect of BNNTs in drug delivery systems. Recently, the promising applications of BNNTs would be hampered due to their aggregation in solution, then lots of methods were employed to improve the dispersion of BNNTs, for example, covalent modification with alkyl chains [9] or hydroxyl groups [10] as well as
∗ Corresponding author. ∗∗ Corresponding author. E-mail addresses: [email protected] (L. Zhang), [email protected] (Z. Kong).
non-covalent wrapping with guest molecules [11,12]. However, the modification degree is relatively low through these methods, which limits the applications of BNNTs [13]. Fortunately, Ciofani et al. reported that the modification degree could be enhanced by wrapping BNNTs with different materials, such as chitosan, polyethyleneglycol (PEG), and polyethyleneimine (PEI) [14,15]. Since chitosan and its derivatives show the advantages of biodegradability, mucoadhesive and natural cationic in low pH solution [15–19], the dispersion and biocompatibility of BNNTs could be enhanced by introducing chitosan and their derivatives. Ciofani et al. reported that the highly biocompatible and concentrated dispersions of BNNTs can be obtained by modifying with chitosan [15]. Moreover, owing to the different pH levels in biosystems (e.g., the low pH around cancer cell [20]), chitosan and its derivatives could be employed as pH sensitive carriers to deliver drug molecules into targeted cells [21–26]. For example, the amino groups in chitosan would be protonated in low pH, which makes the chitosan bind to several mammalian cells possible [21]. Besides, chitosan were also employed to modify other materials in drug delivery systems. Hu et al. synthesized the pH-responsive chitosancapped mesoporous silica nanoparticles, they found that the drug release degree increases with the pH decreases [25]. Zahra et al. revealed that the drug loading efficiency would be enhanced by modifying CNTs via chitosan [26]. Researchers also indicated that the drug transport
https://doi.org/10.1016/j.molliq.2019.111753 0167-7322/© 2019 Elsevier B.V. All rights reserved.
Please cite this article as: J. Li, C. Chen, J. Zhang, et al., Molecular dynamics study on loading mechanism of chitosan into boron nitride nanotubes, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.111753
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J. Li et al. / Journal of Molecular Liquids xxx (xxxx) xxx
efficiency would be influenced by the protonation of amino groups in chitosan. Moreover, as pointed by Rieger et al., the drug delivery would be influenced by the diameter of nanotube [27]. As discussed above, BNNTs-chitosan complex systems show promising application potential in drug delivery systems owing to two advantages. Firstly, the poor dispersion of BNNT would be enhanced by introducing functionalized chitosan to the system. Secondly, the pH sensitive drug carriers could be realized by changing the protonation degree of chitosan. It is important to understand the interaction mechanism between BNNTs and chitosan, which facilitates their potential use in drug delivery systems. Until now, the interaction mechanism between BNNTs and chitosan is still unclear, and the effect of functional group in chitosan and diameters of BNNTs on the interaction mechanism is poorly understood from molecular level. Recently, molecular dynamics (MD) have been confirmed as a powerful tool to reveal the interaction mechanism between polymers and nanotubes from atomic level [28–33]. Aztatzi-Pluma et al. revealed that the chitosan chains depicted a large contacting superficial area via MD simulations, which allows the interaction with the functionalized CNT [32]. Our previous work also indicated that the dispersion of BNNTs could be greatly affected by the type of polynucleotides and the radius of BNNT [33]. We also revealed that the gene loading efficiency would be promoted by chitosan with positive charged functional group [34]. In this manuscript, MD simulations were employed to investigate the interaction mechanism between BNNTs and chitosan. The effect of BNNTs’ diameters, as well as functional group in chitosan (e.g. neutral and positive charge cases) on interaction and loading mechanism were further discussed.
2. Computational methods and simulation details
2.1. Molecular dynamics simulation The initial structures of chitosan with 10 units were generated by replacing the glucose unit –OH group into –NH2,-NH+ 3 , and they were marked as CS_A10 (-NH2 group) and CS_B10 (-NH+ 3 group), respectively (Fig. 1(a)). The armchair BNNT (12,12) and BNNT (14,14) were constructed by VMD software [35] and shown in Fig. 1(b). The length of BNNTs was set to be 80 Å, it is longer than the length of chitosan (~50 Å). All simulations were performed with GROMACS 5.0.7 package [36]. Firstly, chitosan chains with different functional groups were equilibrated in solution for 10 ns simulations, the final configuration of chitosan chains were taken as the initial structure in BNNTs-chitosan systems. Secondly, the axial direction of chitosan was set along the z-axis in BNNTs, and the first unit in chitosan chain was 5 Å away from the entrance of the nanotube (Fig. 1(c)). Four systems named as CS_A10/BNNT (12,12), CS_A10/BNNT (14,14), CS_B10/BNNT (12,12) and CS_B10/ BNNT (14,14) were constructed to investigate the effect of functional group as well as the diameter of BNNTs on their loading dynamics and interaction mechanism between BNNTs and chitosan chains. The parameters of glucose unit replaced with –NH2 and –NH+ 3 groups were derived from the general AMBER force field [37]and the details of the charge information as well as LJ parameters for atoms in BNNT and chitosan chains are listed in Tables S1, S2 and S3 in Supplementary Information. More details about the structure of chitosan and its topology construction can be found in our recent paper [34]. Both the LJ parameters and charge values for atoms in BNNT were taken from Aluru's paper [38]. They have optimized these parameters for atoms in BNNT via first principles quantum Monte Carlo calculations and random phase approximation (RPA) calculations, it is found that water contact angle on bulk hexagonal boron nitride obtained through simulation is closer to the experimental value, which validates the model of BNNTs. Besides, these parameters were also employed by Saikia et al. [39] and our previous work [40,41]. The TIP3P model was employed to describe water molecules [42]. In each system, the cut-off distance was set to be 1.2 nm. The cross interaction between different atoms were calculated through Lorentz-Berthelot rule [43]. The electrostatic interactions between chitosan and BNNTs were calculated by using particle mesh Ewald (PME) method [44]. The time step was set to be 2 f. and some ions (Cl−) were added to balance the charge in the systems. Periodic boundary conditions in all three dimensions were
Fig. 1. (a) The structure of chitosan with 10 units with different functional groups, Chitosan including –NH2 and –NH+ 3 functional group were marked as CS_A10 and CS_B10, respectively. (b) Structure for BNNT (12,12) and BNNT (14,14) from side and top view. BNNTs were shown by licorice model. (c) Initial side view of CS_A10/BNNT (12,12) system, CS_A10 was shown in blue licorice model for clear.
Please cite this article as: J. Li, C. Chen, J. Zhang, et al., Molecular dynamics study on loading mechanism of chitosan into boron nitride nanotubes, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.111753
J. Li et al. / Journal of Molecular Liquids xxx (xxxx) xxx Table 1 Details of binding free energy calculation. Binding free energy calculation Name of system
-NH2 in Water -NH+ 3 in Water -NH2 inside BNNT (14,14) -NH2 outside BNNT (14,14) -NH+ 3 inside BNNT (14,14) -NH+ 3 outside BNNT (14,14)
Number of One unit of chitosan
BNNT
Cl−
1 1 1 1 1 1
0 0 1 1 1 1
0 1 0 0 1 1
Simulation time (ns) 30 × 10 30 × 10 30 × 10 30 × 10 30 × 10 30 × 10
considered. All the bond lengths were constrained by LINCS algorithm [45]. Temperature was kept at 300 K through velocity rescaling with a stochastic term [46]. 50 ns MD simulations were carried out for CS_A10/BNNT (12,12), CS_A10/BNNT (14,14) and CS_B 10/BNNT (12,12) systems in the NVT ensemble. As to the CS_B 10/BNNT (14,14) system, 500 ns MD simulation were performed in CS_B 10 /BNNT (14,14) system with the aim of getting a full equilibrium result of the system. The different dynamic behavior between CS_B10/BNNT (14,14) and CS_A10/BNNT (14,14) systems would be discussed in the next section. 2.2. Thermodynamic integration calculations As shown in Table 1, the binding free energy between one unit in CS_A10/CS_B10 systems and BNNT (14,14) can be calculated by thermodynamic integration (TI) method [47]. The simulation box size was 4 × 4 × 10 nm3. Every system were equilibrated in solutions for 10 ns before calculation, and the binding free energy can be calculated by removing/introducing chitosan in the bound/unbound state gradually. The removing chitosan calculation was divided into two steps, 1) electrostatic interaction was turned off gradually, and the electrostatic coupling variables λ were set as follows: 1.00, 0.90, 0.60, 0.30 during this process; 2) The van der Waals interactions coupling variables λ changed gradually and the value was: 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.0. The “soft-core” Lennard-Jones potentials model was used to prevent system from unstable when both electrostatic and van der Waals interactions were turned off simultaneously. The value of the scaling factor α was 0.5. All systems were repeated and the chitosan in the opposite direction was gradually introduced in the thermodynamic cycle. During the calculation, 30 asymmetric windows were used, and 10ns MD simulations were conducted with different values of λ in each window, then last 5ns were used to produce a reliable ∂H/∂λ curve, from which the binding free energy can be derived. 3. Results and discussion Firstly, the adsorption state of chitosan in BNNTs was investigated and the final configurations of CS_A10 and CS_B10 around the BNNT (12,12) and BNNT (14,14) were shown in Fig. 2. Both the CS_A10 and CS_B10 chains absorb on the outer surface of BNNT (12,12) (Fig. 2(a) and (b)) when the diameter of BNNT is small. It is also found that chitosan chains prefer to enter into the nanotube of BNNT (14,14) (Fig. 2(c) and (d)), this is quite different from that in BNNT (12,12). Besides, the loading dynamics of CS_A10 and CS_B10 entering into BNNT (14,14) are different, CS_A10 enters into the BNNT (14,14) quickly and stays inside the nanotube stably after 10 ns simulation. On the contrary, CS_B10 takes a long time to enter into the BNNT (14,14), the whole chain of CS_B10 just gets into the nanotube until 500 ns simulations. The different adsorption state and loading process may cause by the different interaction mechanism between CS_A10/CS_B10 and BNNTs. To confirm the different adsorption state of CS_A10/CS_B10 in BNNT (12,12)/BNNT (14,14), the radial distribution functions (RDFs) between the center of BNNTs and any atoms in chitosan in the xy plane and the normalized density maps of chitosan molecules around BNNTs were calculated and plotted in Fig. 3. The analytical data were taken from
3
the last 10 ns MD simulations. As shown in Fig. 3(a), three peak positions in g(r) for CS_A10 and CS_B10 in BNNT (12,12) systems (solid black and red line) are almost the same, and the peak positions are around 1.09, 1.25 and 1.35 nm, respectively. All of them are larger than the radius of BNNT (12,12) (0.83 nm, marked as green solid lines in Fig. 3(a)). This suggests that the adsorption state of chitosan on the outer surface of BNNT (12,12) is attributed to the relatively smaller pore size of BNNT (12,12). The normalized density maps of chitosan shown in Fig. 3(b) was also employed to reveal the distribution of chitosan. As shown in Fig. 3(b), both the CS_A10 and CS_B10 chains were adsorbed inside the nanotube of BNNT (14,14) when the diameter of BNNT increases. This is also can be confirmed by the peak positions in g(r) shown in Fig. 3(a), which are smaller than the radius of BNNT (14,14) (0.96 nm, marked as green dash lines). As discussed above, the adsorption state and loading mechanism of chitosan entering into the nanotubes would be influenced both by the diameter of BNNTs and the functional group in chitosan. It is found that the adsorption behavior is mainly determined by the diameter of BNNTs. When the diameter of BNNTs is small, chitosan chains prefer to adsorb on the outer surface of BNNT (12,12), while chitosan chains would like to adsorb inside the BNNTs with the diameter increasing. The helical structure of CS_A10 and CS_B10 inside BNNT (14,14) can be observed from the density map shown in Fig. 3(b). The similar helical structure of biomolecule inside CNTs have been reported by Zhang et al. [48], they found that the encapsulation of peptide would be regulated by the geometry of carbon nanotubes. Water molecules inside the CNTs with varying geometry play an important role in regulating the interaction between biomolecule and nanotube. Our previous work also indicated that the transport speed of water molecules would be promoted owing to their highly ordered state inside BNNTs [40]. Therefore, the RDFs between water molecules inside BNNTs in xy plane was calculated to illustrate the interaction mechanism between chitosan and BNNTs with different diameters. 10 ns MD simulations were performed for pure water in BNNTs, then the last 5 ns data were employed to calculate the RDFs. As shown in Fig. 4(a), two peaks could be detected in the g(r) curves, it indicates that there are two layers of ordered water molecules in the nanotube. The second peak position in g(r) curves for water molecules in BNNT (12,12) and BNNT (14,14) is 0.50 nm and 0.65 nm, respectively, this also confirms more freedom in the radial direction of BNNT (14,14). These results are consistent with earlier studies reported by Aluru et al. [49], they found that ordered water molecules existed in the BNNTs, and the diffusion behavior and structure of water molecules would be modified by the diameter of the BNNTs. They also shown that diffusion coefficient would be slowed down due to the strong interaction between nitrogen atoms and water molecules. The size of solvation layer around chitosan chains was further measured via RDFs, it could be observed that the peak positions in g(r) curves are around 0.46 nm from Fig. 4 (b), that is, the size of solvation layer for chitosan chain is ~0.46 nm. This value is almost the same as the second peak position shown in Fig. 4(a) (0.5 nm for water molecules in BNNT (12,12)). It implies that chitosan chain needs to remove water molecules around it and adjust its conformation to enter the nanotube of BNNT (12,12). While it is difficult to remove water molecules around chitosan chain due to the relatively strong interaction between CS_A10/CS_B10 and water molecules. When the diameter of BNNTs increases, more freedom in the radial direction of BNNT (14,14) make the entrance process of chitosan possible. In summary, the adsorption state of CS_A10/CS_B10 in BNNT (12,12)/BNNT (14,14) was regulated by the diameter of BNNT, the entrance process of chitosan would be prevented by ordered water molecules inside BNNTs when the diameter of nanotube is small. As shown in Fig. 2(c) and(d), the total chain of CS_A10 and CS_B10 could enter into the cavity of BNNT (14,14). This can be validated by the number of contact atoms between chitosan and BNNT (14,14) (black line) as well as the distance between center-of-mass (COM) of chitosan chain and the geometric center of the BNNT (14,14) (red line) in the z-direction during the loading process. From Fig. 5, it can be found that the value of contact number gradually increases to a constant and the distance approaches to zero after 10 ns simulations. As to CS_B10/BNNT (14,14) system, the distance between COM of CS_B10 and BNNT (14,14) exhibits a stepwise decrease, and the stepwise increase of contact number matches well with the decrease of COM distance, this may cause by the interaction between –NH+ 3 group and BNNTs. Similar phenomena have been reported in DNA-SWNT systems in our previous works [50]. The snapshots of CS_B10/BNNT (14,14) system at
Fig. 2. The snapshots of the final state of chitosan-BNNTs systems from side and top view. (a) CS_A10/BNNT (12,12); (b) CS_B10/BNNT (12,12); (c) CS_A10/BNNT (14,14); (d) CS_A10/BNNT (14,14). BNNTs were shown by licorice model, CS_A10 and CS_B10 were shown in blue and red licorice, respectively. Water molecules and ions were not shown for clarity.
Please cite this article as: J. Li, C. Chen, J. Zhang, et al., Molecular dynamics study on loading mechanism of chitosan into boron nitride nanotubes, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.111753
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J. Li et al. / Journal of Molecular Liquids xxx (xxxx) xxx
(b)
(a)
150 CS_A10/BNNT(12,12) CS_B10/BNNT(12,12) CS_A10/BNNT(14,14) CS_B10/BNNT(14,14)
120
g (r)
90 60 30 0 0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
r (nm) Fig. 3. (a) The RDFs of chitosan molecules in xy plane around BNNTs, the x-axis represents distance between the center of the nanotube and any atoms in chitosan chain. The solid green lines (at 0.83 nm) and dotted lines (at 0.96 nm) represent the radius of BNNT (12,12) and BNNT (14,14), respectively. (b) The normalized density maps of all atoms of chitosan molecules around BNNTs in xy plane.
the moment of stepwise loading were shown in Fig. 6, it can be observed that two adjacent –NH+ 3 groups in chitosan is blocked at the entrance of BNNT, then chitosan chain needs to adjust its configuration to make the entrance possible, this results in the stepwise increase of contact number as well as the decrease of distance. It also indicates that there is a relatively larger energy barrier between CS_B10 and BNNTs, owing to the presence of –NH+ 3 groups. To illustrate the different loading process mentioned above, the binding free energy of one unit in chitosan (with –NH2 and –NH+ 3 group) adsorbed outside/inside BNNT (14, 14) were calculated through the thermodynamic integration (TI) method [44]. Taking one unit in chitosan as an example, the thermodynamic cycle employed to calculate binding free energy was shown in Fig. 7. The outside/inside binding free energy (ΔGbind) is defined as ΔGbind = ΔG1+ΔG2+ΔG3 and ΔG'bind = ΔG1+ΔG′2+ΔG′3, respectively. ΔG1 and ΔG3/ΔG ′3 are the free energy required to annihilate chitosan interaction in the unbound and bound states (outside/inside BNNT (14,14)), respectively. Annihilated chitosan are partially transparent, then the value of ΔG2 is equal to zero, this shows non-bonded interactions between chitosan units as well as that for chitosan and it's the environment. Table 2 lists the binding free energy (ΔGbind) between chitosan with different functional group and BNNT (14,14), the electrostatic (ΔGele) and vdW (ΔGvdW) contributions are also listed. Herein, ΔGbind = ΔGele + ΔGvdW. The values of ΔGbind for chitosan with NH2 and –NH+ 3 group adsorbed outside BNNT (14,14) are −12.53 ± 0.21 and −9.91 ± 0.15 kJ/mol, respectively. Meanwhile, the values of ΔGbind for chitosan inside BNNT (14,14) are: −27.65 ± 0.37 and −18.83 ± 0.21 kJ/mol, respectively. The relative strong interaction could be found when chitosan was adsorbed inside the channel of BNNT (14,14), this suggests that the chitosan chain would like to stay inside BNNT (14,14) from the viewpoint of thermodynamics. In addition, the values of ΔGele and ΔGvdW also suggest the adsorption state of chitosan is mainly determined by
the strong vdW interaction between chitosan and BNNTs. Taking the slow loading process in CS_B10/BNNT (14,14) system into consideration, the values of ΔGele for chitosan with – NH2 and –NH+ 3 group adsorbed inside BNNT (14,14) are 14.41 ± 0.07 and 28.47 ± 0.10 kJ/mol, respectively. While the vdW interaction are nearly the same (−42.06 ± 0.93 kJ/mol for CS_A10/BNNT (14,14) and −47.30 ± 0.91 kJ/mol for CS_B10/BNNT (14,14)). This indicates that protonated chitosan shows insufficient driving force to enter the nanotubes due to the strong electrostatic repulsion between chitosan and BNNT. As shown in Figs. 5 and 6, different loading process could be detected in CS_A10/BNNT (14,14) and CS_B10/BNNT (14,14) systems. With the aim of revealing the effect of functional group in chitosan as well as water molecules around chitosan on the loading mechanism, the density distribution of chitosan chain entered into BNNTs were calculated and plotted in Fig. 8(a) and(b). When one unit, two units and five units of chitosan loaded into BNNT (14,14), the density map of chitosan chain inside the tube were listed from left to right. As shown in Fig. 8(a), it could be found that the ordered water molecules inside the nanotube would be broken when the CS_A10 chain entered into the channel of BNNT (14,14). While the CS_B10 entered into the BNNT (14,14) from the middle of the two layers of water molecules, and is located closer to the inside wall of BNNT (14,14). In other words, CS_B10 needs to adjust its conformation then enter into nanotube with the spiraling manner during the loading process, while this manner cannot be detected in the loading process for CS_A10. Eventually, when all units of CS_A10 and CS_B10 enter the channel of BNNT(14,14), then the CS_A10 would adjust its configuration and locate in the two layers of water molecules (shown in Fig. 3(b)). That is, the final state of CS_A10 and CS_B10 chains in BNNT (14,14）is nearly the same, while their entry modes is quite different, which results in the extremely different loading dynamics. In order to investigate the solvation behavior of chitosan, the free energy of solvation (ΔGsol) for one unit in chitosan (-NH2 groups) and protonated chitosan (-NH+ 3 groups) are
(a)
20
Water/BNNT (12,12) Water/BNNT (14,14)
15
(b) Water/NH2 + Water/NH3
g (r)
g (r)
1.5 10
5
0 0.0
1.0
0.5 0.5
1.0
r (nm)
1.5
0.0 0.0
0.5
1.0
1.5
r (nm) Fig. 4. (a) The RDFs between water molecules and BNNTs in the xy plane, the x-axis represents the radial position from the center of the nanotube. (b) The RDFs of water molecules around one unit of chitosan, inset map: atomic pictures of water molecules around one unit –NH2 chitosan.
Please cite this article as: J. Li, C. Chen, J. Zhang, et al., Molecular dynamics study on loading mechanism of chitosan into boron nitride nanotubes, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.111753
J. Li et al. / Journal of Molecular Liquids xxx (xxxx) xxx
7 6 5
6000
4 4000
3 2
2000
1 0
0
10
20
30
Time (ns)
40
0 50
CS_B10/BNNT (14,14)
10000
7
Contact number COM of distance
8000
8 (b) 6 5
6000
4 4000
3 2
2000
1 0
0
100
200
300
Time (ns)
400
COM of distance (nm)
8000
Number of contact atoms
Number of contact atoms
Contact number COM of distance
8 (a)
COM of distance (nm)
CS_A10/BNNT (14,14)
10000
5
0 500
Fig. 5. The number of contact atoms between chitosan and BNNT (14,14) as well as the distance of center-of-mass (COM) of the chitosan to the geometric center of the BNNT (14,14) in the z-direction during the loading process. (a) CS_A10/BNNT (14,14) system; (b) CS_B10/BNNT (14,14) system.
calculated and listed in Table 2, and the values are: −132.57 ± 0.41 kJ/mol (chitosan), and −298.81 ± 1.90 (chitosan with –NH+ 3 group), respectively. The electrostatic contribution for free energy of solvation (ΔGele) are: −126.60 ± 0.53 and −291.87 ± 1.39, respectively. In other words, water molecules around CS_B10 are more order and stable owing to the relative strong electrostatic interaction between them. It's difficult to remove the water molecules from the solvation layer around CS_B10 and exchange with water molecules inside nanotube. The number of hydrogen bond (H-bond) between CS_A10/CS_B10 chains and water molecules was calculated and plotted in Fig. 9, the H-bond number between CS_A10 and water molecules decreases quickly before 10 ns and fluctuates around the constant slightly after 10 ns, this is well agreement with the changing trend of contact number and COM distance shown in Fig. 5(a). This also reveals that chitosan needs to remove the solvation layer around before entering the tube. While this process is more difficult for CS_B10 chain owing to its higher free energy of solvation. The ordered water molecules inside BNNTs cannot be broken by the chitosan with –NH+ 3 group immediately. On the other hand, CS_B10 chain shows more stretched conformations owing to the intramolecular re+ pulsive electrostatic interaction between –NH3 groups. Therefore, it is hard for CS_B10 to enter the tube by twisting the tail like a dragonfly, and CS_B10 can only enter into the nanotube from the middle of the two layers water molecules. As to CS_A10/BNNT(14,14) system, the free energy of solvation and rigidity of the CS_A10 chain is relatively smaller than that for CS_B10, the hydrogen bond network between water molecules can be broken easily, then adjust their conformations more quickly and enter the nanotube. In summary, the slow loading process for CS_B10 entering into BNNT (14,14) could be explained from two aspects, 1) CS_B10 shows insufficient driving force to enter into the nanotube due to strong electrostatic repulsion between CS_B10 and BNNT (14,14). 2) CS_B10 needs to spend more time to adjust their conformation to enter into BNNT
Fig. 6. Typical snapshots during the stepwise loading process of CS_B10/BNNT (14, 14) system (licorice model: chitosan, vdW model: –NH+ 3 group, line model: BNNT (14, 14)). Water molecules and ions were omitted for clarity.
(14,14) owing to the high solvation free energy and rigidity of CS_B10 chain. In other words, the loading process of CS_B10 chains into BNNT (14,14) is not preferred from the thermodynamics.
4. Conclusion In this work, molecular dynamic simulations were employed to investigate the interaction mechanism between chitosan with different functional group (e.g. neutral and positive charge cases) and BNNTs. The adsorption state of chitosan and loading mechanism for chitosan onto/into BNNTs with different diameters are also discussed. Our simulation results show that the diameters of BNNTs regulated the adsorption state. When the diameters of BNNTs is smaller, chitosan can only absorb on the outer surface of BNNT (12,12) due to the relatively larger size of the solvation layer around chitosan chains. Chitosan prefers to enter into the nanotube of BNNT (14,14) owing to the relative strong Gibbs free energy between chitosan chains and BNNT (14,14). The values of ΔGele and ΔGvdW suggest the adsorption behavior is mainly determined by the vdW interaction between chitosan and BNNT (14,14) wall. It is also found that CS_A10 enters into the BNNT (14,14) quickly and stays inside the nanotube stably after 10 ns simulations. On the contrary, CS_B10 takes a long time to enter into BNNT (14, 14), the whole chain of CS_B10 just gets into the nanotube until 500 ns simulations. The slow loading process of CS_B10/BNNT (14,14) system could be explained in two aspects. Firstly, the CS_B10 shows insufficient driving force to get into the nanotube due to the strong electrostatic repulsion
Fig. 7. The thermodynamic cycle employed to calculate the binding free energy of one unit –NH2 chitosan outside (left cycle)/inside (right cycle) BNNT (14,14).
Please cite this article as: J. Li, C. Chen, J. Zhang, et al., Molecular dynamics study on loading mechanism of chitosan into boron nitride nanotubes, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.111753
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System
ΔGele (kJ∙ mol−1)
ΔGvdw (kJ∙ mol−1)
ΔGbind (kJ∙ mol−1)
-NH2 outside BNNT -NH+ 3 outside BNNT -NH2 inside BNNT -NH+ 3 inside BNNT
5.85 ± 0.03 13.28 ± 0.06 14.41 ± 0.07 28.47 ± 0.10
−18.38 ± 0.51 −23.19 ± 0.62 −42.06 ± 0.93 −47.30 ± 0.91
−12.53 ± 0.21 −9.91 ± 0.15 −27.65 ± 0.37 −18.83 ± 0.21
ΔGele (kJ∙ mol−1)
ΔGvdw (kJ∙ mol−1)
ΔGsol (kJ∙ mol−1)
−126.60 ± 0.53 −291.87 ± 1.39
−5.97 ± 0.26 −6.94 ± 0.22
−132.57 ± 0.41 −298.81 ± 1.90
-NH2 in Water -NH+ 3 in Water
H-bond number
Table 2 The binding free energy of glucose unit replaced with –NH2 and NH+ 3 groups adsorbed outside/inside BNNT (14,14), and the free energy of solvation of one unit chitosan (-NH2 and –NH+ 3 ) in a box of water.
80 70 60 50 40 30 80 70 60 50 40 30
CS_A10/BNNT(14,14)
0
Acknowledgments This work was financially supported by the National Natural Science Foundation of China (Grant Nos. 21978274, 51702073, 21674032). It was also supported by the Project Grants 521 Talents Cultivation and Fundamental Research Funds of Zhejiang Sci-Tech University (No. 2019Q070). This work was also supported by the Key Fostering Project of Scientific Research of Hangzhou Normal University (2018PYXML006) and the High Level Returned Overseas Chinese Innovation Projects in Hangzhou. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.molliq.2019.111753.
Fig. 8. The density maps of all atoms of chitosan (a) CS_A10 and (b) CS_B10 have entered inside BNNT (14,14) during the loading process. From left to right, the density distribution of chitosan in the tube was calculated when one unit, two units and five units in CS_A10/CS_B10 load into BNNT (14,14) during the loading process, respectively. (c) The density map for water molecules inside BNNT (14,14). Two black dash circles shown in each figure represent the two layer water molecules inside BNNT (14,14).
20
30
40
50
CS_B10/BNNT(14,14)
0 between CS_B10 and BNNT (14,14). Secondly, CS_B10 spends more time to adjust its conformation to enter BNNT (14,14) owing to the high solvation free energy and rigidity of the CS_B10 chain. The interaction mechanism between chitosan and BNNTs as well as the loading mechanism for chitosan entering into/onto BNNTs revealed in this study would give some useful suggestion to the drug screen and delivery systems. It suggested that encapsulation efficiency of chitosan could be improved by adjusting the ratio functional groups (-NH3+/NH2) in chitosan's chains via changing their protonation degree.
10
100
200
300
400
500
Time (ns) Fig. 9. The number of H-bonds between chitosan and water molecules in CS_A10/BNNT (14,14) and CS_B10/BNNT (14,14) systems versus the simulation time.
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Journal of Molecular Liquids journal homepage: www.elsevier.com/locate/molliq
Molecular dynamics study on loading mechanism of chitosan into boron nitride nanotubes Jiachen Li a, Chen Chen a, Jin Zhang a, Li Zhang a, ∗, Lijun Liang b, Zhe Kong c, ∗∗, Shen Jia-Wei d, Yunxia Xu a, Xinping Wang a, Wei Zhang a a
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, 310018, People's Republic of China College of Life Information Science and Instrument Engineering, Hangzhou Dianzi University, Hangzhou, 310018, People's Republic of China College of Material & Environmental Engineering Science Hangzhou Dianzi University, Hangzhou, 310018, People's Republic of China d School of Medicine, Hangzhou Normal University, Hangzhou, 310016, People's Republic of China b c
a r t i c l e
i n f o
Article history: Received 28 June 2019 Received in revised form 10 September 2019 Accepted 14 September 2019 Available online xxxx Keywords: Molecular dynamics simulation Drug delivery systems Chitosan Loading mechanism Boron nitride nanotubes
a b s t r a c t Boron nitride nanotubes (BNNTs) have been considered as one of the most promising materials in drug delivery systems. It is important to understand the interaction mechanism between chitosan and BNNTs from atomic level. Herein, molecular dynamics (MD) simulation were employed to investigate the interaction mechanism and loading mechanism of chitosan into/onto BNNTs. The effect of functional group in chitosan and the diameter of BNNTs on the interaction mechanism between BNNTs and chitosan were discussed. It is found that chitosan can only absorb on the outer surface of BNNT (12,12) owing to the size of chitosan and its solvent layer. The loading process of chitosan with –NH2 group (CS_A10) into the BNNT (14,14) is much easier than that for –NH+ 3 group system (CS_B10). The different loading dynamics for CS_A10/CS_B10 were explained from Gibbs free energy as well as the solvation behavior of chitosan chains. © 2019 Elsevier B.V. All rights reserved.
1. Introduction Boron nitride nanotubes (BNNTs) have been considered as one of the most promising materials in drug delivery systems owing to their unique physical and chemical properties [1–4]. As one kind analogues of carbon nanotubes (CNTs), BNNTs show better biocompatibility and lower cytotoxicity compared with CNTs [5–8]. For instance, Li et al. reported that the proliferation of human primary mammary fibroblasts and the transformed mammary cell line could be improved by film constructed by BNNTs [7]. Chen et al. revealed that BNNTs could deliver DNA oligomers to the interior of cells due to the noncytocompatibility of BNNTs in high concentration (100 μg/mL) [8]. All these researches indicate the broad prospect of BNNTs in drug delivery systems. Recently, the promising applications of BNNTs would be hampered due to their aggregation in solution, then lots of methods were employed to improve the dispersion of BNNTs, for example, covalent modification with alkyl chains [9] or hydroxyl groups [10] as well as
∗ Corresponding author. ∗∗ Corresponding author. E-mail addresses: [email protected] (L. Zhang), [email protected] (Z. Kong).
non-covalent wrapping with guest molecules [11,12]. However, the modification degree is relatively low through these methods, which limits the applications of BNNTs [13]. Fortunately, Ciofani et al. reported that the modification degree could be enhanced by wrapping BNNTs with different materials, such as chitosan, polyethyleneglycol (PEG), and polyethyleneimine (PEI) [14,15]. Since chitosan and its derivatives show the advantages of biodegradability, mucoadhesive and natural cationic in low pH solution [15–19], the dispersion and biocompatibility of BNNTs could be enhanced by introducing chitosan and their derivatives. Ciofani et al. reported that the highly biocompatible and concentrated dispersions of BNNTs can be obtained by modifying with chitosan [15]. Moreover, owing to the different pH levels in biosystems (e.g., the low pH around cancer cell [20]), chitosan and its derivatives could be employed as pH sensitive carriers to deliver drug molecules into targeted cells [21–26]. For example, the amino groups in chitosan would be protonated in low pH, which makes the chitosan bind to several mammalian cells possible [21]. Besides, chitosan were also employed to modify other materials in drug delivery systems. Hu et al. synthesized the pH-responsive chitosancapped mesoporous silica nanoparticles, they found that the drug release degree increases with the pH decreases [25]. Zahra et al. revealed that the drug loading efficiency would be enhanced by modifying CNTs via chitosan [26]. Researchers also indicated that the drug transport
https://doi.org/10.1016/j.molliq.2019.111753 0167-7322/© 2019 Elsevier B.V. All rights reserved.
Please cite this article as: J. Li, C. Chen, J. Zhang, et al., Molecular dynamics study on loading mechanism of chitosan into boron nitride nanotubes, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.111753
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J. Li et al. / Journal of Molecular Liquids xxx (xxxx) xxx
efficiency would be influenced by the protonation of amino groups in chitosan. Moreover, as pointed by Rieger et al., the drug delivery would be influenced by the diameter of nanotube [27]. As discussed above, BNNTs-chitosan complex systems show promising application potential in drug delivery systems owing to two advantages. Firstly, the poor dispersion of BNNT would be enhanced by introducing functionalized chitosan to the system. Secondly, the pH sensitive drug carriers could be realized by changing the protonation degree of chitosan. It is important to understand the interaction mechanism between BNNTs and chitosan, which facilitates their potential use in drug delivery systems. Until now, the interaction mechanism between BNNTs and chitosan is still unclear, and the effect of functional group in chitosan and diameters of BNNTs on the interaction mechanism is poorly understood from molecular level. Recently, molecular dynamics (MD) have been confirmed as a powerful tool to reveal the interaction mechanism between polymers and nanotubes from atomic level [28–33]. Aztatzi-Pluma et al. revealed that the chitosan chains depicted a large contacting superficial area via MD simulations, which allows the interaction with the functionalized CNT [32]. Our previous work also indicated that the dispersion of BNNTs could be greatly affected by the type of polynucleotides and the radius of BNNT [33]. We also revealed that the gene loading efficiency would be promoted by chitosan with positive charged functional group [34]. In this manuscript, MD simulations were employed to investigate the interaction mechanism between BNNTs and chitosan. The effect of BNNTs’ diameters, as well as functional group in chitosan (e.g. neutral and positive charge cases) on interaction and loading mechanism were further discussed.
2. Computational methods and simulation details
2.1. Molecular dynamics simulation The initial structures of chitosan with 10 units were generated by replacing the glucose unit –OH group into –NH2,-NH+ 3 , and they were marked as CS_A10 (-NH2 group) and CS_B10 (-NH+ 3 group), respectively (Fig. 1(a)). The armchair BNNT (12,12) and BNNT (14,14) were constructed by VMD software [35] and shown in Fig. 1(b). The length of BNNTs was set to be 80 Å, it is longer than the length of chitosan (~50 Å). All simulations were performed with GROMACS 5.0.7 package [36]. Firstly, chitosan chains with different functional groups were equilibrated in solution for 10 ns simulations, the final configuration of chitosan chains were taken as the initial structure in BNNTs-chitosan systems. Secondly, the axial direction of chitosan was set along the z-axis in BNNTs, and the first unit in chitosan chain was 5 Å away from the entrance of the nanotube (Fig. 1(c)). Four systems named as CS_A10/BNNT (12,12), CS_A10/BNNT (14,14), CS_B10/BNNT (12,12) and CS_B10/ BNNT (14,14) were constructed to investigate the effect of functional group as well as the diameter of BNNTs on their loading dynamics and interaction mechanism between BNNTs and chitosan chains. The parameters of glucose unit replaced with –NH2 and –NH+ 3 groups were derived from the general AMBER force field [37]and the details of the charge information as well as LJ parameters for atoms in BNNT and chitosan chains are listed in Tables S1, S2 and S3 in Supplementary Information. More details about the structure of chitosan and its topology construction can be found in our recent paper [34]. Both the LJ parameters and charge values for atoms in BNNT were taken from Aluru's paper [38]. They have optimized these parameters for atoms in BNNT via first principles quantum Monte Carlo calculations and random phase approximation (RPA) calculations, it is found that water contact angle on bulk hexagonal boron nitride obtained through simulation is closer to the experimental value, which validates the model of BNNTs. Besides, these parameters were also employed by Saikia et al. [39] and our previous work [40,41]. The TIP3P model was employed to describe water molecules [42]. In each system, the cut-off distance was set to be 1.2 nm. The cross interaction between different atoms were calculated through Lorentz-Berthelot rule [43]. The electrostatic interactions between chitosan and BNNTs were calculated by using particle mesh Ewald (PME) method [44]. The time step was set to be 2 f. and some ions (Cl−) were added to balance the charge in the systems. Periodic boundary conditions in all three dimensions were
Fig. 1. (a) The structure of chitosan with 10 units with different functional groups, Chitosan including –NH2 and –NH+ 3 functional group were marked as CS_A10 and CS_B10, respectively. (b) Structure for BNNT (12,12) and BNNT (14,14) from side and top view. BNNTs were shown by licorice model. (c) Initial side view of CS_A10/BNNT (12,12) system, CS_A10 was shown in blue licorice model for clear.
Please cite this article as: J. Li, C. Chen, J. Zhang, et al., Molecular dynamics study on loading mechanism of chitosan into boron nitride nanotubes, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.111753
J. Li et al. / Journal of Molecular Liquids xxx (xxxx) xxx Table 1 Details of binding free energy calculation. Binding free energy calculation Name of system
-NH2 in Water -NH+ 3 in Water -NH2 inside BNNT (14,14) -NH2 outside BNNT (14,14) -NH+ 3 inside BNNT (14,14) -NH+ 3 outside BNNT (14,14)
Number of One unit of chitosan
BNNT
Cl−
1 1 1 1 1 1
0 0 1 1 1 1
0 1 0 0 1 1
Simulation time (ns) 30 × 10 30 × 10 30 × 10 30 × 10 30 × 10 30 × 10
considered. All the bond lengths were constrained by LINCS algorithm [45]. Temperature was kept at 300 K through velocity rescaling with a stochastic term [46]. 50 ns MD simulations were carried out for CS_A10/BNNT (12,12), CS_A10/BNNT (14,14) and CS_B 10/BNNT (12,12) systems in the NVT ensemble. As to the CS_B 10/BNNT (14,14) system, 500 ns MD simulation were performed in CS_B 10 /BNNT (14,14) system with the aim of getting a full equilibrium result of the system. The different dynamic behavior between CS_B10/BNNT (14,14) and CS_A10/BNNT (14,14) systems would be discussed in the next section. 2.2. Thermodynamic integration calculations As shown in Table 1, the binding free energy between one unit in CS_A10/CS_B10 systems and BNNT (14,14) can be calculated by thermodynamic integration (TI) method [47]. The simulation box size was 4 × 4 × 10 nm3. Every system were equilibrated in solutions for 10 ns before calculation, and the binding free energy can be calculated by removing/introducing chitosan in the bound/unbound state gradually. The removing chitosan calculation was divided into two steps, 1) electrostatic interaction was turned off gradually, and the electrostatic coupling variables λ were set as follows: 1.00, 0.90, 0.60, 0.30 during this process; 2) The van der Waals interactions coupling variables λ changed gradually and the value was: 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.0. The “soft-core” Lennard-Jones potentials model was used to prevent system from unstable when both electrostatic and van der Waals interactions were turned off simultaneously. The value of the scaling factor α was 0.5. All systems were repeated and the chitosan in the opposite direction was gradually introduced in the thermodynamic cycle. During the calculation, 30 asymmetric windows were used, and 10ns MD simulations were conducted with different values of λ in each window, then last 5ns were used to produce a reliable ∂H/∂λ curve, from which the binding free energy can be derived. 3. Results and discussion Firstly, the adsorption state of chitosan in BNNTs was investigated and the final configurations of CS_A10 and CS_B10 around the BNNT (12,12) and BNNT (14,14) were shown in Fig. 2. Both the CS_A10 and CS_B10 chains absorb on the outer surface of BNNT (12,12) (Fig. 2(a) and (b)) when the diameter of BNNT is small. It is also found that chitosan chains prefer to enter into the nanotube of BNNT (14,14) (Fig. 2(c) and (d)), this is quite different from that in BNNT (12,12). Besides, the loading dynamics of CS_A10 and CS_B10 entering into BNNT (14,14) are different, CS_A10 enters into the BNNT (14,14) quickly and stays inside the nanotube stably after 10 ns simulation. On the contrary, CS_B10 takes a long time to enter into the BNNT (14,14), the whole chain of CS_B10 just gets into the nanotube until 500 ns simulations. The different adsorption state and loading process may cause by the different interaction mechanism between CS_A10/CS_B10 and BNNTs. To confirm the different adsorption state of CS_A10/CS_B10 in BNNT (12,12)/BNNT (14,14), the radial distribution functions (RDFs) between the center of BNNTs and any atoms in chitosan in the xy plane and the normalized density maps of chitosan molecules around BNNTs were calculated and plotted in Fig. 3. The analytical data were taken from
3
the last 10 ns MD simulations. As shown in Fig. 3(a), three peak positions in g(r) for CS_A10 and CS_B10 in BNNT (12,12) systems (solid black and red line) are almost the same, and the peak positions are around 1.09, 1.25 and 1.35 nm, respectively. All of them are larger than the radius of BNNT (12,12) (0.83 nm, marked as green solid lines in Fig. 3(a)). This suggests that the adsorption state of chitosan on the outer surface of BNNT (12,12) is attributed to the relatively smaller pore size of BNNT (12,12). The normalized density maps of chitosan shown in Fig. 3(b) was also employed to reveal the distribution of chitosan. As shown in Fig. 3(b), both the CS_A10 and CS_B10 chains were adsorbed inside the nanotube of BNNT (14,14) when the diameter of BNNT increases. This is also can be confirmed by the peak positions in g(r) shown in Fig. 3(a), which are smaller than the radius of BNNT (14,14) (0.96 nm, marked as green dash lines). As discussed above, the adsorption state and loading mechanism of chitosan entering into the nanotubes would be influenced both by the diameter of BNNTs and the functional group in chitosan. It is found that the adsorption behavior is mainly determined by the diameter of BNNTs. When the diameter of BNNTs is small, chitosan chains prefer to adsorb on the outer surface of BNNT (12,12), while chitosan chains would like to adsorb inside the BNNTs with the diameter increasing. The helical structure of CS_A10 and CS_B10 inside BNNT (14,14) can be observed from the density map shown in Fig. 3(b). The similar helical structure of biomolecule inside CNTs have been reported by Zhang et al. [48], they found that the encapsulation of peptide would be regulated by the geometry of carbon nanotubes. Water molecules inside the CNTs with varying geometry play an important role in regulating the interaction between biomolecule and nanotube. Our previous work also indicated that the transport speed of water molecules would be promoted owing to their highly ordered state inside BNNTs [40]. Therefore, the RDFs between water molecules inside BNNTs in xy plane was calculated to illustrate the interaction mechanism between chitosan and BNNTs with different diameters. 10 ns MD simulations were performed for pure water in BNNTs, then the last 5 ns data were employed to calculate the RDFs. As shown in Fig. 4(a), two peaks could be detected in the g(r) curves, it indicates that there are two layers of ordered water molecules in the nanotube. The second peak position in g(r) curves for water molecules in BNNT (12,12) and BNNT (14,14) is 0.50 nm and 0.65 nm, respectively, this also confirms more freedom in the radial direction of BNNT (14,14). These results are consistent with earlier studies reported by Aluru et al. [49], they found that ordered water molecules existed in the BNNTs, and the diffusion behavior and structure of water molecules would be modified by the diameter of the BNNTs. They also shown that diffusion coefficient would be slowed down due to the strong interaction between nitrogen atoms and water molecules. The size of solvation layer around chitosan chains was further measured via RDFs, it could be observed that the peak positions in g(r) curves are around 0.46 nm from Fig. 4 (b), that is, the size of solvation layer for chitosan chain is ~0.46 nm. This value is almost the same as the second peak position shown in Fig. 4(a) (0.5 nm for water molecules in BNNT (12,12)). It implies that chitosan chain needs to remove water molecules around it and adjust its conformation to enter the nanotube of BNNT (12,12). While it is difficult to remove water molecules around chitosan chain due to the relatively strong interaction between CS_A10/CS_B10 and water molecules. When the diameter of BNNTs increases, more freedom in the radial direction of BNNT (14,14) make the entrance process of chitosan possible. In summary, the adsorption state of CS_A10/CS_B10 in BNNT (12,12)/BNNT (14,14) was regulated by the diameter of BNNT, the entrance process of chitosan would be prevented by ordered water molecules inside BNNTs when the diameter of nanotube is small. As shown in Fig. 2(c) and(d), the total chain of CS_A10 and CS_B10 could enter into the cavity of BNNT (14,14). This can be validated by the number of contact atoms between chitosan and BNNT (14,14) (black line) as well as the distance between center-of-mass (COM) of chitosan chain and the geometric center of the BNNT (14,14) (red line) in the z-direction during the loading process. From Fig. 5, it can be found that the value of contact number gradually increases to a constant and the distance approaches to zero after 10 ns simulations. As to CS_B10/BNNT (14,14) system, the distance between COM of CS_B10 and BNNT (14,14) exhibits a stepwise decrease, and the stepwise increase of contact number matches well with the decrease of COM distance, this may cause by the interaction between –NH+ 3 group and BNNTs. Similar phenomena have been reported in DNA-SWNT systems in our previous works [50]. The snapshots of CS_B10/BNNT (14,14) system at
Fig. 2. The snapshots of the final state of chitosan-BNNTs systems from side and top view. (a) CS_A10/BNNT (12,12); (b) CS_B10/BNNT (12,12); (c) CS_A10/BNNT (14,14); (d) CS_A10/BNNT (14,14). BNNTs were shown by licorice model, CS_A10 and CS_B10 were shown in blue and red licorice, respectively. Water molecules and ions were not shown for clarity.
Please cite this article as: J. Li, C. Chen, J. Zhang, et al., Molecular dynamics study on loading mechanism of chitosan into boron nitride nanotubes, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.111753
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J. Li et al. / Journal of Molecular Liquids xxx (xxxx) xxx
(b)
(a)
150 CS_A10/BNNT(12,12) CS_B10/BNNT(12,12) CS_A10/BNNT(14,14) CS_B10/BNNT(14,14)
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g (r)
90 60 30 0 0.2
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1.4
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r (nm) Fig. 3. (a) The RDFs of chitosan molecules in xy plane around BNNTs, the x-axis represents distance between the center of the nanotube and any atoms in chitosan chain. The solid green lines (at 0.83 nm) and dotted lines (at 0.96 nm) represent the radius of BNNT (12,12) and BNNT (14,14), respectively. (b) The normalized density maps of all atoms of chitosan molecules around BNNTs in xy plane.
the moment of stepwise loading were shown in Fig. 6, it can be observed that two adjacent –NH+ 3 groups in chitosan is blocked at the entrance of BNNT, then chitosan chain needs to adjust its configuration to make the entrance possible, this results in the stepwise increase of contact number as well as the decrease of distance. It also indicates that there is a relatively larger energy barrier between CS_B10 and BNNTs, owing to the presence of –NH+ 3 groups. To illustrate the different loading process mentioned above, the binding free energy of one unit in chitosan (with –NH2 and –NH+ 3 group) adsorbed outside/inside BNNT (14, 14) were calculated through the thermodynamic integration (TI) method [44]. Taking one unit in chitosan as an example, the thermodynamic cycle employed to calculate binding free energy was shown in Fig. 7. The outside/inside binding free energy (ΔGbind) is defined as ΔGbind = ΔG1+ΔG2+ΔG3 and ΔG'bind = ΔG1+ΔG′2+ΔG′3, respectively. ΔG1 and ΔG3/ΔG ′3 are the free energy required to annihilate chitosan interaction in the unbound and bound states (outside/inside BNNT (14,14)), respectively. Annihilated chitosan are partially transparent, then the value of ΔG2 is equal to zero, this shows non-bonded interactions between chitosan units as well as that for chitosan and it's the environment. Table 2 lists the binding free energy (ΔGbind) between chitosan with different functional group and BNNT (14,14), the electrostatic (ΔGele) and vdW (ΔGvdW) contributions are also listed. Herein, ΔGbind = ΔGele + ΔGvdW. The values of ΔGbind for chitosan with NH2 and –NH+ 3 group adsorbed outside BNNT (14,14) are −12.53 ± 0.21 and −9.91 ± 0.15 kJ/mol, respectively. Meanwhile, the values of ΔGbind for chitosan inside BNNT (14,14) are: −27.65 ± 0.37 and −18.83 ± 0.21 kJ/mol, respectively. The relative strong interaction could be found when chitosan was adsorbed inside the channel of BNNT (14,14), this suggests that the chitosan chain would like to stay inside BNNT (14,14) from the viewpoint of thermodynamics. In addition, the values of ΔGele and ΔGvdW also suggest the adsorption state of chitosan is mainly determined by
the strong vdW interaction between chitosan and BNNTs. Taking the slow loading process in CS_B10/BNNT (14,14) system into consideration, the values of ΔGele for chitosan with – NH2 and –NH+ 3 group adsorbed inside BNNT (14,14) are 14.41 ± 0.07 and 28.47 ± 0.10 kJ/mol, respectively. While the vdW interaction are nearly the same (−42.06 ± 0.93 kJ/mol for CS_A10/BNNT (14,14) and −47.30 ± 0.91 kJ/mol for CS_B10/BNNT (14,14)). This indicates that protonated chitosan shows insufficient driving force to enter the nanotubes due to the strong electrostatic repulsion between chitosan and BNNT. As shown in Figs. 5 and 6, different loading process could be detected in CS_A10/BNNT (14,14) and CS_B10/BNNT (14,14) systems. With the aim of revealing the effect of functional group in chitosan as well as water molecules around chitosan on the loading mechanism, the density distribution of chitosan chain entered into BNNTs were calculated and plotted in Fig. 8(a) and(b). When one unit, two units and five units of chitosan loaded into BNNT (14,14), the density map of chitosan chain inside the tube were listed from left to right. As shown in Fig. 8(a), it could be found that the ordered water molecules inside the nanotube would be broken when the CS_A10 chain entered into the channel of BNNT (14,14). While the CS_B10 entered into the BNNT (14,14) from the middle of the two layers of water molecules, and is located closer to the inside wall of BNNT (14,14). In other words, CS_B10 needs to adjust its conformation then enter into nanotube with the spiraling manner during the loading process, while this manner cannot be detected in the loading process for CS_A10. Eventually, when all units of CS_A10 and CS_B10 enter the channel of BNNT(14,14), then the CS_A10 would adjust its configuration and locate in the two layers of water molecules (shown in Fig. 3(b)). That is, the final state of CS_A10 and CS_B10 chains in BNNT (14,14）is nearly the same, while their entry modes is quite different, which results in the extremely different loading dynamics. In order to investigate the solvation behavior of chitosan, the free energy of solvation (ΔGsol) for one unit in chitosan (-NH2 groups) and protonated chitosan (-NH+ 3 groups) are
(a)
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Water/BNNT (12,12) Water/BNNT (14,14)
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(b) Water/NH2 + Water/NH3
g (r)
g (r)
1.5 10
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0 0.0
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r (nm)
1.5
0.0 0.0
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1.0
1.5
r (nm) Fig. 4. (a) The RDFs between water molecules and BNNTs in the xy plane, the x-axis represents the radial position from the center of the nanotube. (b) The RDFs of water molecules around one unit of chitosan, inset map: atomic pictures of water molecules around one unit –NH2 chitosan.
Please cite this article as: J. Li, C. Chen, J. Zhang, et al., Molecular dynamics study on loading mechanism of chitosan into boron nitride nanotubes, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.111753
J. Li et al. / Journal of Molecular Liquids xxx (xxxx) xxx
7 6 5
6000
4 4000
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8000
Number of contact atoms
Number of contact atoms
Contact number COM of distance
8 (a)
COM of distance (nm)
CS_A10/BNNT (14,14)
10000
5
0 500
Fig. 5. The number of contact atoms between chitosan and BNNT (14,14) as well as the distance of center-of-mass (COM) of the chitosan to the geometric center of the BNNT (14,14) in the z-direction during the loading process. (a) CS_A10/BNNT (14,14) system; (b) CS_B10/BNNT (14,14) system.
calculated and listed in Table 2, and the values are: −132.57 ± 0.41 kJ/mol (chitosan), and −298.81 ± 1.90 (chitosan with –NH+ 3 group), respectively. The electrostatic contribution for free energy of solvation (ΔGele) are: −126.60 ± 0.53 and −291.87 ± 1.39, respectively. In other words, water molecules around CS_B10 are more order and stable owing to the relative strong electrostatic interaction between them. It's difficult to remove the water molecules from the solvation layer around CS_B10 and exchange with water molecules inside nanotube. The number of hydrogen bond (H-bond) between CS_A10/CS_B10 chains and water molecules was calculated and plotted in Fig. 9, the H-bond number between CS_A10 and water molecules decreases quickly before 10 ns and fluctuates around the constant slightly after 10 ns, this is well agreement with the changing trend of contact number and COM distance shown in Fig. 5(a). This also reveals that chitosan needs to remove the solvation layer around before entering the tube. While this process is more difficult for CS_B10 chain owing to its higher free energy of solvation. The ordered water molecules inside BNNTs cannot be broken by the chitosan with –NH+ 3 group immediately. On the other hand, CS_B10 chain shows more stretched conformations owing to the intramolecular re+ pulsive electrostatic interaction between –NH3 groups. Therefore, it is hard for CS_B10 to enter the tube by twisting the tail like a dragonfly, and CS_B10 can only enter into the nanotube from the middle of the two layers water molecules. As to CS_A10/BNNT(14,14) system, the free energy of solvation and rigidity of the CS_A10 chain is relatively smaller than that for CS_B10, the hydrogen bond network between water molecules can be broken easily, then adjust their conformations more quickly and enter the nanotube. In summary, the slow loading process for CS_B10 entering into BNNT (14,14) could be explained from two aspects, 1) CS_B10 shows insufficient driving force to enter into the nanotube due to strong electrostatic repulsion between CS_B10 and BNNT (14,14). 2) CS_B10 needs to spend more time to adjust their conformation to enter into BNNT
Fig. 6. Typical snapshots during the stepwise loading process of CS_B10/BNNT (14, 14) system (licorice model: chitosan, vdW model: –NH+ 3 group, line model: BNNT (14, 14)). Water molecules and ions were omitted for clarity.
(14,14) owing to the high solvation free energy and rigidity of CS_B10 chain. In other words, the loading process of CS_B10 chains into BNNT (14,14) is not preferred from the thermodynamics.
4. Conclusion In this work, molecular dynamic simulations were employed to investigate the interaction mechanism between chitosan with different functional group (e.g. neutral and positive charge cases) and BNNTs. The adsorption state of chitosan and loading mechanism for chitosan onto/into BNNTs with different diameters are also discussed. Our simulation results show that the diameters of BNNTs regulated the adsorption state. When the diameters of BNNTs is smaller, chitosan can only absorb on the outer surface of BNNT (12,12) due to the relatively larger size of the solvation layer around chitosan chains. Chitosan prefers to enter into the nanotube of BNNT (14,14) owing to the relative strong Gibbs free energy between chitosan chains and BNNT (14,14). The values of ΔGele and ΔGvdW suggest the adsorption behavior is mainly determined by the vdW interaction between chitosan and BNNT (14,14) wall. It is also found that CS_A10 enters into the BNNT (14,14) quickly and stays inside the nanotube stably after 10 ns simulations. On the contrary, CS_B10 takes a long time to enter into BNNT (14, 14), the whole chain of CS_B10 just gets into the nanotube until 500 ns simulations. The slow loading process of CS_B10/BNNT (14,14) system could be explained in two aspects. Firstly, the CS_B10 shows insufficient driving force to get into the nanotube due to the strong electrostatic repulsion
Fig. 7. The thermodynamic cycle employed to calculate the binding free energy of one unit –NH2 chitosan outside (left cycle)/inside (right cycle) BNNT (14,14).
Please cite this article as: J. Li, C. Chen, J. Zhang, et al., Molecular dynamics study on loading mechanism of chitosan into boron nitride nanotubes, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.111753
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J. Li et al. / Journal of Molecular Liquids xxx (xxxx) xxx
System
ΔGele (kJ∙ mol−1)
ΔGvdw (kJ∙ mol−1)
ΔGbind (kJ∙ mol−1)
-NH2 outside BNNT -NH+ 3 outside BNNT -NH2 inside BNNT -NH+ 3 inside BNNT
5.85 ± 0.03 13.28 ± 0.06 14.41 ± 0.07 28.47 ± 0.10
−18.38 ± 0.51 −23.19 ± 0.62 −42.06 ± 0.93 −47.30 ± 0.91
−12.53 ± 0.21 −9.91 ± 0.15 −27.65 ± 0.37 −18.83 ± 0.21
ΔGele (kJ∙ mol−1)
ΔGvdw (kJ∙ mol−1)
ΔGsol (kJ∙ mol−1)
−126.60 ± 0.53 −291.87 ± 1.39
−5.97 ± 0.26 −6.94 ± 0.22
−132.57 ± 0.41 −298.81 ± 1.90
-NH2 in Water -NH+ 3 in Water
H-bond number
Table 2 The binding free energy of glucose unit replaced with –NH2 and NH+ 3 groups adsorbed outside/inside BNNT (14,14), and the free energy of solvation of one unit chitosan (-NH2 and –NH+ 3 ) in a box of water.
80 70 60 50 40 30 80 70 60 50 40 30
CS_A10/BNNT(14,14)
0
Acknowledgments This work was financially supported by the National Natural Science Foundation of China (Grant Nos. 21978274, 51702073, 21674032). It was also supported by the Project Grants 521 Talents Cultivation and Fundamental Research Funds of Zhejiang Sci-Tech University (No. 2019Q070). This work was also supported by the Key Fostering Project of Scientific Research of Hangzhou Normal University (2018PYXML006) and the High Level Returned Overseas Chinese Innovation Projects in Hangzhou. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.molliq.2019.111753.
Fig. 8. The density maps of all atoms of chitosan (a) CS_A10 and (b) CS_B10 have entered inside BNNT (14,14) during the loading process. From left to right, the density distribution of chitosan in the tube was calculated when one unit, two units and five units in CS_A10/CS_B10 load into BNNT (14,14) during the loading process, respectively. (c) The density map for water molecules inside BNNT (14,14). Two black dash circles shown in each figure represent the two layer water molecules inside BNNT (14,14).
20
30
40
50
CS_B10/BNNT(14,14)
0 between CS_B10 and BNNT (14,14). Secondly, CS_B10 spends more time to adjust its conformation to enter BNNT (14,14) owing to the high solvation free energy and rigidity of the CS_B10 chain. The interaction mechanism between chitosan and BNNTs as well as the loading mechanism for chitosan entering into/onto BNNTs revealed in this study would give some useful suggestion to the drug screen and delivery systems. It suggested that encapsulation efficiency of chitosan could be improved by adjusting the ratio functional groups (-NH3+/NH2) in chitosan's chains via changing their protonation degree.
10
100
200
300
400
500
Time (ns) Fig. 9. The number of H-bonds between chitosan and water molecules in CS_A10/BNNT (14,14) and CS_B10/BNNT (14,14) systems versus the simulation time.
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Please cite this article as: J. Li, C. Chen, J. Zhang, et al., Molecular dynamics study on loading mechanism of chitosan into boron nitride nanotubes, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.111753