Molecular Modeling Characterization of a Conformationally

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J. Phys. Chem. C 2010, 114, 16043–16050

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Molecular Modeling Characterization of a Conformationally Constrained Monolayer-Protected Gold Cluster† Neranjan V. Perera,‡ William Isley,⊥,‡ Flavio Maran,§ and Jose´ A. Gasco´n*,‡ Department of Chemistry, UniVersity of Connecticut, 55 North EagleVille Road, Unit 3060, Storrs, Connecticut 06269, and Department of Chemistry, UniVersity of PadoVa, Via Marzolo 1, 35131, PadoVa, Italy ReceiVed: March 22, 2010; ReVised Manuscript ReceiVed: July 19, 2010

We present a multilevel molecular modeling study aimed at elucidating physical and chemical properties of gold clusters capped by a monolayer of thiolated oligopeptides. The protecting peptides are based on the R-aminoisobutyric acid unit, form intramolecular CdO · · · H-N bonds, and can form intermolecular hydrogen bonds. This study is motivated by recent breakthroughs into the determination of crystal structures of small gold clusters protected with small thiolated molecules. Such structures are characterized by surface gold atoms in the so-called “staple motifs”, as opposed to the commonly assumed structures in which thiolates bind to a high-symmetry gold cluster. It is unclear, however, whether the staple motif is common to all kinds of protecting layers, especially those made of polypeptides that are largely stabilized by intermolecular hydrogen bonding. Structural and spectroscopic properties are presented to understand the nature of peptide-peptide interactions, their structural arrangements, and their effect on the gold-thiol structural motif. 1. Introduction The fabrication of metallic nanoparticles has in recent years developed into an important research area at the frontiers of materials chemistry. Rational design of nanostructured catalysts could lead to new electronic and catalytic properties,1 as in the case of the discovery of high catalytic activity of gold nanoparticles for the oxidation and reduction of hydrocarbons.2-7 Today, catalysis with gold nanoparticles is receiving appreciable attention in various applications: oxidation of CO,8 amination reactions,9 direct nitrene insertion,10 cross-coupling reactions,11 production of alkenes,12 and selective CdO hydrogenation in R,β-unsaturated ketones or aldehydes.13 Use of gold nanoparticles in catalysis has been based on both supported materials and core-shell assembled nanoparticles. In this latter case, a variety of chemically tunable reactions in metallic nanoparticles can be obtained by encapsulation of nanocrystals in alkanethiolate monolayers,14,15 to form hybrid systems known as monolayer-protected clusters (MPCs).14,16-19 Exploiting MPCs for applications in the area of catalysis requires a proper structural and dynamical characterization of the physical properties of the protecting layer.20-22 In the particular case of gold alkanethiolate monolayers, there has been for some time a misidentification in the structure of these MPCs. This was not a minor issue, since the structural details in question were at the surface of the gold cluster and, thus, more likely to play a role in catalysis reactions. In a recent breakthrough, two groups have obtained for the first time a total structure determination of a small cluster, Au25(SCH2CH2Ph)18, in its anionic form,23 and a larger cluster, Au102(p-SPhCOOH)44.24 A similar crystal structure was later found for the neutral form of Au25(SCH2CH2Ph)18.25 Such structures are characterized by surface gold atoms in the so-called “staple † Part of the special issue “Protected Metallic Clusters, Quantum Wells and Metallic Nanocrystal Molecules”. * Corresponding author. E-mail: [email protected]. ‡ University of Connecticut. § University of Padova. ⊥ Current Address: University of Minnesota, Minneapolis, MN.

Figure 1. Thiolated oligopeptide based on the R-aminoisobutyric acid (Aib) unit (n ) 0-3 corresponds to the number of intramolecular hydrogen bonds).

motifs”, as opposed to the commonly assumed structures in which thiolates do not considerably alter the gold cluster and its high symmetry structure. It is still unclear, however, whether the staple motif is also common to a gold cluster protected by a monolayer entirely composed of thiolated peptide ligands. Monolayer formation is driven by the chemical bonding between the sulfur and gold atoms and by interactions between neighboring adsorbate molecules. Typical ligand monolayers include alkanethiolates, and thus, the adsorbates interact mainly through intermolecular van der Waals forces. Additional stability can be obtained by intermolecular CdO · · · H-N hydrogenbonding between embedded amide groups. Recently, Fabris et al.21 produced and characterized a series of gold nanoclusters protected by oligopeptides based on the R-aminoisobutyric acid (Aib) unit (see Figure 1); the peptides were thiolated at the N-terminus, whereas the C-terminus ended with a N-t-butyl amide group. The peptides were devised to form 0, 1, 2, or 3 intramolecular CdO · · · H-N hydrogen bonds, on the basis of their natural tendency to form 310-helical structures. In this context, it is worth stressing that, owing to marked steric hindrance at the R-carbon and, consequently, restricted torsional freedom,26,27 Aib peptides adopt a rigid 310-helical structure, even for short oligomers,28 as opposed to peptides based on coded R-amino acids, which start to form helixes, such as the R-helix, only for rather long oligomers.29 Studies based on X-ray diffraction, IR, and 1H NMR show that helical structures indeed form in the solid state as well as in solution.30,31 Evidence of 310-helical structures has been obtained also for thiolated Aib peptides assembled on gold surfaces32 and gold

10.1021/jp102585n  2010 American Chemical Society Published on Web 08/05/2010

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nanoclusters.21,33 It appears that only quite severe conditions may disrupt the robust 310-helical conformation, as found very recently for Aib peptides self-assembled on a mercury electrode and perturbed by a strong interfacial electric field opposing the direction of the peptide dipole moment.34 Previously, Aib-covered nanoparticles were fully characterized by 1H NMR spectrometry, IR and UV-vis absorption spectroscopies, transmission electron microscopy (TEM), thermogravimetric analysis, and X-ray photoelectron spectroscopy.21 The MPCs were obtained with core diameters in the range of 1.1-2.3 nm (TEM determinations). The smallest MPC obtained was in agreement with the average formula Au38Pep18. On the other hand, similar but alkanethiolate-protected clusters previously thought to have the average formula Au38TG24 (TG ) thiolate group) have been recently unequivocally identified as being Au25TG18.35-38 Under the light of this new finding and taking into account the previously obtained peptide footprint of the Aib monolayer, we now believe that the above clusters could have the average formula Au25Pep14. Despite the rich physicochemical data gathered in this study, additional questions on the monolayer structure and nature of the intra- and intermolecular interactions have come to the surface. Furthermore, the underlying assumption in the study was based on the standard model as far as the Au-S interaction was concerned, not the staple motif model. It is, therefore, rather important to investigate whether the physicochemical features of these peptide MPCs may also be consistent with the staple motif. Moreover, as far as the nature of the monolayer arrangement and the interpeptide interactions are concerned, some issues are not yet fully understood. A fundamental question relates to how these oligopeptides arrange around such a small cluster and what is the pattern that describes interchain interactions. To address these questions, it would be certainly advantageous to design atomistic models to simulate their behavior and to interpret experimental data based on a detailed molecular description. Although a number of theoretical studies have focused on gold clusters passivated by alkanethiolates,39-45 none has so far constructed models of gold clusters protected with large size oligopeptides, in which their self-interactions is as crucial as their interaction with the gold surface. In this work, we construct atomistic models of an Aib-monolayer-protected gold cluster. The construction is primarily guided by what has been indirectly inferred from NMR and IR experiments.21 In turn, the modeled structure provides further insight into the interpretation of the data and generally on the structural features of this type of MPC. 2. Molecular Modeling and Methods Thiolated gold clusters are usually synthesized with a broad distribution of core sizes and, therefore, surface coverage. Some among the smallest clusters have been identified by careful mass spectrometry analyses to possess the formulas Au28-TG16,46 Au38TG24,38 Au38-TG22,47 Au38-TG18,21 and Au25-TG18.38 Very recently, Heaven et al.23 were able to determine the crystal structure of [N(C8H17)4+][Au25(SCH2CH2Ph)18-], followed by Zhu et al.25 for the neutral form of the same cluster, which allowed correction of a labeling error, that is, Au38(SCH2CH2Ph)24, that affected several papers on the optical and electrochemical properties of this species. The “staple-protected” Au13 core, found in these later Au25-TG18 crystal structures, was afterward nicely reproduced by the theoretical work of Akola et al.43 On the basis of this assignment and the considerations made above, we construct in the present work a cluster of Au25 protected with 18 Aib-based ligands. Concerning the stoichi-

Perera et al. ometry and the fact that for Au25, the number of peptide ligands could be smaller than 18, we prefer to focus on the more known Au25TG18 formula, also because the same stoichiometry has been assessed for another peptide-protected cluster, that is, Au25(glutathione)18.38 The MPCs studied here are denoted with the formula AukAib[n]m, where k denotes the number of gold atoms, n is the number of intramolecular hydrogen bonds, and m is the number of oligopeptide ligands. According to this notation, Aib[n] corresponds to a ligand made of (n + 1) Aib units (cf. Figure 1). In the calculations, we included the presence of a N-t-butyl amide group on the C-terminus, as in the experimental study.21 A multilevel theory approach was employed at various stages of the construction and characterization of the model clusters. Density functional theory (DFT) with the hybrid functional B3LYP was carried out to determine the structure of small AukAib templates as well as for the computation of 1H NMR chemical shifts. The valence double-ζ polarized basis set 6-31g** was used for all atoms other than Au. Whenever Au atoms were considered in the DFT calculation (for the small templates and Au38-Aib[1]2 described below), the effective core basis set LACVP* was used for gold. The quantum chemistry package Gaussian 0948 was used for all systems except for Au38Aib[1]2, for which we used Jaguar.49 For the construction of the larger system Au25-Aib[3]18, we used a Monte Carlo procedure using a molecular mechanics (MM) approach with a force field adapted from Amber99.50 DFT was later used on these larger models for optimizations and computation of 1H NMR chemical shifts using Gaussian 09. Auk-Peptide Templates. A central aspect in the atomistic description of MPCs is to correctly describe the sulfur gold interaction. A DFT description (ultimately aimed to compute spectroscopic properties) would be computationally intractable if we were to consider a full-size MPC (∼1400 atoms). Quantum mechanical (QM) detail is nevertheless required to guide the construction of Auk-peptide model units to be used as templates in a larger scale (classical) simulation model. Thus, with the perspective of constructing MM and QM models, DFT calculations were carried out to describe the binding modes of small gold clusters coordinated to thiolated peptides. Such small models were later used to guide us in the attachment of the oligopeptides on Au38 and Au25. Possible coordination of sulfur to gold atoms includes on top of a single gold atom, bound to three gold atoms (on a hole site), and bridging between two atoms. Calculations at the B3LYP/LACVP** level on Au3-SCH3 show that the sulfur atom binds in a bridging mode. This outcome, however, appears to be a general feature, not just a consequence of using a reduced cluster size and a small ligand. More realistic models, in fact, show the same binding mode: on one hand, DFT optimization of a 310-helix made of thiolated Aib oligopeptide (Aib[3]) bound to Au3 leads to the same binding mode (Figure 2, left). On the other hand, increasing the number of gold atoms to a size large enough so that the cluster acquires a 3-dimentional structure (as in Au7) also results in a bridging mode (Figure 2, right). Au25-Aib[3]18 Model. Au25-Aib[3]18 was constructed using the readily available crystal structure of [N(C8H17)4][Au25(SCH2CH2Ph)18] as a template.23 Since a SCH2CH2 group is available in the template structure and common to thiolated Aib, the equivalent groups in Aib were superimposed into these groups. With each Aib[3] containing 76 atoms, the total system consisted of 1393 atoms. As already mentioned, the actual MPCs could be assigned the formula Au25-Aib[3]14. However, since we know with certainty only the structure of Au25-Aib[3]18, we

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Figure 2. DFT optimized structure at the B3LYP/lacvp** theory level for Aib[3] attached to Au3 (left) and Au7 (right).

chose this formula to construct our model. Later, we discuss what effect fewer ligands would have on the structure and NMR spectroscopy. Simulated Annealing via Monte Carlo. The procedure of constructing the MPCs mentioned above rapidly leads to steric clashes between the Aib ligands. To overcome this problem, a Monte Carlo approach was employed to decompress these steric interactions and to search for low energy rotamers. Since the oligopeptides are potentially able to form hydrogen bonds with their neighbors and therefore fold into each other, it is unlikely that the initial construction of the monolayer, even after decompressing steric interactions, would be a good representative of the lowest energy structure. Thus, for these and similar polypeptide monolayers, the MC procedure was essential to drive the system through a large number of energy barriers. Notice that this is a fundamental difference with commonly used alkanethiolate monolayers in gold clusters, where van der Waals interactions dominate. The force field employed in the MC calculations assumes the gold cluster and each S atom always fixed at the configuration used in the initial construction. Assuming a neutral system, partial charges on gold atoms were assumed as zero, whereas van der Waals parameters were taken from the universal force field (UFF) (σ ) 2.394 Å, ε ) 0.039 kcal/mol).51 Since Au and S are fixed, the only new bonding parameters to be defined are the Au-S-C bending terms (kθ ) 51 kcal/mol, θ0 ) 105°). These parameters were roughly estimated so that the MM-optimized geometry of the template and the vibrational frequency of that particular mode reproduced those obtained at the DFT level. Force field parameters for the R-aminoisobutyric acid were assigned on the basis of similarities to already parametrized amino acids (according to the force field Amber99). For instance, parameters for alanine were used as approximations to R-aminoisobutyric acid. Electrostatic potential charges for each thiolated oligopeptide were derived using DFT at the B3LYP/6-31g* level of theory. van der Waals parameters for Aib were taken as such from the Amber99 force field. It is important to emphasize that the overall description of the system by this rather simplified potential has only the purpose of gaining qualitative insight into the possible structural arrangements within the peptide monolayer. In addition, implementation of a more sophisticated potential (e.g., semiempirical, DFT) would not allow one to carry out the large conformational search needed to decompress the system from its initial construction. A metropolis algorithm was employed during the MC procedure. Moves were carried out by only changing the dihedral angles Au-S-C-C, S-C-C-C, and C-C-C-O. All other internal coordinates remained intact, guaranteeing the integrity of the 310-helix, as previously shown experimentally.21 The dihedrals were randomly moved within an interval of (20°, and moves were accepted with a probability of p ) min{exp(-∆E/ kBT), 1}, where kB is the Boltzmann constant, T is the temperature, and ∆E is the change in energy as a result of the move. Typically, about 20 000 MC cycles were carried out (each

MC cycle consists of 3 × 18 moves). After each MC cycle, the temperature was decreased constantly from an initial value of 3000 K to a final value of 0 K. The main objective of the MC procedure was to move the system out of the sterically unfavorable initial state and to favor the formation of interchain hydrogen bonds. Among the five nitrogen atoms that can donate hydrogen bonds, it has been shown experimentally that N(1) is most likely involved in hydrogen bond, and N(2) is much less likely to do so (all other N-H groups form intramolecular hydrogen bonds).21 Thus, guided by these two observations, an ad hoc energy was defined as

E ) Evdw + aEhbond where Evdw is the van der Waals term in the force field energy and Ehbond is defined as

Ehbond ) -E0

∑ ∑ e-(r - r ) /δ -(θ - θ ) /δ 0 2

i

2

r

0

2

2

θ

j

where r and θ are the O · · · H hydrogen bond distance and the O · · · H-N angle involving the NH(1) group of a given Aib (run by the index i) and each oxygen of the rest of the Aib’s (run by the index j). As initial values of the H-bond parameters, we used E0 ) 4 kcal/mol, r0 ) 2.32 Å, δr ) 1.65 Å, θ0 ) 180°, and δθ ) 70°, where E0 is the H-bond energy, r0 is the O · · · H distance, δr is a range of H-bond distances, θ0 is the O · · · H-N angle, and δθ is a typical range for this angle. Notice that these geometric and energetic parameters are based on loose criteria for hydrogen bonds. For instance, r0 was taken as the midpoint between 1.5 and 3.15 Å, and θ0, the midpoint between 145° and 215°. These criteria are sometimes used in molecular graphics viewers, such as Molden.52 The parameter a controls the relative strength of the two energy terms Evdw and Ehbond, and in turn, the number of intermolecular hydrogen bonds involving NH(1). For a ) 1, one or two hydrogen bonds where obtained, whereas for a ) 100, up to 50% of the NH(1)’s become hydrogen-bonded. The final step in the simulated annealing procedure was to minimize the total energy, taking into account all force field terms as expressed in the Amber force field. Notice that in this latter case, the Ehbond term is no longer explicitly considered. The program TINKER53 was used for this minimization. 1 H NMR Chemical Shifts. Shielding constants were computed using the gauge-including atomic orbitals formalism as implemented in Gaussian 09 and referred to the computed shielding constant of hydrogen in tetramethylsilane (TMS). To compute 1H NMR chemical shifts for the entire Au25-Aib[3]18, 18 calculations were carried out separately in the gas phase. If a given Aib was found hydrogen-bonded with another one, the entire pair was extracted from the cluster. After capping the two sulfur atoms, DFT energy minimizations were carried out

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Figure 3. DFT minimum energy structure of Au38-Aib[1]2 showing two possible stable conformations. The case on the left-hand side corresponds to the standard motif, with the Au surface unaffected. The other case corresponds to the staple motif.

on each pair, maintaining the S-S distance fixed. On the resulting structure, NMR calculations were carried out in the gas phase. On the other hand, if an Aib was not forming an intramolecular hydrogen bond, then it was extracted, capped, and optimized, and the NMR calculation was done in the gas phase for that Aib alone. We also considered the effect of basis set superposition error (BSSE), which can be relevant in describing the interaction energy between donor-acceptor hydrogen bond pairs. We constructed a model containing Aib[3] bound via hydrogen bond at the H(1) position with alanine (see Figure 6 and accompanying discussion). The structure of the complex was optimized with and without BSSE. Using the counterpoise method,54,55 we found a maximum of 0.4 ppm difference in the chemical shift at the H(1) position, which is much smaller than the 3 ppm difference one would expect to find when a hydrogen bond is absent. Thus, considering this small difference and the substantial computational effort in minimizing on the counterpoisecorrected energy surface we did not include BSSE for the reported minimizations. 3. Results and Discussion Due to the recent discoveries on the staple-motif nature of the gold-thiol interactions, we were interested in determining if and to what extent the constraints imposed by interpeptide-ligand interactions affected in any way the nature of the Au-S-Au arrangement. Since Au38 in the Oh symmetry corresponds to one of the magic numbers (i.e., 13, 19, 55, etc.) and therefore exhibits high stability, we choose Au38 instead of Au25 to test whether the staple motif could emerge from such a compact structure. Thus, a “naked” Au38 cluster was prepared with Oh symmetry and optimized (without constraints) at the DFT level of theory described above, after which the structure retained its symmetry. Two Aib1’s were placed at various distances from each other so that an interpeptide hydrogen bond was feasible. After full geometry relaxation at the DFT level, we found two distinct cases affording stable conformations. In one case, the Au cluster was just slightly distorted from its initial high symmetry structure, but in the other case, a staple motif emerged naturally during the optimization (Figure 3). Remarkably, this last conformation is roughly 20 kcal/mol more stable than the previous one. Although this calculations took into account only two oligopeptides, it suggests that such a surface motif is also common to this kind of MPC’s having constraints imposed by hydrogen bonds.

Structural Arrangements of the Aib Monolayer. The Monte Carlo procedure described in the previous section followed by energy minimization at the MM level paves the way to constructing realistic models of the Aib[3]-protected gold cluster. In the Supporting Information section, we provide the coordinates of the Au25-Aib[3]18 structure. An immediate observation that can be made is that the monolayer is densely packed, covering the majority of the gold cluster surface (Figure 4, left). Furthermore, due to the small size of the cluster, the notion of a monolayer with peptides oriented toward the surface no longer applies (Figure 4, right). Instead, the peptides arrange by folding into each other, driven by both steric hindrance of the helical structure and by the potential of making intermolecular hydrogen bonds. The modeled structure also reveals that all 18 ligands conserved the 310 helical structure after energy minimization at the MM level. Although we guided the Monte Carlo simulation to maximize the number of intermolecular hydrogen bonds involving NH(1), the resulting structure after minimization contained only six interchain hydrogen bonds, all involving NH(1). Of these six, four are made with the oxygen O(4), one with the O(3), and one with the O(1). Thus, the general trend seems to be the formation of hydrogen bonds between the H(1) of one peptide and the O(4) of another peptide. This finding gives some insight into what was previously an unclear issue concerning the interaction between neighboring peptides.21 Notice that the interchain hydrogen bonds appear to compete with steric contacts involving the CH3 groups and the aliphatic hydrogen atoms. Figure 5 shows a typical hydrogen-bonded pair and the relevant interactions. 1 H NMR. Among the number of physicochemical studies carried out on these systems, 1H NMR spectrometry has been used as a tool to identify the relevant molecular interaction involving the NH groups of Aib.21 Comparison of the 1H NMR spectrum of Au25-Aib[3]18 with that of Aib[3] in solution clearly showed that all H(1)s very likely form interpeptide hydrogen bond while H(2) is much less likely to do so. On the other hand, H(3), H(4), and H(5) form intramolecular hydrogen bonds. Our calculations using small models agree with that observation. As a starting point, we determined whether the level of theory used was able to reproduce the experimental 1H NMR chemical shift of Aib[3] in CDCl3.21 In this context, it is worth noticing that the experimental 1H NMR chemical shifts measured in CDCl3, particularly those of NH(1) and NH(2), which are not involved in the 310-helix intramolecular hydrogen bonds, were essentially unaffected by addition of Me2SO-d6. Similarly, the

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Figure 4. Surface and ribbons representation of the proposed model for Au25-Aib[3]18.

Figure 5. Typical hydrogen-bonded Aib pair. Most of the donor-acceptor pairs involve H(1) with O(4). Double arrows distinguish competing steric interactions.

use of CD3OD in place of CDCl3 did not produce any significant 1 H NMR change. These outcomes show that these strong H-bond acceptor molecules (and, for CD3OD, also donor) are incapable of penetrating the peptide monolayer, or if they do, they are incapable of interacting significantly with the NH groups (no matter what the actual nature of the H-bonds involving such NH groups). In other words, the structure of the peptide monolayer is unaffected by quite severe environmental changes. Figure 6 (left panel) shows a comparison between the computed 1H NMR chemical shifts and the experimental data of Aib[3] in chloroform. To determine the effect of solvent, we optimized Aib[3] at the DFT level in vacuum and in the presence of a single CHCl3 molecule. This molecule was initially placed to loosely bound the oligopeptide near both NH(1) and NH(2) (see inset in Figure 6, left). The computed 1H NMR data agrees very well with experiment for both the vacuum case and the microsolvated case. In this last case, the agreement with experiment is particularly remarkable, suggesting that (1) the level of theory used is appropriate, and (2) the effect of CHCl3 (which also solvates, as CDCl3, the nanoparticles in the experimental work) appears to affect NH(1) by no more than 0.7 ppm. Since we will be looking at much larger changes in the NH(1) chemical shift as a characterizing feature, we use this observation (strengthened by the experimentally observed absence of significant solvent effects on the 1H NMR chemical shifts) as a justification to compute 1H NMR chemical shifts in vacuum for the larger system. The next step was to determine what the effect of gold on the computed 1H NMR chemical shifts is. For this purpose, we

constructed a model with Aib[3] attached to Au3 and optimized it a the DFT level. Comparison was then done with the experimental 1H NMR of the MPC. Comparing the computed chemical shifts of Au3-Aib[3] (Figure 6, right) with that of Aib[3] (Figure 6, left), shows that the effect of Au3 is negligible. Thus, the large downfield effect (∼3 ppm) at the NH(1) position seen in the MPC must be the result of other than the gold surface and chloroform. The cause of such a shift is the formation of a hydrogen bond at the NH(1) position. To further prove that the discrepancy in the chemical shift at the H(1) position is caused by the lack or presence of a hydrogen bond, we approached an alanine molecule to the peptide in such a manner as to allow for the formation of a hydrogen bond between the NH(1) and alanine’s CdO (see inset in Figure 6). We arbitrarily chose alanine just to mimic the effect of a neighboring chain in accepting a hydrogen bond. After DFT energy minimization, the chemical shift of the Au3-Aib[3]/ alanine complex was computed. Computed chemical shifts corresponding to this structure are reported in Figure 6 (right) by the solid squares. The similarity of the chemical-shift trend with that observed experimentally clearly shows the involvement of NH(1) in hydrogen bonds with neighboring adsorbates. Notice that the computed chemical shifts, which are referred to the computed shifts of TMS at the same level of theory, appear to be underestimated by as much as ∼1 ppm, which simply reflects the simplification of the models when compared with the actual Au25-Aib[3]18 experimental data. Despite these quantitative differences, agreement between the calculated values and experiment is remarkable. Qualitative agreement is also obtained after computing chemical shifts on the modeled structure of Au25-Aib[3]18 as described in the previous section. Chemical shifts of H(2) to H(5) remain rather constant from Aib to Aib and independently of whether an Aib is making a hydrogen bond with a neighbor (Figure 7). On the other hand, a large fluctuation is observed at the H(1) position, which is a result of having a mixture of oligopeptides with and without hydrogen bonds at this position. Our particular model contains 6 out of 18 possible hydrogen bonds. Thus, good agreement with experiment is obtained for all amide protons, except for H(1). Table 1 shows the computed and experimental chemical shifts as well as the O · · · H distances. These distances are typical of intramolecular H-bonds (for H(3)-H(5)) in Aib oligopeptides of similar lengths, as results from analysis of X-ray diffraction data56,57 and DFT calculations.58,59

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Figure 6. (left) 1H isotropic chemical shifts for the DFT structure of Aib[3] and the Aib[3]/CHCl3 complex. Experimental values of Aib[3] in solution are also reported.21 (right) Computed 1H isotropic chemical shifts for Au3-Aib3 and the Au3-Aib3/alanine complex. Alanine is added to mimic the effect of a hydrogen-bonded neighboring chain in the MPC. Experimental 1H NMR values for the MPC are also reported.21 All chemical shieldings are referred to TMS.

Figure 7. DFT calculation of 1H isotropic chemical shielding for the structure of Au25-Aib[3]18. Contributions from different Aib’s, whether they form hydrogen bond pairs or not, are explicitly separated. Chemical shieldings are referred with respect to TMS. Experimental values are also reported.21

The distances of Table 1 correlate very well with the trend in the chemical shift, showing that for the MPC, the upfield shift from H(1) to H(3) and from H(3) to H(5) (seen in both experiment and theory) is concomitant with a slight increase in the hydrogen bond distance, regardless whether it is intra- or interchain. Since the decrease in the O · · · H distance is expected to reflect an increase in the strength of H-bonds (see, for example, Kobko et al.60), it appears that the interchain H-bond of the peptide MPC is even stronger than intramolecular H-bonds. This is in line with studies of intermolecular H-bonds

between peptides, such as in β-sheets, evidencing a shorter O · · · H distance relative to R-helices.61 It is worth mentioning that the particular strength of the interchain H-bond was experimentally evidenced also by IR absorption analysis of the amide A region of the Aib-peptide MPCs,21 where a low frequency component at 3287 ( 5 cm-1 was attributed to the N-H groups H-bonded to neighbor peptides.62 When comparing the average results for H(1), it appears that our modeled MPC still lacks interchain hydrogen bonds involving NH(1), which would move the average chemical shift at the H(1) position downfield. In other words, the MC simulations did not drive the monolayer to a global minimum, which would presumably have 18 intermolecular hydrogen bonds or so according to the experimental results. Since we are able to separate the contributions from hydrogen-bonded Aib pairs, we expect that the chemical shifts of H(1) for such a hypothetical structure would be similar to that shown by the red solid squares in Figure 7, in good qualitative agreement with the experiment. Notice that even when the chemical shift at the H(1) position is partially averaged, only taking into account the hydrogenbonded cases (7.9 ( 0.3 ppm), the chemical shift is downfiled with respect to its value at H(3) (7.7 ( 0.1) by a small amount, in contrast with the experimental values and the calculations obtained for the smaller complex (Figure 6). A substantial part of this difference is the result of a small overestimation of the hydrogen-bond distances for the NH(1) · · · O pairs. This can be seen by considering the NH(1) · · · O and NH(3) · · · O distances for the complex Au3-Aib[3]-alanine, in which a difference of 0.04 Å correlates roughly with a 0.3 ppm difference. Since the

TABLE 1: Calculated and Experimental 1H Chemical Shifts (in ppm) for the Aib Amide Protons in the Complex Au3-Aib[3]-Alanine and Au25-Aib[3]18a H(1)

H(2)

calcd O · · · H distance (Å)

7.95 2.05 (inter)

6.07

calcd total average calcd single Aib’s calcd H-bonded Aib’s av O · · · H distance (Å) experiment

5.9 ( 1.5 4.9 ( 0.1 7.9 ( 0.3 2.06 ( 0.08 (inter) 8.8

6.1 ( 0.2 6.1 ( 0.2 6.0 ( 0.2

a

6.8

H(3)

H(4)

H(5)

Au3-Aib[3]-Alanine 7.64 7.01 2.09 (intra) 2.18 (intra)

6.85 2.21 (intra)

Au25-Aib[3]18 7.5 ( 0.2 7.4 ( 0.1 7.7 ( 0.2 2.12 ( 0.03 (intra) 7.6

6.8 ( 0.1 6.8 ( 0.1 6.8 ( 0.1 2.23 ( 0.01 (intra) 7.3

7.0 ( 0.1 6.9 ( 0.05 7.1 ( 0.1 2.19 ( 0.02 (intra) 7.4

In this latter case, contributions from different Aib’s, whether they form hydrogen bond pairs or not, are explicitly separated. Hydrogen bond distances are calculated for all protons except for H(2).

Modeling of a Monolayer-Protected Gold Cluster interchain hydrogen bond must compete with van der Waals interactions (see Figure 5), such discrepancy is not unexpected when using the current DFT functional, which lacks of a proper treatment of dispersion interactions. Nevertheless, the qualitative and semiquantitative agreement reflected in Figure 7 justifies the trade-off between accuracy and efficiency provided by this level of DFT. Finally, we notice that, concerning the qualitative features of the monolayer discussed previously, a larger number of intermolecular hydrogen bonds would still be consistent with the proposed folding arrangement instead of the commonly assumed perpendicular arrangement. 4. Summary In this work, we have constructed a series of atomistic models of Aib-monolayer-protected gold clusters. The recently discovered “staple motif” found in alkanethiolate monolayers also appears to be a common motif in Aib monolayers, despite the different ligand size and nature of the interligand interactions. Guided by a recent X-ray structure of thiolated Au25 and by NMR experiments on the Aib MPCs, we have inferred that the oligopetides are well packed, covering most of the cluster surface by a folding arrangement, in contrast to the commonly assumed notion consisting of an arrangement of peptides pointing toward the surface. Folding is driven by the interplay between the tendency to form interchain hydrogen bonds and the steric hindrance of the Aib helix. Our model also reveals that the peptide secondary structure, characterized by a 310-helix, is maintained upon formation of the monolayer. We have verified the structural correlation with the 1H NMR chemical shifts, which emerged from experiments. We pointed out that our model underestimated the number of intermolecular hydrogen bonds. On the other hand, fewer hydrogen bonds would support the assignment of Au25-Aib[3]14 as the most likely formula for the smallest of this type of MPCs, as we suggested in the introductory remarks. Indeed, fewer ligands would allow more directional freedom and consequently would maximize the number of interchain hydrogen bonds. We expect to perfect our model as a more definite determination of the number of ligands is obtained experimentally, an effort that is currently underway. Acknowledgment. J.A.G. acknowledges financial support from the Camille and Henry Dreyfus New Faculty Award, the NSF Career Award (CHE-0847340), and start-up package funds from the University of Connecticut. Supporting Information Available: Coordinates of the molecular model are provided. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) Haruta, M. Nature 2005, 437, 1098–1099. (2) Haruta, M. Catal. Today 1997, 36, 153–166. (3) Biswas, P. C.; Nodasaka, Y.; Enyo, M.; Haruta, M. J. Electroanal. Chem. 1995, 381, 167–177. (4) Valden, M.; Lai, X.; Goodman, D. W. Science 1998, 281, 1647– 1650. (5) Bond, G. C.; Thompson, D. T. Catal. ReV.sSci. Eng. 1999, 41, 319–388. (6) Bond, G. C.; Thompson, D. T. Gold Bull. 2000, 33, 41–51. (7) Corma, A.; Serna, P. Science 2006, 313, 332–334. (8) Phala, N. S.; van Steen, E. Gold Bull. 2007, 40, 150–153. (9) Zhang, Z. B.; Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2007, 129, 14148–14149. (10) Li, Z. G.; Capretto, D. A.; Rahaman, R. O.; He, C. J. Am. Chem. Soc. 2007, 129, 12058–12059.

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