Regulating Ion Transport in Peptide Nanotubes by Tailoring the

Mar 27, 2015 - Selective Permeability of Truncated Aquaporin 1 in Silico. Karl Decker , Martin Page , Ashley Boyd , Irene MacAllister , Mark Ginsberg ...
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Letter pubs.acs.org/JPCL

Regulating Ion Transport in Peptide Nanotubes by Tailoring the Nanotube Lumen Chemistry Luis Ruiz,† Ari Benjamin,† Matthew Sullivan,‡ and Sinan Keten*,†,‡ †

Department of Mechanical Engineering and ‡Department of Civil and Environmental Engineering, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3109, United States S Supporting Information *

ABSTRACT: We use atomistic nonequilibrium molecular dynamics simulations to demonstrate how specific ionic flux in peptide nanotubes can be regulated by tailoring the lumen chemistry through single amino acid substitutions. By varying the size and polarity of the functional group inserted into the nanotube interior, we are able to adjust the Na+ flux by over an order of magnitude. Cl− is consistently denied passage. Bulky, nonpolar groups encourage interactions between the Na+ and the peptide backbone carbonyl groups, disrupting the Na+ solvation shell and slowing the transport of Na+. Small groups have the opposite effect and accelerate flow. These results suggest that relative ion flux and selectivity can be precisely regulated in subnanometer pores by molecularly defining the lumen according to biological principles.

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An alternative approach of precisely defining the lumen chemistry and pore diameter of a synthetic nanochannel is to self-assemble macrocycles, or ring-shaped subunits, into tubular structures.10,18,20,21 The modular character of chemically tunable macrocycles allows imitation of selectivity strategies employed by biological transmembrane protein channels.22−24 Cyclic peptide nanotubes (CPNs), which are self-assembled stacks of small octapeptide rings stabilized by hydrogen bonds,20 are particularly promising candidates as biomimetic synthetic nanopores because of their remarkable mechanical properties, the possibility of tuning the pore size, and their highly modifiable chemistry.25−28 Recently, a new synthetic route was proposed to modify the lumen chemistry of CPNs by means of an insertion into the peptide sequence of an unnatural amino acid containing a methyl functional group pointing toward the inside of the pore.26 In another recent experimental breakthrough, CPNs were grown through directed selfassembly in block copolymer membranes, creating subnanometer porous thin films where pore size and chemistry are dictated by the CPNs.14 These two advances open the door to utilizing CPNs as tunable nanopores in membranes. Modifications of the lumen chemistry, however, are a relatively little understood design parameter in synthetic tubular systems. The ideal pore size and chemistry will often depend on the application of interest. For example, water desalination would require a nanotube that transports water rapidly but rejects salt ions. An antibacterial application, on the other hand, requires a nanotube with fast cation selective transport for the

he pursuit of nanoscale ion sieves is of great interest due to the central role that ion transport plays in a myriad of technological and biological processes. On the biological side, transmembrane ion channels are essential for sustaining biological functions such as nerve signaling1 and homeostatic balance,2 and their malfunction is responsible for severe pathologies.3 Engineered nanopores with precise regulation of ion transport are needed in many point-of-use industrial separations, such as in water desalination,4 fuel cells, and alkaline ion batteries.5 Medical applications such as artificial kidneys6 or antibacterial agents7 are also envisioned. Solutions to this separation challenge are currently being pursued through several engineered subnanometer porous materials, including metallic−organic frameworks (MOFs), carbon nanotubes (CNTs), nanoporous graphene, and peptide nanotubes.5,8−12 Rectilinear pores, such as subnanometer diameter CNTs, are able to differentiate molecules by size exclusion at Angstrom-level precision. In addition, nanotubes can be embedded in polymer membranes to create straight nanopores that facilitate transport by providing well-defined translocation routes, thereby improving upon the tortuous pathways found in traditional separation materials.13−15 However, it remains challenging to achieve monodisperse pore size distributions in CNTs. Additionally, the lumen in CNTs cannot easily be chemically modified, and thus, size exclusion becomes the primary selectivity principle. Nanotubes with tunable lumen chemistry are highly desirable because of the dramatic effect of inner surface chemistry on transport behavior.16−18 MOFs, on the other hand, offer a uniform porous network with relatively high chemical and morphological design flexibility, but remain to be perfected for many transport applications.19 © 2015 American Chemical Society

Received: February 5, 2015 Accepted: March 27, 2015 Published: March 27, 2015 1514

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The Journal of Physical Chemistry Letters interruption of the homeostatic balance of the bacteria. Taking these applications as model scenarios, the key question that we wish to answer is how tailoring the interior chemistry influences ion and water flux in peptide nanotubes in a way that extends upon size exclusion capabilities. Addressing this knowledge gap is crucial not only for separation applications but also for discovering similarities and differences between biological transmembrane proteins and their synthetic analogues. In this Letter, we use nonequilibrium atomistic molecular dynamics (NEMD) simulations to investigate the fundamental mechanisms of Na+ and Cl− transport in chemically modified CPNs (mCPNs) and the effects of nanotube chemistry. We present a computational screening of the design space to identify lumen features that might otherwise remain long undiscovered due to synthetic challenges. We explore conventional CPNs as well as mCPNs with functional groups inspired by lysine, glycine, and alanine amino acid side chains, representing active sites in ion channel proteins. The polar, neutral, and hydrophobic functional groups are chosen to represent a wide spectrum of possible chemical configurations. Our analysis provides transferable insight into the dramatic effects that small changes in the lumen chemistry have on nanotube ion transport properties. In particular, we identify the atomistic mechanisms responsible for both fast transport and low ion permeability. We also develop a transferable metric to evaluate the relative performance of the nanotubes for both water desalination and antibacterial applications. Our mechanistic results confirm the potential of mCPNs as a tunable platform for a variety of molecular separation applications. Computational Methodology. We use NEMD simulations to study NaCl salt water transport through chemically modified CPNs under an applied electric field. The molecular model consists of a CPN embedded in a low-dielectric membrane made of toluene packed at its equilibrium density in the liquid phase. The nanotube connects two salt water reservoirs placed on both sides of the membrane. All of the nanotubes studied are homomeric (i.e., all of the cyclic peptides in a given nanotube have the same chemistry) and are composed of five cyclic peptides. The dimensions of the simulation box are approximately 60 × 40 × 40 Å3 (Figure 1a). The reservoir, connected through periodic boundaries, contains 18 Cl− ions, 18 Na+ ions, and ∼1900 water molecules (small fluctuations around this number can exist from case to case). The salinity of the reservoir is ∼30 g/L, comparable to that of seawater (∼35 g/L). We study four different types of cyclic peptides, one conventional with a prototypical sequence cyclo-[D-Ala-L-Lys]4 and three chemically modified that have an unnatural amino acid in the peptide sequence that contains a functional group R pointing inward (Figure 1b). The three different functional groups studied are inspired by the alanine (methyl group), glycine (hydrogen), and lysine (amine group) amino acid side chains (Figure 1c), which we will refer to as mCP-A, mCP-G, and mCP-K, respectively. The motivation for studying these particular cases is that the large nonpolar methyl group will enable ion exclusion by steric hindrance as in aquaporins, whereas the smaller hydrogen and polar amine groups will facilitate ion transport as in various ion channels. All of the simulations are carried out using the parallel molecular dynamics software NAMD2.29 The CHARMM36 force field30 is used for the peptide nanotubes. We use a TIP3P standard model for water.31 The CHARMM general force field (CGenFF) is used for the toluene membrane. CHARMM36 and CGenFF are fully compatible force fields. The unnatural

Figure 1. Computational atomistic model. (a) System setup. A nanotube is embedded in a low-dielectric membrane and solvated in a NaCl aqueous saline solution. (b) Snapshots of a conventional (CP) and a chemically modified (mCP) cyclic peptides. (c) Schematic of the different functional groups studied that are inspired from biological amino acid side chains.

amino acids studied here were not fully parametrized in the CHARMM force field. In order to find the missing parameters, we use the software ParamChem 0.9.7.132 with the CGenFF 2b8 force field.33 Further details regarding the parametrization can be found in ref 34. The protocol of the molecular dynamics simulations is as follows. First, we minimize the system for 1000 steps using the conjugate gradient and line search algorithm. Next, we equilibrate the system in the NPT ensemble (constant number of particles, pressure, and temperature) at T = 298 K and P = 1 atm for 1.5 ns. A time step of 1 fs is used for all of the simulations. The pressure is controlled using a modified Nosé− Hoover method in which Langevin dynamics is used to control the fluctuations in the barostat.35 A damping coefficient of 7 ps−1 is used to control the temperature. The electrostatic interactions are calculated using the particle mesh Ewald (PME) method.36 During equilibration, the α-carbons of the peptide backbones are constrained in the x-direction (the longitudinal direction of the nanotube). These constraints do not inhibit the rotation of the cyclic peptides, allowing them to maximize the formation of inter-ring hydrogen bonds. For each case, after equilibration, we perform a single production run where an electric potential of 1 V is applied. We simulate the electric field by applying a constant force proportional to the external field and the partial charge on all of the charges in the system, following the procedure described in ref 37. The validity of this approach to study biomolecular systems has 1515

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transports Na+ ∼7 times slower than the conventional CPN. On the other hand, the mCPN-G is almost 3 times faster than the CPN and ∼17 times faster than the mCPN-A, the slowest of the four. These results demonstrate that the Na+ flow rate in mCPNs can be tuned over a wide range of values by just tailoring the polarity and size of the functional group in the unnatural amino acid. However, the question of how such small changes in the peptide chemistry lead to the dramatic changes in the flow rate remains open. The flow rates measured from our simulations are of the same order of magnitude as other biological ion channels under physiological conditions such as the potassium channel (∼108 ions per second),42 the acetylcholine receptor channel that communicates the nerve impulses (∼107 ions per second),43 or the gramicidin channel (∼107 ions per second).44 The conductance of the nanotubes ranges from ∼0.01 nS for the mCPN-K and the CPN, to ∼0.03 nS for the mCPN-G. The measured conductance of the conventional CPN is comparable to the experimentally reported one, ∼0.055 nS.10 Small differences between simulations and experiments may arise due to the different thickness and nature of the membranes employed, different nanotube length (∼2 versus ∼4 nm), or the difference in the applied voltage (1 V versus 50 mV). We observe that the passage time (Figure 2b), defined as the average time required for a Na+ to permeate through a nanotube, shows the opposite trend compared to the flow rate, with short passage times leading to large flow rates. This inverse relationship (passage time ≈ flow rate −1) between the flow rate and passage time (Figure 2c) suggests that the speed of transport of the Na+ through the interior is a key factor for tailoring the flow rate. The passage time is in turn governed by the interactions between the permeating ion and the nanotube. In particular, the interactions between cations and peptide backbone carbonyl groups have been observed to play a major role in slowing down the permeation of cations in conventional CPNs45,46 and also in the case of the biological ion channels such as the potassium channel KcsA. 47 Given these observations, we then set out to investigate how the functional groups in mCPNs enhance or attenuate these key interactions. To gain insight into the carbonyl−Na+ interactions, we analyze the composition of the coordination shell of the Na+ when within each nanotube, averaged over the length of the nanotube and the time of the simulation (Figure 3). The coordination shell of the ion is calculated based on purely geometric criteria, in which all of the reactive groups at a distance below 3 Å of the ion center are counted in the shell. Inside of the nanotubes, the Na+ can be coordinated by water

been previously demonstrated.38,39 All of the systems are simulated for at least 105 ns and up to 200 ns, which is sufficient to obtain converged values of the ion flow rates (Figure SI.1, Supporting Information). Mechanisms of Ion Transport. Under an applied electric potential of 1 V, we observe that regardless of the chemical modification, CPNs do not allow Cl− passage. Previous studies on conventional CPNs have shown that repulsive electrostatic interactions between the Cl− and the peptide backbone carbonyl groups prevent the ion’s entrance and preclude the possibility of the ion coordinating with peptide amine groups and thus reducing the energy barrier of necessary dehydration.40,41 Because all of the mCPNs also exhibit this behavior, we conclude that the modifications studied cannot lower the energy barrier that leads to the rejection of Cl−. The Na+ flow rates for the different cases, on the other hand, span over an order of magnitude (Figure 2a). The conventional CPN exhibits an intermediate Na+ flow rate of 6.6 × 107 Na+ per second. The mCPN-K, which contains polar functional groups, exhibits a similar flow rate. The mCPN-A, characterized by large hydrophobic methyl groups in the nanotube lumen,

Figure 2. Transport metrics of Na+ as a function of the nanotube chemistry. (a) Flow rate and conductance. (b) Average passage time. (c) Anticorrelation between the flow rate and passage time.

Figure 3. Time average composition of the first coordination shell of Na+ inside of the nanotubes. 1516

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Figure 4. Na+ coordination shell composition along the length of the nanotubes. The plots show curves representing the number of water molecules (continuous red line), carbonyl groups (dotted green line), amine groups (dotted−dashed blue line), and the total coordination number (dashed black line). The panels represent the (a) CPN, (b) mCPN-A, (c) mCPN-G, and (d) mCPN-K.

larger than that of the conventional CPNs. Second, the absence of steric repulsions or electrostatic attractions between the hydrogen functional group and the Na+ and water molecules allows the ion to occupy predominantly the central region of the nanotube (Figure 5a), where the possibilities of interacting with carbonyl groups are minimized. This mechanism, where the ion preserves the solvation shell and minimizes its interactions with carbonyl groups, results in fast transport rates. Only at the end of the nanotube, after the third cyclic peptide (or CP3), does the Na+ have carbonyl groups in its solvation shell. However, in contrast to the mCPN-A case, the lifetime of these interactions is short due to the absence of steric constraints imposed by the functional groups that prevent the ion from translocating. This is evidenced by the fact that the ions spend, on average, ∼26 times more time inside of the mCPN-A than in the mCPN-G, where transport is largely unimpeded. The slow transport exhibited by the mCPN-A is attributed to the large number of long-lived interactions between the carbonyl groups and the Na+ promoted by the steric repulsion between the functional group and the Na+. Up to three carbonyl groups coordinate the ion in the first and last interring spaces (Figures 4b and 5b). In these configurations, where ∼50% of the coordination shell is made of carbonyl groups, the Na+ is trapped in a highly stable configuration. The methyl functional groups impose steric constraints on the Na+ that force it to predominantly occupy peripheral positions and the inter-ring spaces. Once the Na+ is close to the nanotube walls and in between rings, the possibility of interaction with the carbonyl groups is maximized. The methyl groups additionally impose energy barriers on the passage of the ion through the

molecules, by peptide backbone carbonyl groups, or, in the case of the mCPN-K, by the amine functional groups. Figure 3 shows that the total coordination number is mostly conserved between the different cases, with the average of 5−6 water molecules matching the coordination of the Na+ in the aqueous solution of the reservoirs. The nanotube with the lowest flow rate, the mCPN-A, has the highest number of carbonyls in the coordination shell. On the other hand, the coordination shell of Na+ in mCPN-G, the fastest nanotube, is mostly formed by water molecules. A more detailed look at the local composition of the coordination shell along the nanotubes reveals that, for all cases but the mCPN-K (Figure 4d), the total coordination number peaks in the inter-ring spaces (Figure 4a−c). The highest number of carbonyl interactions is always found in the interring spaces, where the steric constraints are less constrictive and the possibilities of interaction between the Na+ and the carbonyls are maximized. The maximum of the water coordination number corresponds to the minimum of that of the carbonyls, indicating that water molecules in the coordination shell are replaced by carbonyl groups in the inter-ring spaces. To facilitate the visualization of the most representative coordination shell for the different cases, we show snapshots in Figure 5 in which the ions are depicted in their most probable configurations. Snapshots of an ion passing through the mCPNs are shown in Figure 5a, b, and d, and a snapshot of the conventional CPN is shown in Figure 5c. In the mCPN-G, which is the fastest nanotube, the Na+ rarely interacts with the peptide carbonyl groups and conserves its coordination shell of water upon entrance into the nanotube. The reason is two-fold. First, the mCPN-G pore size is slightly 1517

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during permeation (Figure 5d). By preventing the Na+ from getting close to the nanotube walls and the inter-ring spaces, the amine group minimizes the contacts of the ion with the carbonyl groups of the peptide backbone. Despite the mCPN-K having the minimum number of carbonyls in the coordination shell of all cases, the flow rate of Na+ is still intermediate because the amine groups act as “sticky” sites, slowing down the translocation of the ions. Potential Applications of the Nanotubes. In a recent study, it was demonstrated that mCPNs are efficient water transporters.34 Our results show that Cl− is completely rejected and that the cation permeability can be modulated by changing the chemistry of the functional group, suggesting water desalination as a potential application of the nanotubes. To measure the relative performance of the nanotubes for desalination of water, we define the ion rejection index as Iion R = H2O ion = 1/(1 + f ion mCPN‑R/f CPN) and the water permeation index as IP 2O 2O 1 − 1/(1 + f HmCPN‑R /f HCPN ), where f stands for flow rate, the superscript designates the species, and the subscript designates the nanotube type (e.g., CPN, mCPN-A, etc.). The value of both indexes for conventional CPNs is 0.5 by construction. An ideal nanotube for water desalination would have an ion rejection index of Iion R = 1 (which corresponds to a zero flow H2O rate of ions, f ion =1 mCPN‑R = 0) and a water permeation index IP H2O (which corresponds to an infinite flow rate of water, f mCPN‑R → ∞). For the water flow rates, we use the data that we obtained in a prior study with an identical setup to quantify pressuredriven water flow.34 The relative performance of the nanotubes for water desalination is shown in Figure 6a. We observe that the mCPN-A exhibits an ion rejection index substantially larger

Figure 5. Snapshots representing the most probable configurations of Na+ in the different nanotubes. The Na+ is colored in yellow, and the coordination shell is composed of the oxygen of water molecules (red), the peptide backbone carbonyl groups (green), or the amine group (blue) in the case of the mCPN-K. The different panels correspond to (a) mCPN-G, (b) mCPN-A, (c) conventional CPN, and (d) mCPN-K.

rings, which allows more time for the Na+ to establish interactions with the carbonyl groups. This “docking” effect leads to long passage times and extremely low flow rates. The higher number of carbonyl interactions observed in the first and last inter-ring spaces is explained by the higher flexibility of the cyclic peptides at the nanotube ends, which deform more easily to accommodate the Na+ and thus maximize the carbonyl interactions. An analysis of the rootmean-squared displacement (RMSD) of the different cyclic peptides along the nanotube supports this interpretation (Figure SI2, Supporting Information). The flexibility of the binding sites has also been seen to play a key role in biological systems, such as the KcsA channel, where the selectivity for K+ versus Na+ arises from the flexibility of the carbonyl groups in the selectivity filter.48 The mCPN-K is the only case where the attractive electrostatic interactions between the functional group and the ion attenuate the ion−carbonyl interactions. The attractive electrostatic interaction between the amine functional group and the Na+ brings the ion close to the amine functional groups

Figure 6. Performance of mCPNs for different applications. (a) Water desalination. The dashed semicircle separates the relative performance of the nanotubes with respect to the conventional CPN. (b) Antibacterial application. The antibacterial index is a measurement of the transport of cations relative to the transport of anions. An index of 1 corresponds to an infinite flow rate of Na+ and a zero flow rate of Cl−. The conventional CPN has an antibacterial index of 0.5 by construction. 1518

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rejection rate and passage time. Insertion of a polar group, (i.e., amine group in the mCPN-K) yields attractive electrostatic interactions that can effectively reduce carbonyl contacts. However, this mechanism does not lead to fast transport due to the relatively large affinity between Na+ and the amine groups. A slightly large pore facilitated by the glycine mimetic functional group (mCPN-G) proves to be the most efficient transporter of Na+ because it conserves the solvation shell of the cation and allows Na+ to translocate in a hydrated state away from the walls of the pore. These findings have important implications for different separations applications. In particular, we highlight the promise of the mCPN-G as an antibacterial agent because of its capability to selectively transport Na+ at very fast rates and the mCPN-A for water desalination purposes due to its low cation to water permeability ratio. The functional groups that facilitate slow and fast transport allow us to now envision synthetic systems with large chemical design flexibility through selfassembly, where the modularity of mCPNs could be further exploited to differentiate charged species. In the future, nanotubes containing cyclic peptides with different functional groups can be potentially used to create pore lumens with chemical diversity mirroring that of transmembrane protein channels.

than that of conventional CPNs but a close water permeation index. This ability of rejecting ions and water in a different fashion renders the mCPN-A a promising candidate for desalination applications. In desalination by separation membranes using reverse osmosis, the performance is usually measured by salt rejection as a function of the water permeability. The salt rejection is often calculated as the salinity of the permeate solution at the time where half of the water has flowed from the feed to the permeate side, relative to the initial salinity of the feed.9 Because we apply periodic boundary conditions in our system in all directions, there are no permeate or feed reservoirs, and therefore, this quantity cannot be defined. Instead, we calculate the index of ion rejection, which does not require the presence of two reservoirs and can be measured for any system settings; thus, it is more general than the salt rejection. Another potential use of the mCPNs is as antibacterial agents. The use of CPNs as antibacterial agents was proposed early on due to their ability to self-assemble preferentially on the surface of bacterial membranes and the capability to selectively transport cations at rates that match those of the naturally occurring antibacterial channels, such as gramicidin A.10,20 A nanotube that conducts more cations per unit time than the conventional CPNs will be a more efficient antibacterial agent because it will require a lower concentration to transport the same amount of ions across the bacterial membrane. To evaluate the relative antibacterial efficiency of the nanotubes with respect to the conventional CPN, we define ion an antibacterial index as Ianti = 1 − 1/(1 + Δf ion mCPN‑R/Δf CPN), +

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ASSOCIATED CONTENT

S Supporting Information *

Convergence of the Na+ flow rate and the root-mean-squared displacement of the cyclic peptides in the conventional CPN and the mCPN-A. This material is available free of charge via the Internet at http://pubs.acs.org.

−

Na Cl where Δf ion CPN = f CPN − f CPN. We find that the mCPN-G almost triples the flow rate measured for conventional CPNs, suggesting that it can improve the antibacterial properties of conventional CPNs (Figure 6b). Although there is no direct experimental evidence available of the transport properties of the mCPNs, there are multiple current efforts being directed toward the synthesis of the different chemistries described in this Letter. A proof of the feasibility of these nanotubes is the fact that the synthesis of at least two of the four cyclic peptide variants studied in this Letter (the CPN and the mCPN-A) is already possible.20,26 Additionally, polymer thin film membranes where CPNs are grown in block copolymer domains to serve as nanopores is an experimentally accessible,14 critical step toward the generation of membranes based on mCPNs for desalination. The antibacterial activity of CPNs has also been experimentally proven.7 The only difference between CPNs and mCPNs is the interior chemistry; therefore, it can be assumed that mCPNs will be able to self-assemble in bacterial membranes through similar mechanisms as CPNs. The remaining challenges involve the synthesis of mCPNs with arbitrary interior chemistries and the fabrication of defect-free membranes that would enable the testing of the design principles laid out in this work. Theoretical work presented here aims to narrow down the scope of future synthesis efforts to accelerate the discovery of novel nanopores for tailored transport applications. The main findings from our investigations can be summarized as follows. Na+ flow rates in cation-selective CPNs can be tuned over an order of magnitude with singlepoint amino acid substitutions alone. A large nonpolar group in the lumen (i.e., mCPN-A) requires Na+ to partially lose its solvation shell and facilitates strong affinity with backbone carbonyl groups, which significantly increases the cation

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: 847-491-5282. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The work presented here is funded by the National Science Foundation (DMREF Award CBET-1234305). A.S.B. acknowledges support from a Walter P. Murphy Fellowship by the McCormick School of Engineering and Applied Science at Northwestern University. The authors acknowledge the support from the Departments of Civil and Environmental Engineering and Mechanical Engineering at Northwestern University as well as the Extreme Science and Engineering Discovery Environment (XSEDE) for a supercomputing grant (TG-DMR140057). We thank our collaborators Ting Xu and Brett Helms for helpful discussions on the physical properties of chemically functionalized cyclic peptide nanotubes.

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REFERENCES

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DOI: 10.1021/acs.jpclett.5b00252 J. Phys. Chem. Lett. 2015, 6, 1514−1520