Article pubs.acs.org/JPCB
Potential Interference of Protein−Protein Interactions by Graphyne Binquan Luan,*,†,‡ Tien Huynh,† and Ruhong Zhou*,†,‡,§ †
Computational Biological Center, IBM Thomas J. Watson Research, Yorktown Heights, New York 10598, United States Department of Physics, Zhejiang University, Hangzhou 310027, China § Department of Chemistry, Columbia University, New York, New York 10027, United States ‡
S Supporting Information *
ABSTRACT: Graphyne has attracted tremendous attention recently due to its many potentially superior properties relative to those of graphene. Although extensive efforts have been devoted to explore the applicability of graphyne as an alternative nanomaterial for state-of-the-art nanotechnology (including biomedical applications), knowledge regarding its possible adverse effects to biological cells is still lacking. Here, using large-scale all-atom molecular dynamics simulations, we investigate the potential toxicity of graphyne by interfering a protein−protein interaction (ppI). We found that graphyne could indeed disrupt the ppIs by cutting through the protein− protein interface and separating the protein complex into noncontacting ones, due to graphyne’s dispersive and hydrophobic interaction with the hydrophobic residues residing at the dimer interface. Our results help to elucidate the mechanism of interaction between graphyne and ppI networks within a biological cell and provide insights for its hazard reduction.
1. INTRODUCTION Carbon, although ranked as the 15th most abundant element in the Earth’s crust, is one of the most essential building elements of living matter due to its versatile bonding characteristics. It is the basis for most organic and biological molecules and is found free in the form of graphite and diamond and also occurs in natural gas, petroleum and coal. Carbon is truly an old but new material. It was first discovered as charcoal and used in prehistoric times, but yet many new crystalline forms of carbon, particularly those at nanoscale, have only been discovered and synthesized very recently. Because carbon possesses three different hybridization states (sp1, sp2, and sp3), it can bind to itself and nearly all other elements, making it possible to form a plethora of carbon allotropes with isolation or combination of these hybridization states. As a result of extensive research efforts, several low dimensional novel carbon allotropes have been discovered and successfully synthesized including zerodimensional fullerene (sp2), one-dimensional carbon nanotube (sp2) and two-dimensional graphene (sp2),1−4 which offer remarkable properties and distinct structural motifs for developing high-performance carbon materials with new functionalities. In particular, graphene has been considered as the “wonder material” with wide applications in areas such as biomedicine, biosensors, electronics, energy, and environmental science due to its amazing electronic, optical, mechanical, and thermal properties.5−8 Recently, graphyne (GY) and graphdiynes (GDY), the “sp1+sp2” hybridized non-natural graphene-like carbon allotropes, have attracted a great deal of attention from both © XXXX American Chemical Society
theoretical and experimental communities because of their similarity to graphene and potentially superior properties. First proposed by Baughman et. al in 1987,9 graphyne is the generic name for a family of 2D materials composed entirely of carbon similar to graphene, except that they contain a percentage of sp1-hybridized acetylenic linkers, with the percentage and geometry of the linkers defining the type of graphyne. As for graphdiyne that contains two acetylenic linkages in each unit cell instead of just one as in graphyne, it is a variant of graphyne first predicted by Haley et al. in 199710 and can be synthesized on a copper substrate by a cross-coupling reaction using hexaethynylbenzene.11 Along with the progress in experimental studies, many theoretical studies have shown that these lowdimensional graphene-like carbon allotropes exhibit unique and intriguing structural, mechanical, optical, thermal and electrical properties that are as fascinating as those of graphene.12−26 Indeed, a recent study using first-principle electronic structure calculations has indicated that the directional electrical conductivity of graphyne is potentially superior than graphene.23 In addition, γ-graphyne has been shown to have a direct energy band gap which is absent in graphene but is important for electronic applications.12,27,28 Clearly, the mixture of single and triple bonds (sp1 carbons) with benzene-like aromatic rings (sp2 carbons), along with an enlarged lattice has contributed to these remarkable properties of GY and GDY, Received: November 23, 2015 Revised: February 16, 2016
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respectively. Each monomer contains 58 residues, among which six hydrophobic residues (LEU242, TRP243, ALA248, VAL250, ILE257, VAL259) lie at the dimer interface. Initially, the hexagonal γ-graphyne sheet containing 402 carbon atoms (see Figure S1 in the Supporting Information) was placed near the dimer interface with its surfaces oriented parallel to the interface. The system was immersed in a cubic water box of size 67.5 × 67.5 × 67.5 Å3 and neutralized with sodium and chlorine ions, yielding the concentration of the resulting electrolyte at 0.1 M. The entire system contains 31 681 atoms. A total of four independent simulations (Sim-1, Sim-2, Sim-3, and Sim-4), starting from the same initial configuration, were performed for this study, all with the graphyne sheet placed in the putative DNA binding site of the dimer,42 as shown in Figure 1b. Following similar protocols used in our previous studies,43−46 we carried out MD simulations with the software package NAMD2.947 on the IBM BlueGene supercomputer. The CHARMM force field48 was applied to the protein, and the standard force field for ions49 was used for NaCl. As for the graphyne sheet (Figure 1b), its force field is listed in the Supporting Information. Initial built graphyne-structures (by removing atoms in graphene) were equilibrated according to this force field. The TIP3P model50,51 was chosen for water. Periodic boundary conditions were applied in all three dimensions of the system. The particle mesh Ewald (PME) method was applied to compute the long-range Coulomb interactions (grid size ∼1 Å) while a smooth cutoff of 10−12 Å was set to calculate the van der Waals interactions for nonbonded pair interactions. After the equilibration of the simulation system at 1 bar and at 300 K (Nosé-Hoover Langevin piston pressure control52), each production run was carried out in the NVT ensemble and run for about 60 ns.
making them ideal materials for applications in electronics, energy storage, filtration technologies, electrode materials, crystal engineering, and hydrogen purification.29−36 Although nanomaterials have been used in a wide range of applications with many of their beneficial properties, there are still large gaps in our knowledge on what kind of biological (adverse) effects they might impose. It is important to study their associated toxicity to better protect the environment and address potential human health impacts. As carbon-based nanomaterials, such as graphene, become more and more accessible to daily life, more research has been devoted to investigate their potential nanotoxicity. For example, Zhou and co-workers,37 have employed experimental and computational approaches to show that pristine graphene and graphene oxide nanosheets can induce the degradation of both inner and outer cell membranes of Escherichia coli and reduce their viability. Gao and co-workers38 have also demonstrated experimentally and theoretically that sharp corners and jagged protrusions along the irregular edges of graphene sheets can pierce cell membranes. Once the membrane is pierced, a graphene sheet can be pulled entirely into the cell and disrupt the cell’s normal function.39 Recently, Walker and co-workers,40 examined how graphene oxide nanoparticles might interact with the environment once they found their way into soil, ground or surface water and discovered that these nanomaterials could stay much more stable and tend to travel further in surface such as lakes or rivers. Until now, the biosafety of a graphyne nanosheet is still largely unknown. In this work, in order to investigate the potential toxicity of graphyne by its interaction with proteins, we employed the C-terminal DNA-binding domain (PDB ID: 1QMC) of human immunovirus-1 (HIV-1) integrase studied previously,41 which forms a dimer in solution with a welldiscerned hydrophobic interface. Through all-atom MD simulations, we revealed the strong hydrophobic interaction between the protein monomer and the graphyne nanosheet that outweighs the hydrophobic monomer−monomer interaction, i.e., the potential interference of a protein−protein interaction (ppI) that is essential in biological processes.
3. RESULTS To analyze the interactions between the graphyne and the HIV1 integrase protein dimer from the simulation trajectories, we first computed the contact area of the dimer based on the solvent-accessible surface area (SASA) of each monomer and the dimer complex to gain an insight on the effect of these interactions quantitatively. SASA is the area of a conforming surface that is about 3 Å away from an object (e.g., a monomer or a dimer) measured by rolling a water molecule around the molecular surface. Assuming the two monomers are labeled as “A” and “B” and the dimer complex is labeled as “AB”, the contact area denoted as SAB can be calculated as SAB = (sA + sB − sAB)/2. where sA, sB, and sAB, are the SASAs of the two monomers and the dimer complex, respectively. When we calculated the SASA of a protein, the presence of graphyne was not considered, which allows the contact area computed from SASA values to reach zero once two monomer are separated. Figure 2a shows the time-dependent contact areas of the dimer obtained from the four simulation trajectories. Initially, the contact areas of all the simulations were at about 350 Å2 due to the intermonomer contact of the flexible loops and terminals. Within a few tens of nanoseconds, the contact areas of both Sim-1 and Sim-4 dropped sharply to zero, indicating the graphyne sheet had cut through the dimer interface and separated the two monomers completely. However, for Sim-2 and Sim-3, their contact areas remained constant during the whole simulation, suggesting the graphyne sheet was not able to enter the dimer within the simulation time-scale. Analyses from the trajectories of Sim-1 and Sim-4 show that the two monomers (labeled as monomer A and B and colored as blue
2. METHODS Figure 1 illustrates the simulation system that contains a dimergraphyne complex viewing from the top and the side,
Figure 1. Illustration of the simulation systems: (a) top- and (b) sideviews. Two protein monomers of the dimer, colored in green and blue, respectively, are in the cartoon representation. Water is shown transparently; sodium and chlorine ions are respectively shown as yellow and cyan spheres. The graphyne nanosheet, placed near the dimer interface, is in bead-stick representation. B
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perpendicular barrel-axes in the dimer turned into nearly parallel ones at the end of the simulation. The trajectory of Sim-1 illustrates a slightly different separation process of the dimer (Figure 2b,g−k). Similar to Sim-4, the dimer also tilted at the beginning (Figure 2g). However, instead of tilting toward an opposite direction, the dimer tilted further in the same direction (Figure 2h), resulting in a significantly larger contact area between monomer B and the graphyne nanosheet. At around 23 ns, the two monomers were separated completely, with monomer B touching the graphyne’s surface while monomer A remained near the graphyne’s edge. After another 20 ns (Figure 2j), monomer A at the edge started contacting the graphyne’s surface as well. Finally, both monomers A and B ended up at the two opposite sides of the graphyne nanosheet, and their motions (rotaion and translation) were relatively independent of each other (Figure 2k). This separation process, by holding one monomer at the graphyne’s edge and pulling the other to the graphyne’s surface, appeared to occur faster than the wiggling separation observed in Sim-4. From these simulation results we observed that there are at least two different mechanisms of the dimer separation by the graphyne nanosheet depending on the relative orientation of the graphyne’s surfaces to the dimer interface. When the graphyne’s surface is approximately parallel to the dimer interface (and stays this way; Figure 2d), both monomers move to the two opposite sides of the graphyne simultaneously. On the other hand, when the graphyne’s surface is far from being parallel to the dimer interface (after some simulation time; Figure 2h), one monomer is ”pulled” toward the graphyne’s surface first (accompanied by the separation of the dimer), and the other one moves from the graphyne’s edge to the surface later. Overall, both Sim-1 and Sim-4 demonstrate the fast and spontaneous separation of the dimer by the graphyne nanosheet. The separation process is driven by the hydrophobic interaction between graphyne and six hydrophobic residues (LEU242, TRP243, ALA248, VAL250, ILE257, and VAL259) at the dimer interface. These six hydrophobic residues are also found inside the contact area between the two monomers, as shown in the crystal structure (PDB ID: 1QMC). Since graphyne is highly hydrophobic, the unfavorable graphyne− water interaction leads to graphyne’s initial contact with one of the monomers in the dimer. As residues at the dimer interface, particularly for this HIV-1 integrase, are generally more hydrophobic than the ones on the dimer surface, it is energetically more advantageous for the graphyne to enter the dimer interface and interact with more hydrophobic residues, eventually resulting in the separation of the two monomers. Because of the strong hydrophobic interaction, it is possible that a protein’s hydrophobic core becomes exposed to the hydrophobic surfaces of carbon-based nanomaterials, causing a denaturing process.53,54 However, such phenomenon is not observed here. To verify that the separation of the dimer by the graphyne is a ”clean-cut” process, we calculated the time-dependent rootmean-square-deviations (RMSDs) for each monomer’s backbone structure. In Sim-1, Figure 3a shows that saturated RMSDs for two monomers are about 1.2 and 1.7 Å respectively. One monomer has a slightly larger saturated RMSD due to the more flexible turn (ARG228 to TRP235) that is located on the protein surface (not in contact with the graphyne). Thus, the interaction between the graphyne and the protein monomer
Figure 2. Dynamics of the insertion of a graphyne sheet into the dimer. (a) Time-dependent contact areas of the HIV-1 integrase protein dimer during the insertion of a graphyne sheet. (b−f) Snapshots of the insertion process of a graphyne sheet into the dimer from the fourth simulation trajectory (Sim-4). (b,g−k) Snap-shots of the insertion process of a graphyne sheet into the dimer from the first simulation trajectory (Sim-1). The monomers A and B are colored in blue and green, respectively.
and green, respectively, in Figure 2) of the dimer can spontaneously disassociate with each other at the edges of the graphyne sheet, as illustrated in Figure 2b−k. Once the dimer is separated by the graphyne sheet, the SASA of the dimer complex sAB, is simply equal to the sum of the SASA of each monomer. Thus, the values of the contact area SAB of Sim1 and Sim-4 decreased to zero as seen in Figure 2a. Figure 2b−f depicts the separation process of the dimer at the graphyne’s edge obtained from the trajectory of Sim-4. Initially, starting at a position with its interface set close and parallel to the graphyne sheet, the dimer gradually tilted to one side, causing monomer B to contact the graphyne sheet more than monomer A at around 22 ns (Figure 2c). For the following 8 ns, the dimer continued wiggling around the edge of the graphyne sheet. During this period, the nanosheet remained in the vicinity of the dimer interface without cutting through the dimer, which is evidenced by the nearly constant value of SAB as seen in Figure 2a for the corresponding time frame. At 30 ns, the dimer tilted to the opposite direction. Consequently, monomer A started to contact the graphyne nanosheet more than monomer B. This wiggling motion of the dimer which took place from 22 to 30 ns eventually led to the initiation of the separation process that lasted from 32 to 47 ns. At the beginning of the separation process, the value of SAB started to decrease sharply. However, toward the end of this process, the value of SAB is observed to fluctuate between 0 and 100 Å2, reflecting the contact from the protein’s flexible parts (Figure 2e). At 47 ns, the two monomers were completely separated and free to move independently. As a result, the value of SAB dropped to zero and stayed there for the remaining time of the simulation. Figure 2f shows that two initially C
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the duration of time when the monomer-graphyne contact area is S and Tsim is the duration of time for the entire simulation. The arrows in Figure 4 show the time-dependent changes of the probability. When the graphyne sheet is at the edge of the protein−protein contact, the contact area between the graphyne sheet and one monomer is about 200 Å2. In Sim-1, Figure 4a shows that SBC was increased to about 500 Å2, indicating that the graphyne sheet preferably contacted monomer B before entering the dimer. This value was further increased to 530 Å2 after monomer B landed on the graphyne’s surface (Figure 2i). Meanwhile, monomer A was still at the graphyne’s edge. Consistently, its contact area remained at around 200 Å2. After monomer A moved to the graphyne’s surface, its contact area SAC also increased and the most probable value is 630 Å2. In the end of the simulation, the contact area SAC is larger than SBC because the flexible graphyne sheet was slightly bent toward monomer A (see Figure 2k). From the trajectory of Sim-4, Figure 4d shows that the graphyne sheet contacted monomer A first. After that, both monomers almost simultaneously moved to the opposite surfaces of the graphyne nanosheet. Thus, in the final simulated state, both SAC and SBC increased to around 600 Å2. In Sim-2 and Sim-3, the graphyne nanosheet was not able to enter the dimer interface during the given limited simulation time. Figure 4b,c shows that the value of SBC increased to around 500 Å2 while the value of SAC kept at around 200−250 Å2, indicating that the graphyne sheet significantly tilted away from monomer A. From the simulation trajectories, it was found that the graphyne’s edge moved away from the entrance of the dimer interface because of thermal fluctuations. Thus, it may take longer simulation time for graphyne to find the entrance again, before entering the dimer interface. As mentioned earlier, hydrophobicity plays a key role in the separation of the dimer by the graphyne nanosheet. The highly hydrophobic surfaces of graphyne make it energetically
Figure 3. Time-dependent root-mean-square deviations (RMSDs) for two protein monomers in the dimer. (a) Sim-1; (b) Sim-4.
can actually stabilize the protein structure somewhat by reducing its thermal-fluctuation at the contacting regions. This conclusion is further confirmed by the calculated monomers’ RMSDs for Sim-4 (Figure 3b). The result shows that the respective saturated values for the two monomers are around 1.0 and 1.2 Å. Therefore, during the separation process, two monomers preserved their secondary structures and no denaturation process was observed within the short simulation time. To further investigate the dimer-separation process, we computed the probability of the contact area between each monomer and the graphyne sheet (SAC and SBC; here the graphyne sheet is labeled as “C”), as shown in Figure 4. The probability of a contact area is defined by TS/Tsim, where TS is
Figure 4. Probability map of contact areas between monomers (labeled as “A” and “B”) and the graphyne sheet (labeled as “C”). Results of four independent simulation trajectories (Sim-1, Sim-2, Sim-3, and Sim-4) are shown in panels a, b, c, and d, respectively. An arrow in each panel shows the probability changes from the beginning to the end of the simulation. D
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the energy decreasing due to the interaction between a monomer and the graphyne sheet being about 55 kcal/mol, suggesting that the insertion of graphyne into the dimer is energetically favorable. This indicates that the graphyne sheet is less favorable in terms of the vdW (dispersion) interaction with proteins than the graphene sheet, due to the less dense carbon atoms on the graphyne sheet (holes in the acetylenic linker triangle region). On the other hand, for the more porous sheet of graphyne, the surface should be more hydrophobic, which is confirmed from independent simulations of water on graphene and graphyne (see Figure S2 in the Supporting Information). Therefore, we conclude that the dispersive interaction played a more important role than the hydrophobic interaction in the insertion of a nanosheet into the dimer interface. We further investigated the free energy change (ΔGa) during the insertion process. Due to the complex interaction/motion among three bodies (graphyne, monomer A and B), it is nontrivial to define a good reaction path for the free energy change (so-called reaction coordinate). Thus, we designed a thermodynamic cycle (Figure 6a) that can avoid the complexity in defining the reaction coordinate and meanwhile reveal the free energy difference among various states (two-body or threebody). According to this cycle, ΔGa = ΔGb + ΔG1 − 2ΔG2, where ΔG1 is the free energy change in the process for separating two monomers, ΔG2 is the free energy change in the process for separating one monomer from the graphyne sheet, and ΔGb (= 0) due to the equivalence between two states. To obtain ΔG1 and ΔG2, we used the steered molecular dynamics (SMD) method56 to calculate the potential of mean force by pulling the monomer A away from monomer B and graphyne, respectively (see the Supporting Information for details). Two SMD simulation systems are illustrated in Figure 6b. After obtaining and integrating six independent force−distance relationships from corresponding SMD simulations (Figure S3 in the Supporting Information), we applied the Jarzynski equality57 that relates the free energy change ΔG with the work ΔW done during the process: e−ΔG/kBT = ⟨e−ΔW/kBT⟩, where kB is the Boltzmann constant. From saturated values of potential of mean forces in Figure 6b, we obtained that ΔG1 = 21 kcal/mol and ΔG2 = 33 kcal/ mol, which also yields that the binding free energy between two monomers is −21 kcal/mol and the binding free energy between a monomer and graphene is −33 kcal/mol. Therefore, the calculated ΔGa from the above-mentioned thermodynamic cycle is −45 kcal/mol. Consistent with previous potential (vdW) analyses, the insertion of graphyne into the dimer is energetically favorable. For comparison, the binding free energy between a monomer and graphyne is −57.4 kcal/mol (Figure S4 in the Supporting Information), consistent with the graphene’s faster (than graphyne) insertion into the dimer.39 It is worth mentioning that the above free energy calculation ignored all possible transition states that may impose an energy barrier for graphyne’s insertion. For example, there exists an entropy barrier for the graphyne sheet to find the dimer interface, and the graphyne sheet may contact protein surface residues (mostly hydrophilic, and thus a lower binding energy) first, other than the hydrophobic dimer interface region. Both will result in some energy barriers for the graphyne’s insertion, but nevertheless, the significantly lower free energy will eventually result in separated monomers with their hydrophobic dimer-interfacial regions attached to the graphyne surface.
unfavorable to expose in water. However, the protein−protein contact of the dimer possesses a hydrophobic interface. Therefore, it is preferable for the graphyne sheet to enter the hydrophobic interface of the dimer to minimize the overall free energy of the entire complex system. Once the insertion of the graphyne occurs, in addition to the stronger hydrophobic interactions (i.e., the exclusion of water or being pushed together by water) among the two monomers and the graphyne sheet due to the exposure of six interfacial hydrophobic residues to the graphyne surface, the vdW interaction (potential) energies between the two monomers and graphyne are also becoming more favorable, which helps to drive the graphyne’s insertion process. To validate this observation, using the software VMD,55 we calculated the time-dependent van der Waals energies for Sim-4: EAB between monomer A and monomer B (black line in Figure 5a), EAC between the
Figure 5. Time-dependent van der Waals interactions between the two monomers in the dimer (black), between monomer A and the graphyne sheet (orange), and between monomer B and the graphyne sheet (blue). These results were obtained from the trajectory analyses of Sim-4.
graphyne sheet and monomer A (orange line in Figure 5a), as well as EBC between the graphyne sheet and monomer B (blue line in Figure 5a). Figure 5b shows corresponding timedependent contact areas SAB, SAC and SBC. Overall, a sharp increase in S(t) data corresponds to a significant drop in E(t), and vice versa. Thus, the interaction energy becomes stronger (more negative) when the contact area increases. In Sim-4, before entering the interface of the dimer, the graphyne sheet was wiggling and contacting both monomers A and B back and forth. This motion is clearly reflected in the calculation of the vdW energies, where it shows alternately one of the values of EAC and EBC is less than the other during this period. At around 35−40 ns, the separation process occurred (black line on Figure 5b). Both EAC and EBC were reduced (more favorably) by about 30 kcal/mol, because of the contact between the graphyne sheet with each monomer. In the end of the simulation, EAC was even lower due to the slight bending of the graphyne toward monomer A in this case (i.e., stronger interaction). Meanwhile, after the separation of the dimer, EAB was increased by about 25 kcal/mol. From our previous study, we learned that for the dimer separation by a graphene sheet, both the interaction energy changes ΔEAC and ΔEBC become more favorable by about 130 kcal/mol.39 Figure 5 shows that E
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normal biological process. These current findings help to build a foundation for a better understanding of the molecular mechanisms behind the interactions between this novel nanomaterial graphyne and proteins. Since graphyne is a promising new nanomaterial that could be soon used in many applications, including biomedical ones, it is critical to evaluate its potential nanotoxicity to biological cells. How to reduce the toxicity of graphyne (and graphene as well) via functionaliztion should be an important future direction.
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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.jpcb.5b11449. Force fields used for simulating graphyne; the atomic structure of γ-graphyne; interfacial densities of water on graphyne and graphene; force−distance relations when pulling two monomers apart; potential of mean force for pulling one monomer away from graphene (PDF) Movies showing the MD trajectory of graphyne’s insertion into the dimer: Sim-1 (MPG) Sim-2 (MPG) Sim-3 (MPG) Sim-4 (MPG)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. Notes
Figure 6. Free energy change for graphyne’s insertion into the dimer. (a) The thermodynamic cycle to obtain the free energy change ΔGa. Protein monomers (A and B) and graphyne are schematically shown as circles and a line segment. (b) Potentials of mean forces versus distances for pulling one monomer away from the other fixed one (blue) and for pulling one monomer away from the fixed graphyne sheet (orange). The distance is defined as D − D0, where D and D0 are later and initial distances between centers of mass (COMs) of monomers or between COMs of the monomer A and graphyne. Inset: simulation systems for pulling two monomers apart (right) and for pulling one monomer away from the graphyne (left). The description for each simulation system is same as that in Figure 1.
The authors declare no competing financial interest.
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REFERENCES
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4. CONCLUSIONS In summary, using MD simulations, we investigate the possible toxicity of a graphyne nanosheet to a protein−protein interaction. Our simulation results demonstrate that a graphyne nanosheet can cause the separation of an otherwise strongly bound protein dimer. The dynamic separation process captured in MD simulation shows that, after the graphyne’s initial insertion into the protein−protein interface, the dimer structure hold by the hydrophobic monomer−monomer interaction can be destabilized and eventually the protein complex is broken. Along with the hydrophobic interaction among the two monomers and the graphyne nanosheet, the vdW interaction between graphyne and protein monomers can significantly help the graphyne’s insertion. During the insertion process, the free energy change is −45 kcal/mol, suggesting that the process is energetically very favorable. The nature of the interactions indicates that this type of ppI disruption can be general and may affect many protein−protein recognitions during a cell’s F
DOI: 10.1021/acs.jpcb.5b11449 J. Phys. Chem. B XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.jpcb.5b11449 J. Phys. Chem. B XXXX, XXX, XXX−XXX
