Structural Damage of a β-Sheet Protein upon Adsorption onto

Article pubs.acs.org/JPCC

Structural Damage of a β‑Sheet Protein upon Adsorption onto Molybdenum Disulfide Nanotubes Yang Ling,†,⊥ Zonglin Gu,‡,⊥ Seung-gu Kang,§ Judong Luo,*,†,‡ and Ruhong Zhou*,‡,§,∥ †

Department of Oncology, Changzhou Tumor Hospital, Soochow University, Changzhou, 213001 China School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China 215123 § Computational Biological Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York 10598, United States ∥ Department of Chemistry, Columbia University, New York, New York 10027, United States ‡

S Supporting Information *

ABSTRACT: Molybdenum disulfide (MoS2), a new type of transition metal dichalcogenides nanomaterial, has attracted significant attention lately in the biomedical industry, with many promising applications such as photothermal-triggered drug delivery agent for cancer. Accompanied with these promising applications are the growing concerns about their potential biocompatibility. Here, we use all-atom molecular dynamics simulations to investigate the interaction of a MoS2 nanotube with YAP65 WW domain, a mostly antiparallel β-sheet model protein widely used in molecular simulations. We find that YAP65 loses most of its secondary and tertiary structures within a few hundred nanoseconds after adsorbing onto the MoS2 nanotube surface, indicating that the MoS2 nanotube displays significant structural damage to YAP65. The strong dispersion interactions, especially from those “signature” aromatic residues (Tyr28 and Trp39), help drive YAP65 adsorption onto the nanotube surface, which thus breaks the native beta strand hydrogen bond network and subsequently destroys the secondary and tertiary structures. These findings might shed new light onto the potential nanotoxicity of MoS2 nanomaterial and its underlying molecular mechanism.

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INTRODUCTION The most common one-dimensional (1D) nanomaterials are probably those carbon-based ones, such as single-wall carbon nanotubes (SWCNTs)1−4 and multiwall carbon nanotubes (MWCNTs),5−7 which have attracted tremendous interest in many fields including biomedicine since their discovery. Novel 1D nanomaterials, such as molybdenum disulfide (MoS2) and tungsten disulfide (WS2) nanotubes,8 as well as boron nitride nanotubes (BNNTs),9−11 are quickly catching up and emerging as a new research frontier. These novel nanomaterials12,13 have been featured with excellent mechanical and electrical properties. Therefore, there have been many attempts to take advantage of various 1D nanomaterials as delivery platforms, diagnostic agents, therapeutic nanodrugs, and tissue engineering scaffolds.14 Even though these 1D carbon nanomaterials have demonstrated many outstanding applications, issues related to their biosafety and nanotoxicity are raising deep concerns lately.15−17 For example, previous studies revealed that exposure to these CNTs may result in damaging health effects with serious impacts on tissues, cells, and various biomolecules.18,19 In particular, when some α-helical peptides were adsorbed onto © 2016 American Chemical Society

CNTs and graphene, they displayed significant conformational changes with severe losses in their helical content.20,21 On the other hand, these conformational changes can also be used advantageously to alter protein behavior and assembly.22,23 To overcome the potential adverse effects, researchers have tried to reduce the toxicity of these nanomaterials via functionalization by conjugating or coating with various chemical molecules like poly(ethylene glycol) (PEG) or proteins,24 which has yielded promising results. Recently, molybdenum disulfide (MoS2),25 a branch in transition metal dichalcogenides nanomaterials, is receiving a tremendous amount of attention in the scientific community. It is believed that MoS 2 nanotubes might share similar physicochemical properties with CNTs and can potentially replicate CNTs’ success in biomedical applications such as drug delivery platforms and photothermal therapeutic agents.26,27 The high near-infrared (NIR) absorbance and extensive specific surface area of MoS2 allow it to be applied in NIR Received: November 16, 2015 Revised: March 9, 2016 Published: March 11, 2016 6796

DOI: 10.1021/acs.jpcc.5b11236 J. Phys. Chem. C 2016, 120, 6796−6803

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The Journal of Physical Chemistry C photothermal-triggered drug delivery platform,28 as well as photothermal29 and chemotherapy combined therapeutic agents of cancer.30 In addition, with Mo’s excellent X-ray absorption capability, MoS2 can be used as a contrast agent in X-ray computed tomography imaging.28 Furthermore, inorganic fullerene-like MoS2, which was synthesized by pulsed laser ablation (PLA) in water, was confirmed to have good solubility and biocompatibility.31 Despite all the incredible properties of MoS2 and its potential applications in the biological field, there have been very limited research efforts devoted to explore its toxicological impact on human health. Therefore, it is essential and urgent to assess the biocompatibility and toxicity of MoS2 before its wider realization of biomedical applications. In this study, as a first attempt, we aim to probe the potential impact of MoS2 nanotube to YAP65, a widely used model protein consisting of three β-sheets. In addition, YAP65 is an important Yes kinase-associated protein domain32 (WW doamin) and is present in a number of signaling and regulatory protein complex systems, often in several copies.33−35 Thus, it has significance in the potential long-term adverse impacts of MoS2 nanotubes on the cellular signaling and regulatory pathways. Our simulation results indicate that YAP65 loses its secondary and tertiary structures quickly once adsorbed onto the MoS2 nanotube surface. The strong van der Waals (vdW) dispersion interactions, especially from those “signature” aromatic residues (Tyr28 and Trp39), predominantly drive YAP65 adsorption onto the nanotube surface, which thus breaks the native beta strand hydrogen bond network and subsequently destroys the secondary and tertiary structures.

employing the LINCS algorithm,57 and water geometry was constrained by employing the SETTLE algorithm.58 During the production runs, a time step of 2.0 fs was used, and coordinates were collected every 20 ps. Four independent MD simulations, with three for the complex and one for the protein-only control, were performed, each having a length of 500 ns. The total aggregated simulation time was larger than 2.0 μs.

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RESULT To ensure the stability of the YAP65 protein, we first conducted MD simulation for the system containing a standalone protein in solvent without MoS2 nanotube for 500 ns (control run; Figure S2). From the overlapping of the first and last frames obtained in the resulting trajectory (Figure S2a), there is little change observed in the final structure of YAP65 as compared to its original one (with an rmsd of 2.08 Å between these two structures). The β-sheet ratio (Figure S2b), defined as the ratio of the number of β-sheet residues to that of the initial structure, fluctuates between 90% and 120% but distributes mostly in the range of 110−120% due to the movement of YAP65 backbone in solvent. Similarly, the hydrogen bond number (Figure S2c) mainly fluctuates between 8 and 12, while the original hydrogen bond number is 10. These data from the control run indicate that the protein βsheet structure has little change; i.e., the standalone YAP65 is indeed very stable in solvent. Now we turn to the MoS2 + YAP65 complex system. Figure 1 shows the initial system setup of the complex, which was

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METHOD The simulated complex system in this study consisted of a MoS2 nanotube and a YAP65 protein (WW domain). The initial structure of YAP65 was downloaded from the Protein Data Bank with the PDB code 1JMQ36 (residues 15−40). The length and chirality of the MoS2 nanotube were set at 7.4 nm and (6,6), respectively. The force field parameters of the MoS2 nanotube were obtained from a previous study by Varshney et al.37 The initial distance (minimum distance) between the nanotube and the protein was set to be 0.8 nm. The complex system was then solvated in a water box (size: 5.00 nm × 6.00 nm × 8.50 nm) that contained 23 965 atoms in total. One chloride ion was also added to the solvated box to neutralize the system. This final solvated system was then simulated with molecular dynamics (MD), an approach widely used in the studies of both biomolecules38−42 and nanomaterials.43−47 Here, the MD simulation was performed with the software package GROMACS (version 4.6.6).48 The VMD software49 was used to visualize the MD trajectories and draw molecular pictures. The CHARMM 27 force field50 was applied to handle all solutes in this system, and the TIP3P water model was used for the water molecules.51,52 The simulation temperature was maintained at 300 K through NVT ensemble using the Parrinello v-rescale thermostat method,53 which was widely used in previous studies.20,54,55 Periodic boundary conditions (PBC) were applied in all directions. To avoid the interaction of solutes with their mirror images in PBC, the MoS2 nanotube was frozen throughout the simulation process. The long-range electrostatic interactions were treated with the particle mesh Ewald (PME) method,56 and the van der Waals (vdW) interactions were calculated with a cutoff distance of 1.0 nm. All solute bonds were constrained to their equilibrium values

Figure 1. Initial system setup, which consists of a MoS2 nanotube and a YAP65 WW domain: (a) top view, (b) side view. The YAP65 is shown with cyan (secondary structure). The molybdenum atoms are depicted with pink vdW balls, while the sulfur atoms are exhibited with white vdW balls. The red dot is the chloride ion.

designed to explore the potential impact of MoS2 nanotube on YAP65 protein structure. The starting minimum distance between the heavy atoms of YAP65 and the MoS2 nanotube was 0.8 nm. Three independent MD simulations, each of a duration of 500 ns, were carried out for this study. The initial structure of YAP65 is given in Figure 2a, whereas its final conformations obtained from three independent simulations are presented in Figures 2b−d, respectively. The original structure of YAP65 displays three clean antiparallel β-sheet segments,36 namely B1, B2, and B3 sheets (Figure 2a). However, at the end of the simulations, all three trajectories indicate that YAP65 has lost most of its β-sheet structures. In Figure 2b and c, the corresponding B3 segment moved away from B2, with its tertiary contacts with B2 mostly lost as well, while in Figure 2d, the B1 was found away from the other two segments. In the first (Figure 2b) and second trajectories (Figure 2c), both B1 and B2 sheets resulted in a much shorter length even though some tertiary contacts between them 6797

DOI: 10.1021/acs.jpcc.5b11236 J. Phys. Chem. C 2016, 120, 6796−6803

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The Journal of Physical Chemistry C

structural damage to YAP65 after its adsorption, despite the difference in the detailed time sequence of which beta sheet lost secondary structure first. To gain a deeper understanding of the structural deformation process of YAP65 caused by MoS2 nanotube at the molecular level, we chose one representative trajectory for further analysis (other two trajectories’ analyses can be found in the Supporting Information, PS3 and PS4). Figures 3a−c show the changes of hydrogen bond number, β-sheet ratio, and secondary structure as a function of time, which clearly exhibit a stair-step pattern indicative to the progressive structural change of YAP65. Some snapshots illustrating the significant moments of this process are depicted in Figure 3d. First, at t = 0.7 ns, YAP65 originally packs to the MoS2 nanotube with Gln35 (on its B3 segment) anchoring onto the surface of the nanotube. At t = 26 ns, more residues from the protein adsorb onto the MoS2 nanotube surface, including the two aromatic residues Trp39 and Tyr28 which form the stable “face-to-face” configurations like π−π stacking59 between their side chain aromatic rings and the

Figure 2. (a) Secondary structure of YAP65 in the first frame of the system including a YAP65 and a MoS2 nanotube. (b)−(d) Secondary structures of YAP65 in the last frames after interacting with MoS2 nanotube for 500 ns.

remained intact to some extent, while B3 lost the beta sheet structure. On the other hand, in the third trajectory (Figure 2d), the B2 and B3 sheets became much shorter, while B1 lost the beta sheet structure. Overall, all three trajectories demonstrated that the MoS2 nanotube had considerable

Figure 3. (a) Hydrogen bond number as a function of simulation time where these hydrogen bonds are among the backbone of YAP65. (b) β-sheet ratio with respect to the first frame. (c) Secondary structure of YAP65 as a function of time. (d) Some snapshots in some key moments. 6798

DOI: 10.1021/acs.jpcc.5b11236 J. Phys. Chem. C 2016, 120, 6796−6803

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Figure 4. Contact number map among each residue’s heavy atoms of YAP65 in the first frame (a) and last frame (b). Contact number map among the more specific backbones of YAP65 in the first frame (c) and last frame (d). Hydrogen bond pictures of YAP65 in the first frame (e) and last frame (f) where the amaranthine lines are hydrogen bonds.

frames of the trajectory are constructed (Figure 4a−b), wherein patterns (i) and (ii) represent the initial (nonspecific) contacts between B1 and B2, B2 and B3, respectively. At the end of the simulation, the contacts between B1 and B2 (pattern (i)) partly alter, while those between B2 and B3 (pattern (ii)) mostly disappear due to the movement of Trp39 and Gln40 in the B3 segment as discussed above. Simultaneously, the more specific contact maps among the backbones of YAP65 (Figure 4c−d) indicate that the orientations of B1 and B2 backbones are altered somewhat (Figure 4c, pattern (iii)), while those between B2 and B3 completely disappeared (Figure 4d, pattern (iv)). These data clearly show the complete destruction of the hydrogen bonding network between B2 and B3 and the partial disruption between B1 and B2 upon the adsorption onto the MoS2 nanotube. From snapshots shown in Figures 4e and f, it is obvious that B3 moves away from B2 with their original tertiary contacts diminishing entirely. The loss of hydrogen bonding network ultimately results in the damage of secondary and tertiary structures of YAP65. In order to further explore the underlying molecular mechanism during the adsorption process, the vdW and

surface of the nanotube. Meanwhile, the packing of Gln40 is also important for subsequent movement of the B3 segment. As evidenced by the steep decreases observed in the hydrogen bond number (∼4) and the β-sheet ratio (∼23%), it is clear that the adsorption of both residues Trp25 and Gln26 is a main cause of the loss of the secondary structure of B3 β-sheet. Then, at t = 165 ns, as some of the residues in B1 and B2 segments are also adsorbed onto the surface of the nanotube, especially Gln26 and His32, the secondary structures of these two segments also start to lose partly as seen in Figures 3c and d. These changes are reflected in the hydrogen bond number which declines from ∼6 to ∼2 and the β-sheet ratio which sharply decreases from ∼76.9% to ∼30.8%. From 165 to 443 ns, the secondary structures of B1 and B2 fluctuate as seen in Figures 3b and c. During this period, the Asn31 also tightly binds to MoS2 nanotube surface starting at 200 ns. After 443 ns, both B1 and B2 retain their partial β-sheet structure to the last frame. To analyze the change of hydrogen bonding network of YAP65 upon adsorption onto the MoS2 nanotube, the contact maps among each residue’s heavy atoms from the first and last 6799

DOI: 10.1021/acs.jpcc.5b11236 J. Phys. Chem. C 2016, 120, 6796−6803

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Figure 5. (a) Interaction vdW (black line) and Coulomb (red line) energies between YAP65 and MoS2 nanotube. (b) Interaction vdW energy map for each residue (kcal/mol) is computed along the simulation time.

Figure 6. (a) Secondary structure of YAP65. Yellow, white, and cyan structures represented β-sheet, coil, and turn, respectively. (b) Mean vdW energy of each residue using the last 100 ns data from all three independent runs. Magenta line was a boundary for relative strong interaction (lower than 15.0 kcal/mol).

all residues, the aromatic residue Trp39 truly stands out as the energy is more negative in all three trajectories (−29.3 ± 2.4, −32.0 ± 1.2, and −31.8 ± 1.7 kcal/mol, respectively). Other aromatic residue, such as Tyr28, also shows strong interaction energy in at least two trajectories indicating that it may play an important role as well. More interestingly, the Trp17 (located near the end of the B1 sheet) in trajectory 3 has the strongest vdW energy at −34.41 ± 2.72 kcal/mol. To probe the energy difference of this Trp17 residue in three trajectories, we highlighted it in the last frame of each trajectory (Figure S5). From this plot, we can clearly see that Trp17 directly interacted with MoS2 nanotube forming “face-to-face” configuration in trajectory 3, while in the other two trajectories, Trp17 were mostly exposed to the solvent. These observations validate the important role of the aromatic residues in the adsorption of YAP65 to MoS2 nanotube which has also been found in previous studies.19,47,59−69 Moreover, the glutamines also play a significant role in binding, particularly Gln26, Gln35, and Gln40, because glutamine has a long side chain that can interact with the MoS2 nanotube with a favorable interaction energy. Based on the data obtained from these analyses, it is adequate to conclude that the powerful adsorption of YAP65 onto the MoS2 nanotube surface, which causes considerable damage to its structure, can be largely attributed to the two aromatic residues Trp39 and Tyr28 and the three glutamines (Gln26, Gln35, and Gln40). Finally, it is interesting to note that as shown in previous studies,21,70−73 protein−nanomaterial interactions often result in dewetting effects.74,75 However, in this particular case, the dewetting effect is relatively small, largely due to the fact that the MoS2 nanotube is small (in diameter) with a curved surface, while the beta sheet protein is also quite small but with a relatively flat and rigid surface. Thus, the two surfaces do not “match” as well as those seen in

Coulomb interaction energies (Figure 5a) are calculated as a function of simulation time. It is easy to see that the Coulomb interaction energy is in general weaker than the vdW energy along the simulation, suggesting that the vdW interaction between YAP65 and MoS2 nanotube is the main force leading to its adsorption. To further probe each residue’s contributions, the detailed vdW interaction energy map was also computed for each residue (Figure 5b). As early as t = 0.7 ns, the vdW energy quickly drops to ∼−29.1 kcal/mol, upon the very first contact of YAP65 with MoS2 nanotube, where residue Gln35 contributes ∼−19.9 kcal/mol, consistent with the aforementioned initial contact of Gln35. Then, at t = 26 ns, the significant changes of the vdW energies of Tyr28 (∼−25.1 kcal/mol), Trp39 (∼−29.0 kcal/mol), and Gln40 (∼−18.9 kcal/mol) induce the sharp decline of the total vdW energy in Figure 5a, indicating that these three residues play an important role in guiding the further adsorption that causes the complete loss of the B3 secondary structure (Figure 3). When t = 165 ns, the energies of Gln26 and His32 reduce to ∼−25.7 and ∼−14.2 kcal/mol, respectively, causing partial damage of B1 and B2 (Figure 3). At t = 200 ns, Asn31 starts contacting with the MoS2 nanotube, with its vdW energy at ∼−14.6 kcal/mol; meanwhile, the vdW energy of His32 also decreases to ∼−23.4 kcal/mol. From 200 to 500 ns, the total vdW energy fluctuates around −249.66 kcal/mol, with no significant changes afterward indicating a metastable state was reached. These underlying molecular interaction details provide a deeper understanding of the adsorption process with key residues identified along the process. We further calculated the mean vdW interaction energy for each residue using the last 100 ns data from all three independent trajectories (Figure 6). The last 100 ns is chosen since all three trajectories converged in that time frame. Among 6800

DOI: 10.1021/acs.jpcc.5b11236 J. Phys. Chem. C 2016, 120, 6796−6803

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The Journal of Physical Chemistry C previous studies.70−72 The relatively large partial charges on MoS2 surface atoms (Mo = +0.76 e and S = −0.38 e) also limit the dewetting effect.

(BK20151174, BE2015631). R.Z. acknowledges the support from IBM Blue Gene Science Program, a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection.

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CONCLUSION Over the past few years, MoS2-based nanomaterials have caught increasing attention due to their unique and outstanding properties.76−79 Accompanying these widespread applications, including those in biomedical fields, there is also a growing concern about their nanotoxicity and biocompatibility. In this study, we have conducted MD simulations to explore the potential nanotoxicity of a MoS2 nanotube to a representative protein, YAP65 WW domain, ubiquitous in protein−protein interactions involved in cellular signaling and regulatory pathways. Upon its adsorption onto the MoS2 nanotube surface, the YAP65 protein is found to exhibit considerable structural damage with most of its β-sheet contents disappeared. The main driving force is the strong vdW dispersion interaction between the MoS2 nanotube and YAP65, in particular, the interactions from the two “signature” aromatic residues Tyr28 and Trp39, as well as the three glutamines Gln26, Gln35, and Gln40. As a result, the hydrogen bonding networks among the three β-sheets of YAP65 are broken, especially those between B2 and B3 β-sheets, which subsequently causes the disruption of protein secondary and tertiary structures. Further studies on the nanotoxicity of MoS2 to other proteins, DNA, cell membranes, as well as cells, tissues, and animal models, are highly desired for a deeper understanding of its toxicity. We also envision more development efforts on applying MoS2 nanotubes as a new type of 1D nanomaterials in biomedical applications such as drug delivery platforms and photothermal therapies. These studies on MoS2 nanotube toxicity can also stimulate and facilitate the cytotoxicity studies of other related 1D nanomaterials in this emerging field of nanotoxicology.

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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.5b11236. Detailed information about relation between the diameter and chirality of MoS2 nanotube; control trajectory and other runs analyses; Trp residue snapshots in three trajectories (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Author Contributions ⊥

These authors contribute equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Bruce Berne, Tien Huynh, Hongsuk Kang, and Xuanyu Meng for helpful discussions. This work was partially supported by the National Natural Science Foundation of China under Grant Nos. 11374221, 11574224, and 81402518 and Jiangshu Provincial Special Program of Medical Science 6801

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