Published on Web 06/24/2009
Nature of Molecular Interactions of Peptides with Gold, Palladium, and Pd-Au Bimetal Surfaces in Aqueous Solution Hendrik Heinz,*,† Barry L. Farmer,‡ Ras B. Pandey,§ Joseph M. Slocik,‡ Soumya S. Patnaik,‡ Ruth Pachter,‡ and Rajesh R. Naik‡ Department of Polymer Engineering, UniVersity of Akron, Akron, Ohio 44325, Air Force Research Laboratory, Materials and Manufacturing Directorate, AFRL/RX, Wright-Patterson AFB, Ohio 45433, and Department of Physics and Astronomy, UniVersity of Southern Mississippi, Hattiesburg, Mississippi 39406 Received January 27, 2009; E-mail:
[email protected] Abstract: We investigated molecular interactions involved in the selective binding of several short peptides derived from phage-display techniques (8-12 amino acids, excluding Cys) to surfaces of Au, Pd, and Pd-Au bimetal. The quantitative analysis of changes in energy and conformation upon adsorption on even {111} and {100} surfaces was carried out by molecular dynamics simulation using an efficient computational screening technique, including 1000 explicit water molecules and physically meaningful peptide concentrations at pH ) 7. Changes in chain conformation from the solution to the adsorbed state over the course of multiple nanoseconds suggest that the peptides preferably interact with vacant sites of the face-centered cubic lattice above the metal surface. Residues that contribute to binding are in direct contact with the metal surfaces, and less-binding residues are separated from the surface by one or two water layers. The strength of adsorption ranges from 0 to -100 kcal/(mol peptide) and scales with the surface energy of the metal (Pd surfaces are more attractive than Au surfaces), the affinity of individual residues versus the affinity of water, and conformation aspects, as well as polarization and charge transfer at the metal interface (only qualitatively considered here). A hexagonal spacing of ∼1.6 Å between available lattice sites on the {111} surfaces accounts for the characteristic adsorption of aromatic side groups and various other residues (including Tyr, Phe, Asp, His, Arg, Asn, Ser), and a quadratic spacing of ∼2.8 Å between available lattice sites on the {100} surface accounts for a significantly lower affinity to all peptides in favor of mobile water molecules. The combination of these factors suggests a “soft epitaxy” mechanism of binding. On a bimetallic Pd-Au {111} surface, binding patterns are similar, and the polarity of the bimetal junction can modify the binding energy by ∼10 kcal/mol. The results are semiquantitatively supported by experimental measurements of the affinity of peptides and small molecules to metal surfaces as well as results from quantum-mechanical calculations on small peptide and surface fragments. Interfaces were modeled using the consistent valence force field extended for Lennard-Jones parameters for fcc metals which accurately reproduce surface and interface energies [Heinz, H.; Vaia, R. A.; Farmer, B. L.; Naik, R. R. J. Phys. Chem. C 2008, 112, 17281-17290].
1. Introduction
A variety of inorganic-biological nanostructures and biomimetic materials with distinct functionalities can be assembled using nanoparticles of various chemical composition, peptide linkers, surfactants, and polymer matrices.1-16 Peptides may †
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regulate crystal growth of the inorganic material,1,3-8,13 attract metal nanoparticles of a certain composition and size to form characteristic metal-coated wires,3-5 assemble in predefined (8) Slocik, J. M.; Naik, R. R. AdV. Mater. 2006, 18, 1988. (9) Xu, A.-W.; Ma, Y. R.; Colfen, H. J. Mater. Chem. 2007, 17, 415– 449. (10) Slocik, J. M.; Tam, F.; Halas, N. J.; Naik, R. R. Nano Lett. 2007, 7, 1054–1058. (11) Chen, J.; Wiley, B. J.; Xia, Y. Langmuir 2007, 23, 4120–4129. (12) Schiffrin, A.; Riemann, A.; Auwarter, W.; Pennec, Y.; Weber-Bargioni, A.; Cvetko, D.; Cossaro, A.; Morgante, A.; Barth, J. V. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 5279–5284. (13) Grohe, B.; O’Young, J.; Ionescu, D. A.; Lajoie, G.; Rogers, K. A.; Karttunen, M.; Goldberg, H. A.; Hunter, G. K. J. Am. Chem. Soc. 2007, 129, 14946–14951. (14) Jadzinsky, P. D.; Calero, G.; Ackerson, C. J.; Bushnell, D. A.; Kornberg, R. D. Science 2007, 318, 430–433. (15) Heinz, H.; Vaia, R. A.; Farmer, B. L. Langmuir 2008, 24, 3727–3733. (16) Cossaro, A.; Mazzarello, R.; Rousseau, R.; Casalis, L.; Verdini, A.; Kohlmeyer, A.; Floreano, L.; Scandolo, S.; Morgante, A.; Klein, M. L.; Scoles, G. Science 2008, 321, 943–946. 10.1021/ja900531f CCC: $40.75 2009 American Chemical Society
Interactions of Peptides with Au, Pd, and Pd-Au Surfaces
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Table 1. Peptide Names, Binding Targets, and Amino Acid
Sequences name
binds to
peptide sequencec
a +
A3 Au, Pd Ala-Tyr-Ser-Ser-Gly-Ala-Pro-Pro-Met-Pro-Pro-PheFlg-Na3 Au, Pda +Asp--Tyr-Lys+-Asp--Asp--Asp--Asp--Lys+- · 3 Na+ + Pd2-Cl Pdb Asn-Phe-Met-Ser-Leu-Pro-Arg+-Leu-Gly-His-Met-His- · Cl+ Pd4-Cl Pdb Thr-Ser-Asn-Ala-Val-His-Pro-Thr-Leu-Arg+-His-Leu- · Cl+ Flgd-Na2 Asp--Tyr-Lys+-Asp--Asp--Asp--Lys+- · 2 Na+ Gly10 Gly10 Pro10 Pro10 a References 7, 8. b These peptide sequences from phage display are newly reported here. c The approximation of the charge state equivalent to pH ) 7 in the models is indicated.
nanoscale patterns,12 and influence optical properties of the inorganic nanostructures.2,10,11 For example, the plasmon resonance frequency of metal nanorods depends on the size and shape of the nanoparticles as well as on the presence of molecular recognition groups, such as peptides or surfactants attached to the surface. In this configuration, binding of an external agent to surface-attached peptides can induce sufficient shifts in UV/vis absorption to support sensor capabilities.2 A major challenge lies in the tremendous number of potential peptides and lack of control over binding affinities. For example, given a pool of 20 natural amino acids to assemble a 12-peptide, there are N ) 2012 ) 1015.6 different potential peptides. The screening of all peptides is currently impossible; however, phage display techniques allow researchers to identify peptide sequences with specific binding affinity to nanoparticles and surfaces.1,3,5-8,17-19 In this procedure, commercial libraries of several billion phages with distinct peptide sequences expressed at the PIII minor coat protein were screened on various surfaces of gold, palladium, and silver nanoparticles, as well as on surfaces of montmorillonite, silica, germanium oxide, tin oxide, titania, and zinc oxide.5,8 After incubation of the entire library of phages, including the displayed peptides of typically 8-12 amino acid length, with the nanoparticles in solution, and after several washing cycles with HEPES buffer solution near pH ) 7, the most strongly binding peptides remain bound to the inorganic surfaces. These sequences have been identified by analysis of the corresponding phage DNA (some shown in Table 1).6 The relative binding strength, transmission electron microscopy (TEM), IR spectroscopy, NMR spectroscopy, and thermochemical data were recorded to characterize the peptidemodified nanoparticles in comparison to the peptides in solution.1-13,17-19 The molecular reasons for highly specific binding in the absence of thiol groups in the peptides, however, have remained largely a matter of speculation. Several studies attempted an explanation on the basis of experimental1,3-13,17-20 and simulation data;21-31 however, evidence about the acting mechanisms is often vague, and modeling studies often employed excessively crude approximations. We present the first steps using molecular simulation as a tool to understand the reasons for binding of (17) Willett, R. L.; Baldwin, K. W.; West, K. W.; Pfeiffer, L. N. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 7817–7822. (18) Roach, P.; Farrar, D.; Perry, C. C. J. Am. Chem. Soc. 2005, 127, 8168– 8173. (19) Zorbas, V.; Smith, A.; Xie, H.; Ortiz-Acevedo, A.; Dalton, A. B.; Dieckmann, G. R.; Draper, R. K.; Baughman, R. H.; Musselman, I. H. J. Am. Chem. Soc. 2005, 127, 12323–12328. (20) Li, Z.; Calaza, F.; Gao, F.; Tysoe, W. T. Surf. Sci. 2007, 601, 1351– 1357.
Figure 1. Modeling peptide-surface interactions and biological self-
assembly using techniques at various levels. The currently distinguishable number of dodecapeptides for each technique is indicated in parentheses. We focus on classical atomistic simulation in comparison with experiment and simulation at other levels.
selected experimental and control peptide sequences, including the computation of adsorption energies, changes in peptide conformation upon adsorption, and the strength of interaction of amino acid residues upon interaction with the surface in aqueous solution (Figure 1). In contrast to earlier work, our approach includes an accurate representation of metal surface energies32-36 using a Lennard-Jones model for face-centered cubic (fcc) metals compatible with various force fields,29 considers the dynamics on the time scale of nanoseconds at 298 K as opposed to static calculations at 0 K, and involves approximately 1000 water molecules as opposed to unspecific implicit water models, few static water molecules, or no water molecules at all. Therefore, temperature, pH, and ionic concentration are tangible quantities in the simulation. We also benefit from an efficient new method for the computation of binding energies for the peptides. The viability of this approach is supported by recent improvements in the accuracy of force field parameters for inorganic components29,37-41 and the identification of polarization effects on metal surfaces42-46 as modest contributions. (21) Haftel, M. I.; Bernstein, N.; Mehl, M. J.; Papaconstantopoulos, D. A. Phys. ReV. B 2004, 70, 125419:1–15. (22) Vassilev, P.; van Santen, R. A.; Koper, M. T. M. J. Chem. Phys. 2005, 122, 054701. (23) Oren, E. E.; Tamerler, C.; Sarikaya, M. Nano Lett. 2005, 5, 415–419. (24) Schravendijk, P.; van der Vegt, N.; Delle Site, L.; Kremer, K. ChemPhysChem 2005, 6, 1866–1871. (25) Kantarci, N.; Tamerler, C.; Sarikaya, M.; Haliloglua, T.; Doruker, P. Polymer 2005, 46, 4307–4313. (26) Schravendijk, P.; Ghiringhelli, L. M.; Delle Site, L.; van der Vegt, N. F. A. J. Phys. Chem. C 2007, 111, 2631–2642. (27) Miao, L.; Seminario, J. M. J. Phys. Chem. C 2007, 111, 8366–8371. (28) Ghiringhelli, L. M.; Delle Site, L. J. Am. Chem. Soc. 2008, 130, 2634– 2638. (29) Heinz, H.; Vaia, R. A.; Farmer, B. L.; Naik, R. R. J. Phys. Chem. C 2008, 112, 17281–17290. (30) Pandey, R. B.; Heinz, H.; Feng, J.; Farmer, B. L.; Slocik, J. M.; Drummy, L. R.; Naik, R. R. Phys. Chem. Chem. Phys. 2009, 11, 1989– 2001. (31) Hong, G.; Heinz, H.; Naik, R. R.; Farmer, B. L.; Pachter, R. ACS Appl. Mat. Interf. 2009, 1, 388–392. (32) Tyson, W. R.; Miller, W. A. Surf. Sci. 1977, 62, 267–276. (33) Menon, S. K.; Martin, P. L. Ultramicroscopy 1986, 20, 93–98. (34) Flueli, M.; Borel, J. P. J. Cryst. Growth 1988, 91, 67–70. (35) CRC Handbook of Chemistry and Physics, 84th ed.; Lide, D. R., Ed.; CRC Press: Boca-Raton, FL, 2003. (36) Osman, M. A.; Keller, B. A. Appl. Surf. Sci. 1996, 99, 261–263. (37) Heinz, H.; Castelijns, H. J.; Suter, U. W. J. Am. Chem. Soc. 2003, 125, 9500–9510. (38) Heinz, H.; Suter, U. W. J. Phys. Chem. B 2004, 108, 18341–18352. (39) Heinz, H.; Suter, U. W. Angew. Chem., Int. Ed. 2004, 43, 2239–2243. (40) Heinz, H.; Koerner, H.; Vaia, R. A.; Anderson, K. L.; Farmer, B. L. Chem. Mater. 2005, 17, 5658–5669. (41) Heinz, H.; Vaia, R. A.; Farmer, B. L.; Heinz, H.; Vaia, R. A.; Farmer, B. L. J. Chem. Phys. 2006, 124, 224713. (42) Bardeen, J. Phys. ReV. 1940, 58, 727–736. (43) Lang, N. D.; Kohn, W. Phys. ReV. B 1973, 7, 3541–3550. (44) Smith, N. V.; Chen, C. T.; Weinert, M. Phys. ReV. B 1989, 40, 7565– 7573. (45) Finnis, M. W. Surf. Sci. 1991, 241, 61–72. J. AM. CHEM. SOC.
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Therefore, semiempirical classical simulation in close relation to experiment and other theoretical approaches can provide insight into the nature of molecular interactions at such inorganic-organic interfaces (Figure 1). We limit the investigation to well-defined even {111} and {100} surfaces; the influence of the shape and composition of the nanoparticles shall be considered elsewhere. Further background information on simulation methods can be found in section S1 of the Supporting Information. The paper is organized as follows. In section 2, we describe the peptide sequences and summarize the computational approach. Sections 3 and 4 are dedicated to the presentation of simulation results on even monometallic surfaces and on bimetallic surfaces. Section 5 focuses on the comparison of results to experiment and explains our hypothesis of the specificity and strength of peptide interactions with metal surfaces. A summary is presented in section 6. The Supporting Information includes a description of the computational screening approach (S2), simulation protocols (S3), and additional evidence on the binding mechanism from earlier simulations (S4). 2. Peptide Sequences and Computational Details 2.1. Sequence of the Peptides. We have chosen four peptides named A3, Flg-Na3, Pd2-Cl, Pd4-Cl, which were identified as the strongest metal-binding peptides from a pool of ∼109 peptides by phage display.7,8 The neutral peptide A3 and the three-fold negatively charged peptide Flg-Na3 at pH ) 7 have shown affinity to Au and Pd nanoparticles. The peptides Pd2-Cl and Pd4-Cl are newly reported here and have shown affinity to Pd nanoparticles. For comparison, we also include the peptide Flgd-Na2, deficient in one Asp residue compared to Flg-Na3, as well as the arbitrarily chosen peptides Gly10 and Pro10 of unknown specificity of adsorption (Table 1). We assume pH ) 7, which is characterized by protonation or deprotonation of the corresponding amino acid side chains according to their pKa values, including a zwitterionic structure of the peptides with a protonated N-terminal end and a carboxylate C-terminal end. For amino acids whose charges do not compensate to zero within the peptide, equivalent amounts of counterions Cl- or Na+ are added to maintain charge neutrality. 2.2. Efficient Computation of Adsorption Energies. The quantitative computation of adsorption energies requires the inclusion of explicit water molecules and ionic solutes due to the formation of spatially oriented hydrogen bonds which change their orientation when peptides (or other adsorbates) move from the solution to the surface. We utilize a new, efficient approach which involves the simulation of four systems, (1) the surface-solutesolvent system of average energy E1, (2) the solute-solvent system of average energy E2, (3) the solvent system of average energy E3, and (4) the surface-solvent system of energy E4 under consideration of equal molecular volumes for each component under NVT conditions. The adsorption energy is calculated from the average energy of each of the four systems as Eads ) E1 - E2 + E3 - E4. Each simulation requires an accurate summation of Coulomb interactions on the order of e0.1 kcal/mol uncertainty for the entire system as well as precise temperature control or energy corrections to a reference temperature, respectively. Details can be found in section S2 of the Supporting Information. 2.3. Models, Force Field Parameters, and Simulation Protocol. Fully atomistic models of the peptides, metal surfaces, and water were prepared using the Hyperchem47 and Materials Studio Visualizers.48 Box dimensions were typically 3 nm × 3 nm × z whereby the additive box height z amounts to g1.2 nm for metal (46) Guidelli, R.; Schmickler, W. Electrochim. Acta 2000, 45, 2317–2338. (47) HyperChem 7.5; Hypercube Inc.: Gainesville, FL, 2006. (48) Materials Studio 4.0, Discover Program, Cerius2, and User Guide; Accelrys, Inc.: San Diego, CA, 2005. 9706
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Figure 2. Representative snapshots of the peptides in solution. The peptides A3, Flg-Na3, and Flgd-Na2 assume unspecific 3D conformations, and a tendency toward intramolecular interactions between the charged -CO2groups and H3N+-/Na+ ions is seen for Flg-Na3 and Flgd-Na2. The peptide Gly10 prefers an extended conformation and is conformationally very flexible. Polyproline Pro10 assumes a helical structure.
substrates, and to g3.5 nm for water and aqueous solutions of the peptides. The size was chosen such that 25% to 40% of the surface area is covered by the peptide, close to experimental conditions. The consistent valence force field (CVFF)48,49 extended for accurate Lennard-Jones parameters for fcc metals29 was employed in the simulation of the metal-water-peptide hybrid systems. The parameters for fcc metals reproduce surface energies and interface energies in quantitative agreement with experiment (1-10%), down from deviations up to 500% in earlier force fields. The Discover program48 as well as LAMMPS50 were employed to carry out molecular dynamics simulations. Models, force field, simulation protocols, and accuracy are described in section S3 of the Supporting Information. 3. Adsorption of Peptides on Even {111} and {100} Surfaces of Au and Pd
The peptides were relaxed in aqueous solution (Figure 2) and on the metal {111} and {100} surfaces (Figure 3) by molecular dynamics simulation. Corresponding adsorption energies (Table 2) indicate that peptides are generally attracted to the metal surfaces, supported by the observation of direct contact with the metal surface or the presence of one or two water interlayers in the models (Figure 3). The order of magnitude of computed binding energies for the oligopeptides, between 0 and -100 kcal/mol, is in the range of noncovalent interactions (
