Unravelling the Structural Changes in α-Helical Peptides on

Article pubs.acs.org/JPCC

Unravelling the Structural Changes in α‑Helical Peptides on Interaction with Convex, Concave, and Planar Surfaces of BoronNitride-Based Nanomaterials S. K. Mudedla,†,‡ K. Balamurugan,† and V. Subramanian*,†,‡ †

Chemical Laboratory, CSIR-Central Leather Research Institute, Adyar, Chennai 600 020, India Academy of Scientific and Innovative Research (AcSIR), CSIR-CLRI Campus, Chennai 600 020, India

‡

S Supporting Information *

ABSTRACT: The interaction between polyalanine (PA) peptide in a αhelical conformation with boron-nitride-based nanomaterials such as boron nitride nanotube (BNNT) and boron nitride sheet (BNS) has been studied using classical molecular dynamics simulations and density functional theory (DFT)-based calculations. PA interacts with convex (exohedral mode) and concave (endohedral mode) surfaces of BNNT. The interaction of PA with the planar surface of BNS is also investigated. It is evident from the findings that the helical structure of the peptide undergoes conformational changes, which depend on the nature of curvature of the surface. It is found from the results that transition of α-helical conformation to turns takes place in the presence of these BNS, in contrast with the interaction of PA with graphene. The large structural changes in the PA upon interaction with BNS compared with graphene are due to the appreciable van der Waals interaction between PA and BNS. The DFT calculations have also predicted that the dispersion interaction is responsible for the stabilization of alanine on the surface of boron nitride sheet. Furthermore, to assess the effect of amino acid composition of peptide in the interaction pattern with BNS, we have also explored the adsorption of polyphenylalanine (PF), amphiphilic peptide (Nano-1), and a peptide derived from membrane protein (SNARE) on the surface of BNS. Results reveal that BNS induces the secondary structural changes in these peptides.

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curvature of CNTs.30,31 The adsorption strength of biomolecules has been found to increase with the decrease in the curvature of CNTs. The noncovalent interaction between CNTs and biomolecules is governed by the van der Waals interaction. Both noncovalent and covalent functionalizations of CNTs help us to overcome the difficulties associated with poor solubility of CNT.32,33 CNTs are toxic to the cells in the absence of functional groups.34,35 Previous study has shown that the insertion of CNT leads to the severe damage of the cell membrane.36 The damage is directly proportional to the curvature of the CNTs.37 The toxicity of CNTs has been addressed in a previous study.38 Recently, boron nitride nanotubes (BNNTs), which are structurally similar to the CNTs, have received widespread attention of researchers due to their properties such as large electronic band gap and mechanical strength.39,40 The band gap of BNNTs is independent of the diameter of tube when compared with CNTs. 39,40 BNNTs have found many applications in nanomedicine due to their biocompatibility.41

INTRODUCTION The potential applications of carbon-based nanomaterials such as fullerenes, carbon nanotube (CNT), and graphene in several fields have been investigated because of their extraordinary mechanical, electronic, catalytic and transport properties.1−8 In particular, CNT and graphene have attracted significant interest of researchers due to their applications in nanobiotechnology.9,10 CNTs have been widely used in the biosensors, biomedical devices, tissue engineering, and drug delivery.11−14 The outer surface (convex surface) of CNTs is highly reactive toward reactive species due to the correct disposed sp2 hybrid carbon atoms for the formation of chemical bonds. The inner surface (concave surface) of CNTs is inert, and it can hold the highly reactive species by encapsulation. Many studies have shown the translocation of CNTs loaded with peptide, protein, and nucleic acids across the cell membrane.15−17 The encapsulation of peptides, proteins, and nucleic acids into the CNTs has been investigated using molecular dynamics simulations.18−20 The adsorption phenomenon of biomolecules has been studied using experimental and computational techniques.21−26 The secondary structural elements of proteins and peptides have been affected upon interaction with CNTs.27−29 The induced structural changes depend on the © 2016 American Chemical Society

Received: August 25, 2016 Revised: October 24, 2016 Published: November 21, 2016 28246

DOI: 10.1021/acs.jpcc.6b08587 J. Phys. Chem. C 2016, 120, 28246−28260

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and (24,24) and BNSs were built with the help of materials studio package.65 The length of BN nanotubes was taken as 73.5 Å. To simulate an infinite BN nanotube, a segment of length equal to the Lz of the box dimension was aligned along the Z direction to share the chemical bond between terminal boron and nitrogen atoms. In the case of infinite BN sheet, a segment of length equal to Lx and Ly of box was aligned along the X and Y directions such that the sharing of chemical bond between boron and nitrogen atoms is possible. Molecular dynamics simulations were performed for the complexes of BN model systems with PA using GROMACS-4.6.2 package.66−68 The Lennard-Jones parameters for boron and nitrogen atoms of BN materials (BNNT and BNS) were adopted from the previous investigations.47,50,51,69 The charges of boron and nitrogen atoms are 0.4 and −0.4 e, respectively. Previous studies showed that the Amber03 force-field parameters were suitable for the PA; the same were used to carry out the MD simulations.70,27,29 The complexes of BN materials with PA were placed in a box and solvated with the TIP3P water model. Energy minimization was performed for all complexes using the steepest decent method to relax the whole system. Furthermore, the minimized structures were subjected to equilibration for 1 ns at 293 K temperature and 1 bar pressure by imposing position restraints on the system. Velocity rescale and Parrinello−Rahman algorithms were used to control the temperature and pressure with a coupling constant of 0.1 and 2.0 ps, respectively.71−73 The production run was carried out for 60 ns using 2 fs as time step in isothermal−isobaric ensemble. During the simulation the position of BN materials was restrained using harmonic potentials. Particle Mesh Ewald method was used to calculate the electrostatic interactions with interpolation order of 4 and a grid spacing of 1.6 Å.74 Bonds between hydrogen and heavy atoms were constrained at equilibrium bond lengths using the LINCS algorithm.75 The trajectories were visualized by using the VMD package.76 The analysis of the trajectories was performed using available tools in GROMACS package. PF with 40 residues of phenylalanine and amphiphilic peptide (Nano-1) (ACE EVEAFEKKVAAFESKVQAFEKKVEAFEHG NME) was constructed in the α-helical conformation to study the conformational changes upon interaction with BNS. SNARE is a membrane protein that consists of α-helices. The structure of α-helical peptide was taken from the respective crystal structure (PDB ID: 1SFC).77 The sequence number from 141 to 199 was extracted from the H-chain of SNARE. Density functional theory (DFT) calculations were carried out to understand the noncovalent interactions between PA with BNNT, BNS, and graphene. The alanine molecule with ends capped using methyl groups was taken to study the interaction with BN materials. It has been found from previous studies that functionals such as ωB97XD and M062X were used to study the noncovalent interactions.22,23 Hence the geometries of complexes of alanine and BN models were optimized using the ωB97XD/6-31G* level of theory. The interaction energies (IEs) were calculated for all of the complexes using the supermolecular approach

The water-dispersible BNNTs have been found to be useful for the drug delivery, neutron capture therapy, and electroporation therapy.42−44 BNNT is good potential candidate for the drug delivery due to its chemical inertness and resistance to the oxidation.45,46 In a recent study, the stability and insertion mechanism of BNNT through the cell membrane have been investigated, and the results have also been compared with those obtained for CNT.47 Previous studies have revealed that the BNNTs are nontoxic to the health and environment.48,49 The transport properties of water in the BNNTs have shown that they could be used as water conductors.50 The structure and dynamics of confined water in the BNNT have been studied using molecular dynamics simulations.51 BNNTs can deliver DNA oligomers to the interior of cells.52 A previous study has shown the noncovalent functionalization of BNNTs using proteins.52 The adsorption strength of amino acids on the surface of BNNT is substantially high when compared with CNT.53 The adsorption of polar amino acids on the surface of BNNTs is more favorable than the hydrophobic residues.54,55 In addition to BNNTs, boron nitride sheets (BNSs) exhibit high thermal and chemical stabilities.56,57 Water-soluble BNSs have been used in the synthesis of high-performance hydrogels.58 However, BNNTs and BNSs are not soluble in water and also in common organic solvents.59 Modifications have been made in BNSs to improve the solubility properties using covalent and noncovalent functionalizations.60−62 Isolation of BNNTs has been carried out with the help of peptide, which is in amphiphilic nature.63 BNNTs and BNSs can be used for the delivery of biomolecules such as DNA, peptides, and proteins. The investigations on interaction of BNNTs and BNSs with biological systems will enhance fundamental understanding between the two systems, which will be immensely useful to the development of biocompatible systems for the biomedical applications. Hence the knowledge on the interaction of biomolecules with BNNTs and BNSs is necessary. The origin of structural changes in the biomolecules upon interaction with BNNTs and BNSs is still elusive. Therefore, the adsorption of helical peptides on the surface of BNNTs and BNSs has been studied in this investigation using classical molecular dynamics simulations. Polyalanine (PA) has been used as a model to explore the secondary structural changes upon interaction with BNNTs and BNSs. Furthermore, polyphenylalanine (PF), peptide derived from membrane protein (SNARE), and amphiphilic peptide (Nano-1) have also been chosen to unravel their interaction with BNS. The following points have been addressed in the present study. 1. To understand the interaction of BNNTs and BNSs with the PA in α-helical conformation. 2. To unravel the difference in the interaction between exohedral and endohedral modes of interaction of peptides with BNNTs. 3. To compare the interaction patterns of peptide and BNS with that of graphene. 4. To understand how amino acid composition and nature of peptides influence the interaction pattern.

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IE = EC − (EM1 + EM2)

COMPUTATIONAL DETAILS PA peptide with 40 residues was chosen as a model peptide based on the previous studies.27,29 The PA with the ends capped by acetyl (ACE) and N-methylamine (NME) was constructed in the perfect helical conformation using Pymol tool.64 BNNTs with various diameter such as (12,12), (18,18),

(1)

where IE is the interaction energy of the complex, EC is the energy of complex, EM1 is the energy of BN model, and EM2 is the energy of alanine. The IEs of the optimized geometries were calculated at ωB97XD/6-31+G** by performing single-point calculations, 28247

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Figure 1. Adsorption of PA on the convex surface of BNNTs with different chiralities.

intermolecular complexes of PA- and BN-based nanomaterials, are displayed in Figures 1−3. It can be noted from Figure 1 that the PA wraps around the surface of (12,12)BNNT(convex). Because of the increase in the surface area, the adsorption of PA on the flat surface of (18,18)BNNT and (24,24)BNNT takes place. The adsorption of PA on the concave surface of (12,12)BNNT is different from that on convex surface. The PA remains at the center of tube during MD simulation due to nonavailability of space for structural relaxation. The adsorption pattern of PA inside (18,18) and (24,24)BNNT is different from that of (12,12)BNNT(concave) due to the availability of free space around the PA. The PA also interacts with the basal plane of BNS to model the effect of surface planarity. It can be seen from Figures 1−3 that the loss of helical structure in PA takes place after the adsorption onto the surface of BN nanomaterials. To assess the structural changes in the PA upon interaction with BN materials, we calculated the secondary structure of peptide and associated number of hydrogen bonds in the PA. The residue-wise secondary structural details of PA in the convex, concave, and planar BN system-based complexes were calculated using DSSP tool in GROMACS package.83 The calculated residue-wise secondary structural details are displayed in the Supporting Information (Figure S1). It can

and these IEs were corrected for BSSE (basis set superposition error) using the counterpoise method, as suggested by Boys and Bernardi.78 All DFT calculations were performed with the help of the Gaussian 09 suit of programs. 79 Energy decomposition analysis was carried out by using BLYP-D dispersion-corrected Grimme’s functional available in Amsterdam Density Functional theory (ADF) package.80−82

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RESULTS AND DISCUSSION Interaction of Polyalanine with BNNTs, BNSs, and Graphene. MD simulations have been performed for all complexes of peptide with BN nanomaterial model systems to investigate the intrinsic changes in the structure of selected model peptides, as induced by the different surfaces. BNNTs of chiralities of (12,12), (18,18), and (24,24) have been selected. Initially, the distance between two systems was kept at 15 Å while modeling the interaction of BNNT(convex) and BNS with PA. The helical axis of the peptides was aligned parallel to the central axis of the BNNT(convex) and surface of BNS. In the case of BNNT(concave), the helical axis of the peptide was aligned with the central axis of the tube. It is found from MD simulation that the distance between the surface of BNNT(convex)/BNS and PA decreases due to the interaction. Initial and final structures, as collected from MD simulation of various 28248

DOI: 10.1021/acs.jpcc.6b08587 J. Phys. Chem. C 2016, 120, 28246−28260

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Figure 2. Interaction of PA with the surface of BNS.

Figure 3. Adsorption of PA on the concave surface of BNNTs with different radii.

be clearly observed that the helical conformation of PA is significantly disrupted upon interaction with convex surface of (12,12)BNNT and the peptide undergoes conformational transition from helix to turn. It can be noted that the propensity of breaking of helix increases for (18,18)BNNT(convex) and (24,24)BNNT(convex) when compared with the highly curved surface of (12,12)BNNT(convex). It is possible to note that the disruptions in the helical structure are substantially high for BNS. The average helical content of PA upon interaction with (12,12)BNNT(convex), (18,18)BNNT-

(convex), (24,24)BNNT(convex), and BNS is 58, 51, 44, and 35%, respectively. The ability to induce conformational transitions in the helical conformation is inversely proportional to the curvature of the BN materials. The calculated secondary structural details of PA after the interaction with concave surface of (12,12)BNNT, (18,18)BNNT, and (24,24)BNNT are shown in the Supporting Information (Figure S1). It can be seen from Figure S1 that the disruption in the helical structure of PA increases for (18,18)BNNT(concave)−PA and (24,24)BNNT(concave)− 28249

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Figure 4. Interactions between backbone of PA and surface of BN materials. (a) Direct backbone interaction. (b) Water interactions with surface and backbone of PA. Distances in angstroms.

The hydrogen bond between CO (carbonyl) group of ith residue and N−H groups of i+4th residue is responsible for the stability of helical conformation. To understand the stability of helical conformation upon interaction with BN materials, we calculated the number of hydrogen bonds in PA. The calculated number of hydrogen bonds in PA upon interaction with convex, concave, and planar surface is given in the Supporting Information (Figure S2). In all of the complexes, the number of hydrogen bonds decreases after the adsorption of PA on the surface of BNNTs. The average of number of hydrogen bonds in PA for (12,12)BNNT(convex)−PA, (18,18)BNNT(convex)−PA, (24,24)BNNT(convex)−PA, and BNS−PA is 25, 24, 21, and 18, respectively. The same for (18,18)BNNT(concave) and (24,24)BNNT(concave) is 23 and 21,

PA complexes when compared with (12,12)BNNT. The helical conformation of peptide undergoes conformational transition from helix to turn, random-coil, and 310-helix after interaction with the concave surfaces. Previous studies have shown that the polar confinement destabilizes the folded peptide.84 Findings from the present study are also in accordance with the previous report.84 The average helical content of PA upon adsorption onto the concave surface of (18,18)BNNT and (24,24)BNNTs is 45 and 42%, respectively. The loss of helical content increases with the decrease in the curvature of concave surface of BNNTs. Overall results reveal that the helix breaking propensity is high for the BNS and concave surfaces when compared with convex surface. 28250

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Figure 5. Snapshot of adsorbed PA on the surface of graphene as obtained from MD simulation.

complexes of PA and BN materials. The average number of contacts is 4442, 4612, 5041, 8131, 7056, 6454, and 5772 for (12,12)BNNT(convex), (18,18)BNNT(convex), (24,24)BNNT(convex), (12,12)BNNT(concave), (18,18)BNNT(concave), (24,24)BNNT(concave), and BNS, respectively. The number of contacts is also directly proportional to the IEs between PA and BN nanomaterials. Comparison of concave and convex systems shows that the IE is more for BNNT(concave)−PA complexes. Furthermore, to understand the interactions between PA and BN materials, we performed the DFT calculations. The single alanine (A) residue was taken as the model that was capped with methyl groups. The B120N120H48 (it is referred to as BNNTH in remaining part of text) was taken as model for (12,12)BNNT. The alanine was placed in different orientations above the surface of convex BNNTH. In the case of concave model of BNNTH, alanine was kept inside the tube. The optimized geometries as obtained from ωB97XD/6-31G* level of calculations are shown in the Supporting Information (Figure S5). The alanine residue interacts through −CO, −NH, and −CH3 with π-cloud. The IEs were calculated for all of the complexes and given in Figure S5. The calculated IEs for BNNTH−alanine complexes are −10.48 and −11.44 kcal/mol for convex and concave surfaces, respectively. A higher IE is found for alanine with the concave surface of BNNTs than convex. Results from the DFT calculations are corroborated with the results obtained from MD simulations. The PA interacts with surface of BN models through carbonyl of backbone (−CO), −NH, and −CH3 groups. This is in accordance with the results from DFT calculations. In addition to the direct interaction with surface, water-mediated interactions are also found. The hydrogen-bonded water molecules with carbonyl (−CO) group of backbone of peptide directly interacts with the surface and also through water chain. Various interactions between PA and surface of BN models are depicted in Figure 4. It is found from a previous study that the decrease in the transitional entropy of water molecules due to confinement and formation of water−peptide hydrogen bonds stabilizes the unfolded state of peptide.85

respectively. It can be seen from the results that the reduction in the number of hydrogen bonds in BNS is higher than that of convex and concave surfaces. The reduction in hydrogen bonds increases with the decrease in the curvature. Thus the increase in the planarity of BN materials strongly affects the intramolecular hydrogen bonds in PA and concomitant secondary structure. The displacement of water molecules lying between BN systems and PA is one of the factors responsible for the changes in the conformation of PA. This is directly related to the increase in the contact area upon interaction. To understand the same, the contact area between BN systems and PA was calculated with the help of solvent-accessible surface area (SAS) using eq 2. contact area =

1 [[SASPA + SASBNNT(BNS)] 2 − SASBNNT(BNS) − PA complex ]

(2)

The calculated contact areas for all intermolecular complexes are shown in Supporting Information (Figure S3). It is evident that the contact area increases with enhancement in planarity of surfaces, and contact area is appreciably high for BNS. Analysis of results reveals that the reduction in the secondary structural content and the number of hydrogen bonds is directly proportional to the contact area. The calculated contact areas for different concave surfaces decrease with the increase in the planarity. The contact area of PA with (18,18)BNNT(concave) and (24,24)BNNT(concave) decreases by increase in the diameter of tube. The contact area for PA on BNNT(concave) surface is higher than that of the BNNT(convex). The number of water molecules accommodated inside the nanotube in the presence of PA is less when compared with the bare tube. The loss in SAS reflects the increase in contact area between BNNT and peptide. The calculated IEs are given in the Supporting Information (Figure S4). The contact area is directly proportional to IE of PA and BNNT complexes. The calculated number of contacts between PA and BN nanomaterials within 6 Å increases with the time evolution of the intermolecular 28251

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Figure 6. Residue-wise calculated secondary structure of PA upon interaction with graphene.

to 310 helix is the predominant transition in graphene−PA model. Hence, the nonpolar flat surface in graphene induces the 310 helix conformation. On the contrary, the planar surface in BNS induces turn conformation in PA. To elucidate the difference, we calculated the contact area of graphene−PA model and compared it with that of the BNS−PA system. The calculated contact area of BNS is similar to that of graphene. The calculated IEs and contact area of graphene−PA and BNS−PA models are displayed in Figure 7. It can be clearly seen that the IE is high for BNS when compared with that of graphene. The calculated average IEs over three different simulations with random velocity distributions for the complex of PA with BNS and graphene are shown in Figure S9. The average IE is higher for BNS than that of graphene. The van der Waals energy between BNS and PA was calculated and compared with those values of graphene−PA model. It is found that the van der Waals contribution is more for BNS−PA model than that of graphene−PA model. The contribution of electrostatic energy is marginal. The relatively high van der Waals interaction between BNS and PA is responsible for the large structural changes in PA when compared with those induced by graphene. Furthermore, to assess the nature of interaction between PA and graphene as well as PA and BNS, the DFT calculations were made to predict the IE. The alanine (A) residue was placed parallel to the surface of a model boron nitride sheet passivated with hydrogen atom (BNSH). The molecular formula is B27N27H18. To model graphene, a graphene flake passivated with hydrogen (GRH) was taken. Its molecular formula is C54H18. It can be seen from the optimized geometries (Figure S10 in Supporting Information) that the noncovalent interactions such as C−H···π, N−H···π, and CO···π are responsible for the stabilization of GRH-A model system. Similar interactions are also observed in the case of BNSH-A system. The calculated IE for BNSH-A is −16.42 kcal/mol, which is higher than that of GRH-A (−14.76 kcal/ mol) at the ωB97XD/6-31+G** level of theory. Furthermore, to understand the origin of the stability of complexes, we carried out the energy decomposition. The calculated energies (Table 1) reveal that the dispersion interaction stabilizes the complex when compared with electrostatic and orbital IEs. The contribution from dispersion energy is marginally higher for BNS than that of graphene. In addition to dispersion energy,

Therefore, analysis of such interactions in concave system is significantly important. The calculated number of hydrogen bonds between water and PA upon interaction with concave surface of BNNTs is shown in Figure S6 in the Supporting Information. The number of hydrogen bonds increases with time. The initial number of hydrogen bonds between PA and water is 15 for (18,18)BNNT(concave) system. The same for (24,24)BNNT(concave) is 23. The average value of number of hydrogen bonds after interaction with BNNTs is 42 and 49 for (18,18)BNNT(concave)−PA and (24,24)BNNT(concave)− PA models, respectively. The increase in hydrogen bonds leads to decrease in the transitional entropy of water molecules that present in the polar confinement of BNNTs. The PA− water hydrogen bonds destabilize the intramolecular hydrogen bonds in PA. To further understand the interaction trends, we have performed multiple simulations for the same initial structures with different velocity distribution. For each complex of PA and BN materials three simulations were carried out with different randomized velocities. All of these simulations reveal that the secondary structural changes are inversely proportional to the curvature of BN materials (BNNTs (convex and concave) and BNSs). The IEs and number of hydrogen bonds were averaged over three different simulations for each complex of PA with BN materials (Figures S7 and S8 in Supporting Information). The average values of IEs are also given in the Supporting Information (Table S1). The IEs also follow the same trend as previously discussed in the case of convex and concave surface. There are no changes in the trends observed from single MD simulation. A previous study has shown that the reduction of helical content is significant after interaction with graphene when compared with the interaction of PA with CNT.30 The van der Waals interaction is responsible for the adsorption of PA on the surface of graphene. Graphene and BNSs are nonpolar surfaces.86 To compare the structural changes in PA on interaction with graphene and BNS, we performed the simulation for the complex of graphene−PA. The snapshots are shown in Figure 5. The calculated secondary structural details are presented in Figure 6. It can be noted from the results that the α-helix breaking propensity is less for graphene when compared with that of BNS. The predominant structural transition in BNS−PA model is α-helix to turn, whereas α-helix 28252

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Figure 7. (a) Contact area, (b) interaction energy, and (c) van der Waals and electrostatic interaction energies contribution in the interaction of PA with BNS and graphene surface.

Table 1. Energy Decomposition Analysis of Complexes of BNSH and GRH with Alanine at BLYP-D/TZP Level of Theory complex

electrostatic energy (kcal/mol)

orbital interaction energy (kcal/mol)

Pauli repulsion energy (kcal/mol)

dispersion energy (kcal/mol)

interaction energy (kcal/mol)

BNSH-A GRH-A

−12.58 −8.50

−7.11 −5.22

27.06 21.86

−23.74 −23.55

−16.37 −15.41

model system in α-helical conformation. Molecular dynamics simulation was performed on BNS-PF model system for 60 ns. The initial and final snapshots are displayed in Figure 8. It can be seen that the phenyl ring stacks with the surface of BNS. Furthermore, it can be noted that a portion of α-helical conformation is retained after interaction with BNS with the aid of the π−π stacking interaction. The phenyl rings lie at a distance of ∼3.0 to 3.5 Å from the basal plane of BNS. The calculated IE for the BNS-PF system is shown in Figure 9. The interaction of side chains is higher than the backbone of PF. The side chains of PF hinder the interaction of backbone atoms

electrostatic energy is also high for BNS when compared with graphene. Thus the electrostatic interaction also plays an important role in the stabilization of alanine on the surface of BNSH. The above findings are in accordance with the results obtained from molecular dynamics simulations. Interaction of Polyphenylalanine with BNS. Although PA interacts with aid of π···CO and π···CH3 mode of interaction, the π···π stacking interaction between aromatic amino acids and BNS plays a crucial role in the interaction pattern.63 To understand the role of aromatic amino acid in the interaction pattern, we took the PF with 40 residues as the 28253

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Figure 8. Snapshots of the complex of polyphenylalanine and BNS as obtained from MD simulation (a) at 0 ns and (b) at 60 ns.

acid (Glu) and aspartic acid (Asp). To further understand the role of basic and acidic amino acids in the adsorption process of SNARE peptide, snapshots of adsorbed peptide at different time intervals are shown in Figure 10. It can be clearly seen that arginine initiates the adsorption process by interacting with the surface through planar guanidium ion. After the adsorption of arginine, the remaining amino acids interact with the surface. Furthermore, it can be noted that the acidic amino acids (Glu and Asp) are not involved in the adsorption. The carboxylate groups are involved in the formation of salt bridge and hydrogen bonds with arginine and other amino acids, respectively. The carboxylate groups that are situated in the direction perpendicular to BNS surface are stabilized by the solvation of water molecules. Lysine is found to be in contact with the surface via NH3 group. Interaction of Nano-1 with BNS. Nano-1 has been designed to be amphiphilic in nature, and it has been used for the dispersion of CNTs.87 Nano-1 peptide binds to CNT surface through hydrophobic interaction. The adsorption of nano-1 peptide on CNT helps to solubilize CNT in water. To explore the nature of amphiphilic peptide on the surface of BNS, we interacted the nano-1 peptide with BNS surface. The initial and final snapshots of the complexes of BNS with nano-1 peptide are presented in Figure 11. Nano-1 peptide binds to the BNS surface with the help of aromatic rings (phenylalanine)

with the surface of BNS. The calculated residue-wise secondary structural details are given in Figure 9. The helical content of PF significantly decreases upon adsorption onto the BNS surface. Although phenylalanine has significant propensity scale to adopt α-helical conformation, the steric hindrance in the stretches of phenyl rings may also disrupt the α-helical structure. Interaction of SNARE Peptide with BNS. To elucidate the importance of amino acid sequence and composition in the interaction pattern, we selected two models to investigate the interaction with the BNS. A fragment of helix containing hydrophilic and hydrophobic residues was chosen from SNARE protein. The helical fragment was interacted with the surface of BNS. The calculated secondary structure of SNARE (ACEARENEMDENLEQVSGIIGNLRHMALDMGNEIDTQNRQIDRIMEKADSNKTRIDEANQRA NME) peptide upon interaction with BNS is given in Figure 10. The helical conformation transforms to turn and coil after interaction with BNS. Previous study has been shown that CNT induced more secondary structural changes in amino acids (12−22 in SNARE peptide) that have low propensity to form helix.27 In the case of BNS, irrespective of their helical propensities of amino acids, helical fragment undergoes appreciable conformational changes. The basic and acidic amino acids present in SNARE peptide are arginine (Arg) and lysine (Lys) as well as glutamic 28254

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Figure 9. (a) Interaction energy of backbone and side chains of polyphenylalanine with BNS. (b) Calculated residue-wise secondary structure of polyphenylalanine upon interaction with BNS.

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CONCLUSIONS The interaction between PA peptide, PF peptide, membrane peptide (SNARE), and amphiphilic peptide (Nano-1) with boron-nitride-based nanomaterials such as BNNTs and BNSs has been investigated with the help of classical molecular dynamics simulations and DFT-based calculations. The interaction patterns of PA with concave, convex, and planar surfaces of BN models are different. The induced structural transitions increase with the decrease in the curvature of convex and concave surface of BNNTs. The increase in the planarity of the surfaces strongly disrupts the α-helical conformation of PA. The strong interaction of PA with boron nitride nanomaterial surfaces induces the conformational transitions from α-helix to turn. Furthermore, the interaction pattern of PA with BNS has also been compared with that of graphene. It is interesting to note that the surface of BNS induces transitions from α-helical conformation to turn, whereas the same conformation is transformed to 310-helix, which is another form of helix in the presence of graphene. Helical conformation is partially affected in the presence of graphene, whereas BNS strongly affects αhelical structure. Thus the nature of surface profoundly influences the interaction pattern. The van der Waals interaction is responsible for the destabilization of α-helical conformation on the surface of BNS. Similar findings have also

and hydrophobic aliphatic alkyl chains (lysine, glutamic acid, Val). However, the acidic and basic groups (carboxylate and ammonium) do not interact with the BNS surface because these groups are surrounded by water molecules. The calculated distance between phenyl rings of phenylalanine and BNS is displayed in Figure 11. All aromatic rings stack to the basal plane of BNS at a distance of 3.0 to 3.2 Å. Furthermore, to understand the interaction of aromatic rings and carboxylate (from glutamic acid) and ammonium (from lysine) groups with BNS, we calculated the number of contacts between BNS and these groups within 4 Å, and results are given in Table 2. The number of contacts shows that the COO− and NH3+ are not involved in the adsorption process. Therefore, aromatic amino acids and arginine have an important role in the adsorption of peptides on BNS surface. The nano-1 peptide acts as hydrophilic due to the exposed carboxylate and ammonium groups to water. To characterize the conformational changes of nano-1 peptide upon interaction with the surface of BNS surface, we calculated the residue-wise secondary structure. It is evident from Figure 11 that nano-1 peptide undergoes conformational changes from helix → turn → coil. 28255

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Figure 10. (a) Calculated residue-wise secondary structure of SNARE peptide upon interaction with BNS. (b) Snapshots for the adsorbed SNARE peptide on the surface of BNS (van der Waals model, arginine; stick model, carboxylate and ammonium group), as derived from MD simulation.

interaction with the surface plays an important role in the adsorption process. The aromatic side chain of phenylalanine residues stacks with the BNS surface, leading to disruptions in helical conformation of the peptide. To unravel the amino acid sequence and composition, we have interacted membrane-

been emanated from the DFT calculations on the smaller model systems. Furthermore, the role of stacking of aromatic amino acids in the interaction between BNS and peptides has also been investigated by taking PF as a model system. The stacking 28256

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Figure 11. (a) Snapshots for the adsorbed Nano-1 peptide on the surface of BNS (yellow color is phenyl rings) from MD simulation. (b) Calculated distance between phenyl ring and BNS from MD simulation. (c) Calculated residue-wise secondary structure of Nano-1 peptide upon interaction with BNS. 28257

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Table 2. Number of Contacts of Phenyl Ring, Carboxylate, and Ammonium Groups of Nano-1 Peptide with BNS amino acid

average number of contacts

PHE6 PHE13 PHE20 PHE27 GLU2 GLU4 GLU7 GLU14 GLU21 GLU25 GLU28 LYS8 LYS9 LYS16 LYS22 LYS23

56 56 51 50 2 0 0 4 3 0 1 0 4 0 0 1

AUTHOR INFORMATION

Corresponding Author

*Tel: +91 44 24411630. Fax: +91 44 24911589. E-mail: [email protected], [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

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REFERENCES

We thank the Board of Research in Nuclear Sciences (BRNS), Mumbai, India, and Nanomaterial−Safety, Health and Environment (NanoSHE BSC0112) project funded by Council of Scientific and Industrial Research (CSIR) New Delhi, India, for Financial Support. We acknowledge Design and Development of Two Dimensional van der Waal Solids project (No. EMR/ 2015/000447) funded by and Department of Science and Technology (DST) New Delhi, India, for financial support. S.K.M thanks DST, New Delhi, India for providing INSPIRE Fellowship (Senior Research Fellow).

based SNARE peptide with the surface of BNS. Regardless of propensity of amino acids to form α-helical conformation, the peptide undergoes appreciable changes in the conformation. Findings from Nano-1 peptide reveal that amphiphilic α-helical peptide is also destabilized by the presence of BNS surface. Overall results highlight that during the interaction between globular proteins and BN-based nanomaterials, the α-helical content of the peptide would be significantly affected and undergoes conformation transition from α-helix to predominantly turn structure.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcc.6b08587. Table S1. Calculated average interaction energies using MD trajectories obtained from three different simulations for the same initial structure. Figure S1. Residue -wise secondary structure of PA after the interaction with BN materials (BNNTs and BNSs). Figure S2. Calculated number of hydrogen bonds in PA upon interaction using MD trajectories. Figure S3. Calculated contact area between PA and BN materials using MD simulation. Figure S4. Interaction energy of PA with convex surface of BNNTs and planar surface of BNSs and concave surfaces of BNNTs and planar surface of BNSs. Figure S5. Optimized geometries of complexes of alanine with convex and concave surface of BNNTH and their interaction energies. Figure S6. Calculated number of hydrogen bonds between water and PA for concave surface of BNNTs employing MD trajectories. Figure S7. Average interaction energy of PA with convex surface of BNNTs and planar surface of BNSs and concave surfaces of BNNTs and planar surface of BNSs over three different simulations. Figure S8. Average hydrogen bonds in PA upon interaction using MD trajectories obtained from three different simulations for the complexes of PA with BN nanomaterials. Figure S9. Calculated average interaction energy of PA with BNS and graphene using the trajectories obtained from three different simulations. Figure S10. Optimized geometries of complexes of alanine with GRH and BNSH. (PDF) 28258

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