Adsorption Mechanism of Amyloid Fibrils to Graphene Nanosheets

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C: Physical Processes in Nanomaterials and Nanostructures

Adsorption Mechanism of Amyloid Fibrils to Graphene Nanosheets and Their Structural Destruction Nan Zhang, Xiaoling Hu, Ping Guan, Kaiyang Zeng, and Yuan Cheng J. Phys. Chem. C, Just Accepted Manuscript • DOI: 10.1021/acs.jpcc.8b09893 • Publication Date (Web): 07 Dec 2018 Downloaded from http://pubs.acs.org on December 11, 2018

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The Journal of Physical Chemistry

Adsorption Mechanism of Amyloid Fibrils to Graphene Nanosheets and Their Structural Destruction Nan Zhang,†δ§ Xiaoling Hu,†* Ping Guan,† Kaiyang Zengδ, and Yuan Cheng§* †

School of Natural and Applied Science, Northwestern Polytechnical University, Xi’an, P. R.

China, 710072; δ

Department of Mechanical Engineering, National University of Singapore, 9 Engineering

Drive 1, Singapore 117575; §

Institute of High Performance Computing, A*STAR, Singapore, 138632;

Corresponding Author * [email protected] * [email protected]

Abstract A detailed understanding of the interaction mechanisms between pathogenic protein aggregates and nanomaterials is indispensable to the application and development in biomedical area. Here, allatom molecular dynamics (MD) simulations were performed to characterize the interaction between a graphene nanosheet with amyloid fibrils domain, a mostly parallel β-sheet model as a typical representative. It was found that graphene had strong capabilities to interact with Aβ fibrils, which firstly demonstrated prominent impacts on the molecular structure of the outer side chains of Aβ fibrils, then secondary structures of amyloid fibrils partially collapsed to varying degrees, indicating that the introduction of graphene nanosheets can cause severe structural disassociation and configuration change owing to adsorption of amyloid fibrils. As for the adhesion of Aβ fibrils to graphene, van der Waals (vdW) interaction was mainly responsible for driving Aβ fibrils binding to graphene, which effectively inhibited the self-association and aggregation of Aβ fibrils. While the solvent also collaboratively promoted graphene-mediated disruption on fibrils. Structural features and other effects, including polarization and spatial effects, acted synergistically on the adhesive 1

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strength to enable the interaction energy. Furthermore, the interaction mechanism between Aβ fibrils domains and unconstrained graphene was also explored as comparison, and it was found that graphene tended to be faster but irregularly reduced the contents of β-sheets to dissociate amyloid fibers. These observations provide some clues for understanding an underlying molecular mechanism of adsorption-induced destruction based on the graphene-amyloid interaction and an attack-direction dependence of graphene on amyloid fibril structure damage. 1 Introduction Alzheimer’s disease (AD) is a progressive neurodegenerative disease. Clinical manifestations included cognitive impairment involving the loss of memory, judgment, and reasoning and the change of personality and behavior.1-4 A small number of drugs can manage symptoms of the disease, unfortunately, there is still no treatment can stop its progression currently. 5 Although the molecular mechanism of the pathogenesis of AD is not completely comprehended, abundant evidence manifests that the accumulation of misfolded/aberrant neurotoxic amyloid-beta peptide (Aβ) and the formation of amyloid aggregates including fibril plaques and oligomers on cell membrane are crucial steps in the disease pathogenesis.6,7 Hence, for the treatment of such neurodegenerative diseases, the graphene-amyloid interactions,8,9 the interruption of monomeric fibrosis and the disaggregation of amyloid aggregates are taken for the primary strategies.10,11 However, the reported small-molecule initiators,12,13 polymers,14,15 quantum dots16,17 and metal oxides18,19 have some unsatisfactory performance in dissociating and inhibiting the formation of pre-formed amyloid aggregates.20,21 Therefore, more effective AD treatment should be explored and developed imperatively. The atomically-thick two dimensional (2D) materials can be used as extremely effective antimicrobial materials due to high cytotoxicity on their active surfaces - especially graphene and graphene oxide - are sp2 hybridized carbon materials whose unique mechanical properties,22 high specific surface area,23,24 strong antibacterial activity,25-28 contiguous topography and biopersistence29-31 have enabled a widely application in biomedical area such as drug delivery and tumor therapy. Due to the superior surface area of graphene, efficient contact between graphene and biomolecules could enhance their interaction. It is also expected that, due to the conjugated hydrophobic planar structure of graphene, hydrophobic and π-π stacking interactions between graphene and biomolecules may occur. 2


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On account of above excellent nature of graphene, there have been many experimentally attempts to further reveal that graphene and its derivatives demonstrated enormous potential in the field of prevention and treatment of AD. For example, Li et al. found that multi-functionalized GO could be utilized upon high near-infrared (NIR) laser irradiation to effectively dissociate amyloid aggregation and inhibit Aβ-mediated cellular toxicity.32 In addition, Qing et al. employed Cys enantiomorph modified graphene oxide as a model to suppress the processes of adsorption, nucleation, and fiber elongation of Aβ1-40. In this study, R-cysteine modification not only largely inhibited the formation of amyloid fibril on the surface but also greatly affected the conformation transformation of Aβ1-40 from α-helix to β-sheet. GO sheets was able to promisingly delay and inhibit amyloid beta fibrillation process by adsorbing amyloid monomers.33 Besides, Xiao et al. designed a new nanomaterial (GQDG) conjugated neuroprotective peptide with graphene quantum dots. They found that GQDG was capable of preventing the Aβ (1-42) aggregation and protecting the synapse and promote the neurogenesis, thus contributing to improve the learning and memory ability.34 Furthermore, it was reported that there were some preliminary studies on the interaction between graphene derivatives and amyloid fibrils. For example, Nedumpully-Govindan et al. used discrete molecular dynamics (DMD) simulation to study the interaction between Human islet amyloid polypeptide (hIAPP) aggregates and graphene oxide (GO).35 The results showed that GO was able to inhibit the aggregation of hIAPP. It was also showed that hydrogen bonds and aromatic stacking drove the strong binding of hIAPP to GO nanosheets, and the binding of peptide-GO effectively inhibited the self-association and aggregation of hIAPP on the surface of nanosheets. On the other hand, Zhou’s group employed full-atomistic MD simulation to reveal that a large number of preformed amyloid fibrils can be infiltrated and extracted by graphene nanosheets.6 Moreover, the atomic force microscope (AFM) and all-atom MD simulations were performed to analyze the unfolding behavior of RNA molecule on graphene surface and the stacking interaction between biomolecules and graphene.36 However, elaborate kinetic processes and potential molecular mechanisms associated with graphene-induced destruction and dissociation of preformed Aβ aggregates have not been completely illuminated. So far, various therapeutic approaches have been put forward and performed to study amyloid aggregates assembly or disassembly by controlling their molecular structures and bonding interactions. As a complement to numerous experimental studies, computational modeling has been 3



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used to characterize the dissociation mechanism of these transient and polymorphic Aβ oligomers. The inhibition and destruction mechanism of pre-formed amyloid fibrils driven by graphene was investigated using all-atom MD simulations, which was widely populated in the study of biomolecules and nanomaterials.6,37,38 We select an Aβ fibrils rich in β-sheet structures as a representative model, as illustrated in Figure 1, to study their biological behavior involving in the interactions with graphene and inquire into the impacts on the conformational changes from three different initial orientations. We aim to figure out three questions: (i) How the amyloid fibrils dissociate under the different attack directions of graphene, (ii) how the solvent regulates the interplay between amyloid fibers and graphene and (iii) how amino acid residues affect the Aβ fibrils adsorption on the surface of graphene. We detected the adsorption mechanisms of amyloid fibrils on 2D nanomaterials, the changes concerning energy profiles, secondary structure and hydrogen bonds change, to gain a comprehensive understanding of the interaction between amyloid fibrils and graphene. 2 Models and Methodology 2.1 The Structure of U-shaped Amyloid Fibril Pentamer Model. In this simulation, we select a pre-formed Aβ17-42, extracted from Protein Data Bank entry: 2BEG,39 which is a typical represent amyloid model. Owing to such observations (i) it is the largely hydrophobic core fragment in character which is able to represent a typically hydrophobic protofibril;40 (ii) it also exhibits abundant β-sheet topology contains two β-strands connected by a turn, within which hydrogen bonds formed along the peptide backbone in either a parallel or an antiparallel motif;41 (iii) this option significantly reduces the extensive computational cost caused by simulating longer and more complex Aβ1-42 fibrils. As exhibited in Figure 1a, Aβ fibrils, have five peptide chains with the same amino acids residue sequence. Thereafter, we describe the fibril as three domains labeled as P1 (residues 17-26), P2 (residues 31-42) and P3 (residues 27-30), respectively. Figure 1c highlights the hydrophobic residues acids of 2BEG. As shown in Figure 1b and Figure 1d, an individual peptide chain extracted from Aβ fibrils, there are 28 residues with the sequence of QKLVFFAEDVGSNK-GAIIGLMVGGVVIA. Its initial conformation includes both β-sheet and random coil configuration. Top layer: P1

(a) ACS Paragon Plus Environment Turn: P3

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Figure 1. Initial Aβ peptide structures. (a) Aβ fibrils structure, blue, green, yellow and mauve colors represent nonpolar, polar, acidic and basic amino acids residues; (b), (c) one full-length chain of Aβ17-42 fibrils containing both C terminal and N terminal; (d) highlights the hydrophobic amino acids in the Aβ fibrils structure. These initial structure are used for our simulations with and without graphene nanoplates in aqueous environments. A pre-equilibrated structure was employed to simulate its interaction with graphene in an explicit aqueous solvent. (e) Schematic of system setups: disparate initial configuration for simulations were produced by rotating Aβ fibrils by three directions with Aβ peptide implanted in water box employing a perpendicular (P1⊥Gra, C1) and two parallel (P1 ∥ Gra, C2 and P3 ∥ Gra, C3) orientation relative to the graphene surface. The subunit was placed so that the bottommost was 5 Å above the surface. To study the interaction between Aβ fibrils and graphene nanosheets, MD simulations were carried out on the graphene-Aβ complex for each case in a cubic box. The initial setups for Aβ fibrils on graphene, as well as different positions, are depicted in Figure 1e. To simulate the behaviors of Aβ fibrils in full-solvation environment, the systems of case1 (C1), case2 (C2) and case3 (C3) 5



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consist of 163136, 163073 and 161030 atoms, respectively. 2.2 Simulation Methods for Aβ-graphene Interactions. All MD simulation were performed using the GROMACS package 5.1.2.42 The potential parameters of Aβ was modeled using the AMBER03 force field.43 To model the potential of carbon atoms on the graphene, the Morse potential, the harmonic cosine of the bend angle, the double twist potential, the vdW interaction and LJ parameters for graphene were adopted to describe the interaction between carbon atoms, with an equilibrium distance of σ = 3.4 Å and potential well depth cc

of ε =0.086 kcal mol-1, corresponding to sp2 hybrid carbons in AMBER03 force field.44,45 The cc

Lorentz-Berthelot rules were utilized to calibrate vdW parameters for different atoms types in AMBER03 force field.46 Simliar potential and parameters were adopted by earlier studies and validated by qualitatively compared with experimental results.8 The employed graphene nanosheet had a dimension of 40 × 82 Å2. The combined complexes were solvated in a cubic box with an at least 10 Å distance between the solutes and periodic box boundary. The SPC/E water model was adopted and five counterions (sodium ions) were added to balance the system.47 LINCS algorithm was employed to constrain covalent bonds relating carbon atoms. The long-range electrostatic interactions were calculated using the particle grid Ewald (PME) method.48,49 The cutoff for the van der Waals interaction was set as 10 Å. A 2000 steps energy minimization was implemented to acquire an equilibrium structure of the system. The time step was set to 0.001ps, and full solvation simulations were manipulated at the room temperature of 300 K and the pressure of 1 bar throughout the simulation while fixing the graphene substrate. To analyze and visualize the simulation results, the secondary structure was calculated using the STRIDE algorithm50,51 and DSSP52 was used to determine the secondary structure content. The conformational dynamics were determined by calculating the root mean square deviation (RMSD) of the backbone atoms of the peptide relative to their initial structure, the amount of hydrogen bonds within the peptide, and the fraction of the original alpha-helix content. During this data collection, temperature was maintained by the Nosé-Hoover thermostat,53 and the pressure was regulated by Parrinello-Rahman barostat isotropically.54 This combination of thermostat and barostat make sure sampling of true NPT ensembles. 3 Results and Discussions 3.1 The Interaction Mechanism between Graphene Substrate and Aβ Fibrils. 6


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3.1.1 Time Evolution of Structure Change upon Binding

(a)

(b)

(c)

t = 0 ns

t = 44 ns

t = 177 ns

t = 488 ns

t = 845 ns

t = 1000 ns

t = 0 ns

t = 47 ns

t = 221 ns

t = 400 ns

t = 654 ns

t = 1000 ns

t = 0 ns

t = 65 ns

t = 200 ns

t = 813 ns t = 1000 ns t = 452 ns Figure 2. Aβ fibrils adsorption on graphene in MD simulations. Three representative trajectories of amyloid fibrils destruction by graphene nanosheet in three cases: C1 (a), C2 (b), and C3 (c). The graphene sheet was shown in black sheet. The convergence and stability of the MD simulation was evaluated before data collection. To detect the effect of initial orientation of Aβ fibrils on the surface of graphene on possible binding mechanism and adsorption process, simulations were implemented for all the three cases, with the rotation of Aβ fibrils orientation by different directions towards graphene substrate. Figure 2 exhibited representative trajectories of interaction evolution between graphene nanoplatelets and 7



Aβ fibrils. Our simulation clearly indicated that, in three initial configurations, Aβ fibrils gradually adsorbed onto the graphene sheets, and then pre-formed amyloid fibrils were destroyed by graphene nanosheets to varying degrees. In contrast, the control run (without graphene nanosheet) showed a relatively stable amyloid fibril structure, and the folded structure remained almost intact during the same simulation time (see supporting information Figure S1). In case1 (Figure 2a), with graphene nanosheet attacking from the orientation of perpendicular to P1, the Aβ fibrils started to deform at around 44 ns. After 177 ns, it followed by a distorting of the fibrils. By the 488 ns time point, the entire fibril was completely attached to the graphene nanosheets. As the simulation time continued, a fibril had almost dispersed, especially the outermost polypeptide chains in amyloid fibrils had completely dissociated from the fibril. From Table 1 and Figure 3a, we can also see that the secondary structure of Aβ fibrils had destroyed owing to adsorption compared with the secondary structure of Aβ fibrils in explicit water solvent. In case2 (Figure 2b), with graphene flake interacting from the direction of parallel to P1, After about 47 ns, the Aβ fibrils had clung to the surface of the graphene and transformed. Accordingly, the graphene also contributed to the conformational change, adsorption and disaggregation process of amyloid fibril on graphene surface. We found that it underwent even stronger conformational damage to β-sheet structures after being adsorbed on graphene surface or introduction of graphene into solution system. The results were further supported by the change of secondary structure content (Table 1 and Figure 3b). In case3 (Figure 2c), with graphene nanoplatelet assaulting from the angle of parallel to P3, the Aβ fibrils started to twist obviously around 65 ns under attack of graphene. The Aβ fibrils Chain1Chain2Chain3Chain4Chain5

17 LEU (a)stuck to the surface of graphene at 200 ns. After 221 ns, the outermost polypeptide chain completely 41 ILE 19 PHE 39 VAL had been completely dispersed. As were also shown in Table 1 and Figure 3c, a decrease in the 17 LEU 39 VAL 17 LEU of the β-sheet and an increase in the random coil structure of Aβ fibrils were observed in content 41 ILE 19 PHE theVAL existence of graphene. 39 17 LEU 42 ALA

Residue No.

800

17 LEU 41 ILE 19 PHE 39 VAL 17 LEU 39 VAL 17 LEU 41 ILE 19 PHE 39 VAL 17 LEU 42 ALA

900

950

850

900

950

1000

(b)

800

(c)


1000 Chain1Chain2

17 LEU 41 ILE 19 PHE 39 VAL 17 LEU

850

Chain1Chain2Chain3Chain4Chain5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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T

Figure 3. Time evolution of secondary structure with graphene of Aβ fibrils as a function of simulation time in C1 (a), C2 (b) and C3 (c). For an intensive analyze possible transformation in the secondary structure of Aβ fibrils, the time-evolution of structure contents with and without graphene nanosheet were inspected. As can be seen in Figure 3a-3c, β-sheet with the existence of graphene unfolded to varying degree for each cases, while the formation of turns and coils structure were promoted by graphene compared to systems without graphene (see supporting information Figure S2b and S3). Accordingly, in the existence of graphene sheet, due to the strong binding between polypeptides and graphene, the peptides adopted turns and coils structures to facilitate stronger interactions with the graphene sheet. The conformational transition from β-sheet to random coil throughout the simulation can be verified by comparing with earlier studies via Thioflavin T measurement, atomic force microscopy, and circular dichroism spectroscopy.55,33 For example, atomic force microscopy and Thioflavin T fluorescence experiments showed that hydroxylated SWCNTs had a significant inhibitory effect on the formation of β-sheets and can transform the conformation of Aβ16-22 aggregates from ordered βsheets structure to disordered coil aggregates.56 Hence, the conformation changes from abundant βsheet to more turns and coils responsible for the reduction in the number of hydrogen bond in Aβ fibrils when it was adsorbed onto graphene. Table 1. Comparison of secondary structure content with and without the presence of graphene plate. 9



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Structure type Content of secondary structure (%)

Aβ fibrils without Gra

3-10 helix

1.32 ± 0.09

β-sheet

C1

C2

C3

0.00

1.80 ± 0.07

0.12 ± 0.01

30.24 ± 0.14

21.57 ± 0.11

26.06 ± 0.12

19.75 ± 0.11

turns

21.01 ± 0.21

25.29 ± 0.23

26.14 ± 0.19

23.66 ± 0.12

random coils

42.57 ± 0.11

48.23 ± 0.16

44.18 ± 0.30

53.62 ± 0.31

isolated bridge

4.86 ± 0.02

4.91 ± 0.04

1.82 ± 0.05

2.85 ± 0.01

The remaining constituents are primarily random coil structures.

Overall, structural deformation and β-sheet content loss were discovered among all cases, which clearly illustrated that graphene was capable of destroying the structure of Aβ fibrils. Graphene first demonstrated extraordinarily destructive effects on the outer side chains of Aβ fibrils, then causing severe structural disassociation and conformation break to varying degree owing to adsorption of amyloid fibril on graphene flake.57 Especially in case3, the changes in the β-sheet were the largest in the binding-induced conformational conversion, which also pointed out that it was more efficient to attack amyloid aggregates from this direction. Furthermore, experimental study reported that graphene oxide may cause disaggregation of the amyloid deposits and aggregates, and the functional GO may be used to reduce Aβ-mediated cytotoxicity. It was also shown via experimental study that graphene oxide could cut Aβ fibrils into pieces. For example, introducing GO nanosheets to the mature Aβ fibrils, any clear markers of the fibril presence could not been observed. Meanwhile, almost helical filaments fibrillation occurred without GO. Graphene could dissociate the amyloid aggregates, which is in accord with the experimental results. Therefore, inhibition of Aβ aggregation and destabilization of performed Aβ fibrils are therapeutic and preventive strategies for AD treatment.58 3.1.2 Time Evolution of the Interaction Energy To examine the underlying inducement of graphene-induced fibrils disassembly, van der Waals (vdW) interaction energy and heavy atom contact numbers were extracted for analysis. As shown in Figure 4a, total vdW energies between Aβ fibrils and graphene substrate in three entities reduced as the increase of simulation time, and the average vdW interaction energy were respectively about -1154 kJ/mol, -682 kJ/mol and -1367 kJ/mol at equilibrium, which were responsible for driving the Aβ fibrils binding to graphene mainly via hydrophobic interaction. As regards to the difference in 10


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the position of graphene, the equilibrium vdW energy between Aβ fibrils and graphene was the lowest in case3, indicating the strongest binding affinity between them. Conversely, as shown in Figure 4b, the number of heavy atom contact between Aβ fibrils and graphene augmented until the equilibrium period was reached and finally increased to 688, 513 and 819, respectively. Corresponding to these data, protein adsorption dependent on initial attacking direction by graphene can be observed. These data validated our conjecture that the higher the adhesion energy in the initial state, the more pronounced protein adsorption become eventually.

Figure 4. The vdW energies (a), contact number (b) between protein and graphene (Gra) sheets (C1, black curve), (C2, red curve) and (C3, blue curve) as a function of simulation time. There are many reasons for this phenomenon, which related to van der Waals interaction energies, hydrogen bonds, the competence of intra-peptide interaction and the interplay of solvents (SOL) with graphene and solvent and protein. Upon binding to graphene nanosheets, as illustrated in Figure 5, the hydrogen bonds between peptide chains were disturbed due to the significantly enhanced Aβ fibrils-graphene attraction and the simultaneous decreased intra-peptide interaction. Detailed analysis about hydrogen and the interaction of Aβ fibrils-SOL and SOL-graphene will be discussed in next section. 3.1.3 Time Evolution of Hydrogen Bonds It is generally believed that the structure of proteins is closely related to hydrogen bonds, so great efforts have been made to understand the dynamics of hydrogen bonds in biological systems.32,59,60 The structural destabilization of Aβ fibrils is accompanied by alterations of hydrogen bonds in the intra-peptides.61,62 The hydrogen bond is formed when the distance between the donorhydrogen-acceptor atoms is less than 0.35 nm and the angles between the donor-hydrogen-acceptor atoms is less than 30º. Therefore, to obtain a deeper insight into the structural transformation process of Aβ fibrils resulted from graphene nanosheet on the molecular scale, we evaluated the time 11



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evolution of the number of hydrogen bonds in amyloid fibrils. In the three cases where graphene appeared and did not appear, the hydrogen bond number of Aβ fibrils and Aβ fibril-SOL as a function of time were illustrated in Figure 5. Based on the data shown in Figure 5a, compared with the average hydrogen bonds number of Aβ fibrils in the absence of graphene (Figure S2a), the mean hydrogen bonds number with graphene reduced to some extent. The average hydrogen bonds number without graphene is 64, while that with graphene were respectively 45, 55 and 37 (all averaged over the last 200 ns simulation) in successive three cases. In the preliminary phase of the interaction, the number of hydrogen bonds in case3 declined dramatically and then remained at the minimum with slight fluctuation. On the contrary, the hydrogen bonds number descended mildly and maintained at a higher value in case2. This is in agreement with the findings of energy and simulation trajectory. Besides, it was noteworthy that the numbers of Aβ fibrils-SOL hydrogen bonds were enhanced in processes (Figure 5b). After the dissociation of intra-peptide hydrogen bonds, the peptide chain had larger area exposed to the solvent. Amino acid residues with polar side chains (e.g., carboxyl and amino groups) binded to water molecules, which was more advantageous for peptide-SOL interactions. Thus, these results clearly showed that Aβ fibrils was a steady conformation without graphene, while the presence of the graphene substrate was responsible for the break of protein intra-molecule hydrogen bonds, which in turn increased the number of hydrogen bonds between peptides and SOL. In a word, the presence of graphene has a significant impact on the molecular structure of protein aggregates. Therefore, graphene can strongly attract Aβ fibrils, which is capable of inducing cleavage of hydrogen bonds between peptide chains and subsequent secondary structures. Once the fibrils are bound to the graphene, the structural distortions of the fibril almost begin to occur. These findings strongly support the exceptionally inhibition and deformation to Aβ fibrils that the graphene material exhibits.

(a)

(b)

12


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Figure 5. Hydrogen bonds number with and without Gra, wherein hydrogen bonds are the backbone of Aβ fibrils (a) and Aβ fibrils -SOL (b). Black, red, blue and cyan colors represented the hydrogen bonds numbers of protein 2BEG in C1, C2, C3, and in the absence of graphene, respectively. 3.2 Role of Solvent in Mediating Interactions between Aβ Fibrils and Graphene. (a)

(b)

(c)

(d)

Figure 6. The vdW interaction energy between Aβ fibrils-graphene (black curve) and Aβ fibrilsgraphene (light cyan curve), and smoothing line (blue curve) was achieved by moving average of 20 in (a), (b) and (c). Light cyan, red and blue colors respectively represent the Coulombic energy between Aβ fibrils and solvent in C1, C2, and C3 in (d). To demonstrate the important role of solvent on adsorption of the fibril to graphene, the vdW interaction energies and coulombic energies corresponding to Aβ fibril-SOL contacts. At the interface, the combination of Aβ fibrils and graphene replaces the portion of the water solvation shell between the Aβ fibril-graphene, which results in the dehydration of Aβ fibrils and graphene, respectively. It can be observed from Figure 6a-c that as the adsorption process occurred in the simulation, the energy between Aβ fibrils and solvent rose slightly, and increased more as the augment of adhesion energy of Aβ fibrils on graphene . We can also see that the vdW energy between Aβ fibrils and graphene decreased along the adsorption process, and this has been discussed in detail in Section 3.1.2. It is obvious that in vdW interaction between Aβ fibrils and graphene is strongly negative, 13



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while there is a positive change in the vdW interaction between Aβ fibrils and solvent (since water is removed from the interface of graphene) relative to the adsorption energy of Aβ fibrils onto graphene. Both the changes in the vdW interactions of Aβ fibrils-water are advantageous, albeit with not the total interaction energy, which helps driving the adsorption process (Figure S4). In summary, the energy release of graphene-Aβ fibrils interaction mainly compensated for these two parts: graphene monolayer dehydration and Aβ fibril dehydration (C1: -780 kcal/mol; C2: -757 kcal/mol; C3: -557 kcal/mol), which partially counteracted the loss in the Aβ fibrils-graphene interaction. This is completely different from other two-dimensional materials such as molybdenum disulfide. Additionally, we also calculated the electrostatic interaction energy of Aβ fibrils-solvent, which did not change substantially (Figure 6d). 3.3 Sequence-dependent Adsorption of Aβ Fibrils on Graphene To reveal the sequence-dependent interaction mechanism between amyloid protein and the graphene, the averaged vdW energy between each amino acid residue in amyloid fibrils and the graphene nanosheet was further summarized. The carbon atoms on graphene were treated as uncharged atoms, and the dominant interactions between graphene and peptides were the van der Waals interaction. The affinity of different amino acids on graphene was determined based on analysis of the MD simulation. The data presented in Figure 7a revealed that, among all residues, the hydrophobic residues Phe19 (-46.9 kcal/mol) (Figure 7b), Met35 (-35.4 kcal/mol) and Val36 (41.6 kcal/mol) were prominent as the energy was the strongest in case 1, showing a strong affinity to adhere strongly to graphene surface. Other hydrophobic residue, such as Ile31, displayed strong interaction energy, which may also play a significant role. These hydrophobic residues promote hydrophobic interactions that are also presumably important in the disaggregation of amyloid fibrils. More interestingly, it can be obviously seen that, in case2 and case3, Phe19 had no direct interaction with graphene to form “face-to-face” profile, which were mostly exposed to the solvent. However, the polar hydrophobic residue Lys28 (located in the core of polypeptide chain) in case2 (Figure 7c) and case3 (Figure 7d) had the strongest vdW energy at -50.3 kcal/mol and -53.5 kcal/mol, respectively. And the other quite strong interactions on graphene were also differentiated by residues with prominent hydrophobic side groups. (a)

(b)

14


Phe

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Figure 7. (a) Mean vdW energy of each residue using the last 200 ns from all three different orientations. (b) Snapshots of C1 at equilibrium. Residues Phe were highlighted. (c) Snapshots of C2 at equilibrium. Residues Lys were highlighted. (d) Snapshots of C3 at equilibrium. Residues Lys were highlighted. It should be mentioned that, generally, polar and charged residues such as lysine generally have weaker interactions with graphene, showing weaker affinity with graphene; aromatic six carbon residues such as Tyr and Phe and graphene show stronger affinity due to geometric compatibility.63,64 But why are our simulation results so different? The reason for this phenomenon is a result of the combination of various actions, such as, amino acids position in peptide chain and adsorption configuration of the residues in the protein structure, surface property of graphene and the direction of interaction. Moreover, the observations confirm the crucial role of Ile residue in the adsorption of Aβ fibrils to graphene which has also play a vital role in binding, especially owing to a favorable interaction energy of Ile-graphene and a relatively long side chain in three cases. Based on above analyses, it was found that Aβ fibrils could strongly adsorb onto the graphene surface, which was pretty disruptive to its structure and can be primarily considered to be caused by hydrophobic and polar amino acid residues. Finally, dewetting effect resulted from proteinnanomaterial interactions occurred in these three cases, which was consistent with previous research results. 65,66 In short, in the presence of large biomolecules, such as Aβ fibrils, the average interaction 15



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energy for each residue is calculated to be sensitive to the position and adsorption configuration of the residues in the protein structure. In particular, when data is averaged over residues, having a greater number of residues located away from the matrix will reduce the reported interaction energy. The contribution within Aβ fibrils is affected by the surface, which can vary based on adjacent amino acids, flexibility, and overall protein orientation. 3.4 The Influence of Unconstrained Graphene Flakes on Aβ Fibril Structures Based on a series of analyses above, another question arises naturally: once the constraints on graphene and Aβ fibrils were all removed, how will the deformation of graphene nanosheet affect the structure changes of Aβ fibrils? Hence, additional sets of simulations were performed to study the evolution when the constraints on the graphene and Aβ fibrils were removed. All cases (C4, C5 and C6) with disparate directions were inspected. As show in Figure S5, relaxing the graphene substrate, it was observed that the graphene undergoes significant deformation. All for three cases, Aβ fibrils were rapidly adsorbed onto graphene nanosheets with structural distortion. Structural deformation and the β-sheet collapse were more serious than the cases with restraints. And in the action direction of P3∥Gra, namely C6, the damage caused by adsorption is the most significant. In the directions of C4 and C5, the adsorption and dissociation states were similar. The corresponding changes in vdW energy(Figure 8), contact number (Figure S7a) and area (Figure S7b) between graphene and amyloid fibers, reduction of hydrogen bonds inside the Aβ fibrils (Figure S9), and alteration in the content of secondary structures (refer to Figure S6 and Table S2 in detail) were consistent with the process of structural evolution. Besides, in all the cases, the graphene can wrap around the amyloid fibril, having the effect of shielding the water molecules surrounding the amyloid structure. The structural damage of amyloid fibrils caused by graphene nanosheets was due to the adsorption behavior of amyloid aggregates on the surface of graphene. Based on our simulation results and previous works, the controlled adsorption of Aβ fibrils on waved graphene, might be achieved by tuning the morphology of the graphene surface.67,68 Therefore, both mechanisms appear to help destroy the preformed Aβ fibrils. Our MD simulation can further complement and illustrate the experiments described by Zhou’s group.6 In summary, our systematic study provides important information for control/therapy of AD by introducing graphene to change the molecular conformation and assembly structure of fibrils to dissociate their aggregates.

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Figure 8. The vdW energies between protein and graphene (Gra) sheets (case4: C4, P1⊥Gra, black curve), (Case5: C5, P1∥Gra, red curve) and (Case6: C6, P3∥Gra, blue curve) removing constraints as a function of simulation time. The inset Figures were respective snapshots of representative trajectory and secondary structure of destroyed peptide chains highlighted with red. 4 Conclusion In this work, atomistic simulation was performed to study the adsorption of mature Aβ amyloid fibrils on graphene sheets in different directions and their structural damage. The unique twodimensional structure of graphene and the large amount of β-sheet structure in amyloid fiber make the graphene and amyloid fibrils have a strong hydrophobic interaction, which is beneficial to dispersion of Aβ amyloid fibrils by graphene. The non-bonded interaction, including van der Waals forces, hydrogen bonds, etc., between the internal polypeptide chains of Aβ fibrils are severely destructed and then depolymerized by graphene, which is considered to be a molecular mechanism for inhibiting aggregation. The most severe destructive direction of adsorption observed is P3∥ Gra, and in this direction, graphene nanosheets can effectively decompose pre-formed amyloid aggregates. The mechanisms that destroy and break down amyloid fibrils and other protein aggregates are associated with many protein conformational diseases. Our work may provide structural insight for understanding the interaction mechanism between graphene and protein aggregates, and be helpful to the development of Alzheimer's nanotherapy. 17



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Supporting Information Standalone Aβ Fibrils in solvent without graphene; adhesion energy in C1, C2 and C3; simulation methods, representative trajectories, secondary structure change, interaction (including vdw energy, contact number and area), hydrogen bonds and the effect of residues of Aβ Fibrils in three cases (C4, C5 and C6) removing constraints; the role of solvent in mediating interactions between Aβ fibrils and graphene. Acknowledgement The anthors from Northwestern Polytechnical University are grateful for the financial support of China Scholarship Council, the National Nature Science Foundation of China (grant No. 51433008). YC is grateful for the supports from the Agency for Science, Technology and Research (A*STAR) and from A*STAR Computational Resource Centre, Singapore (ACRC). The computational work for this article was partially performed on resources of the National Supercomputing Centre, Singapore (http: // www.nscc.sg). References (1) Chiti, F.; Dobson, C. M. Protein Misfolding, Functional Amyloid, and Human Disease. Annu. Rev. Biochem. 2006, 75, 333-366. (2) Dobson, C. M. Protein Folding and Misfolding. Nature 2003, 426, 884-890. (3) Soto, C. Unfolding the Role of Rrotein Misfolding in Neurodegenerative Diseases. Nat. Rev. Neurosci. 2003, 4, 49-60. (4) Karch, C. M.; Goate, A. M. Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis. Biol. Psychiatry 2015, 77, 43-51. (5) Wang, C.; Yang, A.; Li, X.; Li, D.; Zhang, M.; Du, H.; Li, C.; Guo, Y.; Mao, X.; Dong, M. et al. Observation of Molecular Inhibition and Binding Structures of Amyloid Peptides. Nanoscale 2012, 4, 1895-1909. (6) Yang, Z.; Ge, C.; Liu, J.; Chong, Y.; Gu, Z.; Jimenez-Gruz, C. A.; Chai, Z.; Zhou, R. Destruction of Amyloid Fibrils by Graphene Through Penetration and Extraction of Peptides. Nanoscale 2015, 7, 18725-18737. (7) Mulligan, V. K.; Chakrabartty, A. Protein Misfolding in the Late‐onset Neurodegenerative Diseases: Common Themes and the Unique Case of Amyotrophic Lateral Sclerosis. Proteins: Struct., Funct., Bioinf. 2013, 81, 1285-1303. 18


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Chem. Phys. 2017, 189, 111-117.

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Adsorption Mechanism of Amyloid Fibrils to Graphene Nanosheets

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