Use of a Compact Tripodal Tris(bipyridine) Ligand to Stabilize a Single

Article Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

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Use of a Compact Tripodal Tris(bipyridine) Ligand to Stabilize a Single-Metal-Centered Chirality: Stereoselective Coordination of Iron(II) and Ruthenium(II) on a Semirigid Hexapeptide Macrocycle Yuka Kobayashi,† Masaru Hoshino,† Tomoshi Kameda,‡ Kazuya Kobayashi,§ Kenichi Akaji,§ Shinsuke Inuki,† Hiroaki Ohno,† and Shinya Oishi*,† †

Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koutou-ku, Tokyo 135-0064, Japan § Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan ‡

S Supporting Information *

ABSTRACT: Fe(II)-coordinating hexapeptides containing three 2,2′-bipyridine moieties as side chains were designed and synthesized. A cyclic hexapeptide having three [(2,2′bipyridin)-5-yl]-D-alanine (D-Bpa5) residues, in which D-Bpa5 and Gly are alternately arranged with 3-fold rotational symmetry, coordinated with Fe(II) to form a 1:1 octahedral Fe(II)−peptide complex with a single facial-Λ configuration of the metal-centered chirality. NMR spectroscopy and molecular dynamics simulations revealed that the Fe(II)−peptide complex has an apparent C3-symmetric conformations on the NMR time scale, while the peptide backbone is subject to dynamic conformational exchange between three asymmetric β/γ conformations and one C3-symmetric γ/γ/γ conformation. The semirigid cyclic hexapeptide preferentially arranged these conformations of the small octahedral Fe(II)−bipyridine complex, as well as the Ru(II) congener, to underpin the single configuration of the metal-centered chirality.

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ions.22 Three bipyridine ligands coordinate with Fe(II) with high affinity to form an octahedral [FeII(bpy)3] complex. This complex exists in a rapid equilibrium between two inseparable mirror-image Δ and Λ isomers of the propeller-like helical arrangements of the bipyridine ligands because of the configurational lability of Fe(II) (Figure 1). When enantiomerically pure chiral bipyridine derivatives are employed for the Fe(II)-coordination, the dynamic metal-centered chirality (Δ and Λ) may be controlled, leading to preferential formation of

INTRODUCTION A number of biological processes and organic transformations are driven by chiral metal complexes having stereogenic metal center(s).1−5 Metal-centered chirality also contributes to the construction of a variety of supramolecular architectures.3,6−8 For example, desferrioxamine B is an achiral trihydroxamic acid siderophore that forms an Fe(III)−siderophore complex, ferrioxamine B.9 The two mirror-image isomers (Λ and Δ forms) of ferrioxamine B are stereoselectively recognized by the iron-siderophore transport proteins, FhuD from Escherichia coli and FhuD2 from Staphylococcus aureus, respectively.10,11 Similarly, other complexes of siderophores adopt a variety of characteristic shapes with distinct configurations with metalcentered chirality, which are favorable for uptake into the microorganisms.12 Additionally, there have also been several reports on the applications of chiral metal complexes to medicinal chemistry research,13−15 including kinase inhibitors16,17 and TNF-α inhibitors.18,19 Investigations of the effective scaffolds to stabilize metal-centered chirality, as well as to enhance understanding of the underlying mechanism(s) that generate the metal-centered chirality, facilitate the design of molecular architectures for novel organometallic catalysts and medicinal applications.20,21 2,2′-Bipyridine (bpy) is one of the most well-known bidentate ligands that coordinates with a variety of metal © XXXX American Chemical Society

Figure 1. Dynamic equilibrium of the Fe(II)−tris(2,2′-bipyridine) complex between the Λ and Δ forms. Received: February 20, 2018

A

DOI: 10.1021/acs.inorgchem.8b00416 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry

in which a single Fe(II) ion was captured by a tripodal tris(bipyridine) ligand on a cyclic hexapeptide scaffold in a stereoselective manner. The solution structures of this chiral octahedral complex, as well as the congeners, were probed using NMR spectroscopy and circular dichroism (CD) analysis, which demonstrated the unusual formation of an apparent C3symmetric mononuclear complex. We also conducted molecular dynamics (MD) simulations to investigate the conformations of the scaffold that supports the metal-centered chirality. These structural analyses, accompanied by theoretical calculations, provide insight into the chiral cage-like architecture of Fe(II)−bipyridine complex. Investigation of the Ru(II)− bipyridine complex congener was also conducted.

the Fe(II) complex(es) with a thermodynamically favorable configuration.23−28 For example, Fe(II)-coordination with valabipy L1, in which L-valine moieties are attached at the bipyridine 5- and 5′-positions, afforded a 2:1 ratio of diastereomer complexes (Δ-[FeII(L-L1)3] and Λ-[FeII(L-L1)3]) initially, while only the thermodynamically preferred Δ form was present after overnight standing (Figure 2).24 C2-symmetric

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RESULTS AND DISCUSSION Design and Synthesis of Cyclic Hexapeptides with Three Bipyridine Moieties. Cyclic hexapeptides are a useful scaffold for host−guest chemistry32 and pharmaceutical applications.33 Previously, we have investigated the structure− function relationships of cyclic hexapeptide siderophores and derivative peptides for their Fe(III)- and Fe(II)-coordinating properties.34,35 The functional groups, linker lengths, and arrangements of the component amino acids considerably altered the coordination preferences and affinities for Fe(III) and Fe(II). For example, appropriate spatial arrangement of three 2-(1H-1,2,3-triazol-4-yl)pyridines on the cyclic hexapeptide allowed the Fe(II) coordination to provide a mononuclear Fe(II)−peptide complex with moderate affinity.35 On the basis of these findings, we hypothesized that three bipyridine ligands on a cyclic hexapeptide could capture a single Fe(II) ion and induce highly preferential metal-centered chirality. From this perspective, two cyclic hexapeptides (1 and 2) having [(2,2′bipyridin)-4-yl]alanine (Bpa4) and [(2,2′-bipyridin)-5-yl]alanine (Bpa5) were designed, in which Bpa (Bpa4 or Bpa5) and Gly are alternately arranged to give 3-fold rotational symmetry (Figure 3). The spatial dispositions of the three bipyridine ligands were varied depending on the substituted positions (bipyridine 4- and 5-positions) to investigate possible different coordination modes with Fe(II). The open-chain congeners (1L and 2L) were also designed as control peptides to verify the contribution of the macrocyclic structure to the Fe(II)-coordination in peptides 1 and 2, respectively. Initially, bipyridine-containing amino acids were prepared as the building blocks for Fmoc-based solid-phase peptide synthesis (Schemes S1 and S2). In the key process, alkylation of (diphenylmethylene)glycine ester with the appropriate (bipyridinyl)methyl bromide and subsequent separation using chiral acids were employed to provide protected Bpa (Fmoc-DBpa4-OH and Fmoc-D-Bpa5-OH) with D-configurations. Using the resulting Bpa amino acids, cyclic hexapeptides 1 and 2 and linear peptides 1L and 2L were synthesized by the standard protocol (for details, see the Supporting Information). All peptides were obtained with satisfactory purity (>95%), and had the correct m/z values for [M + H]+ by matrix assisted laser desorption/ionization-time-of-flight (MALDI-TOF) MS and electrospray ionization (ESI)-MS analyses. Fe(II) Coordination of Bipyridine-Containing Cyclic Hexapeptides. The formation of the complexes between Fe(II) and the Bpa-containing peptides was assessed by UV− vis spectral analysis (Figure 4). The [FeII(bpy)3] complex shows an unique absorption band in the 450−650 nm range, which is derived from the metal-to-ligand charge transfer (MLCT) transition.25,36 When each of the cyclic hexapeptides

Figure 2. Examples of bipyridine-containing chiral ligands.

pinene-bipyridine-type ligand L2 is an alternative chiral bipyridine ligand that forms two diastereomeric Fe(II) complexes with a slight preference for the Δ configuration.26 The resulting isomers Δ-[FeII((−)-L2)3] and Λ-[FeII((−)-L2)3] were discernible as two independent signals by NMR spectroscopy. The tripodal ligand L3 containing three pinenebipyridine moieties coordinates with a single Fe(II) ion to form a 1:1 complex with only the Λ configuration.25 The metal-centered chirality of bipyridine ligands can be also preferentially induced by peptide secondary structures. For example, Fe(II) coordination with three polyproline II-type helices with a bipyridine ligand at the N-terminus led to folding of a collagen triple helix.29 The associated bipyridine moieties predominantly formed the Δ isomer at the Fe(II) center because of the right-handed supercoils of the polyproline IItype helices. In addition, chiral metalloproteins have been designed in which one or more bipyridine motifs were incorporated into the peptide backbone. When bipyridine ligands were arranged via short peptide spacers, Ru(II), Co(II), and Ni(II) were able to be coordinated to form chiral octahedral complexes.30,31 Assembly of three C2-symmetric helical peptides with a single bipyridine moiety in the presence of Fe(II) and Co(II) also induced metal-centered chirality by remote control via the helical chirality.27 These approaches have provided unprecedented and unique molecular architectures with preferential chirality; however, relatively large peptide structures were required for stabilization of the metal-centered chirality. In this article, we describe the successful characterization of a small Fe(II)−bipyridine complex with metal-centered chirality, B


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Inorganic Chemistry

Figure 4. UV−vis absorption spectra of peptides and the Fe(II) complexes (0.05 mM) in CH3CN/H2O (1:1).

In contrast, the Fe(II) complexes of Bpa5-peptides 2 and 2L displayed a single peak by HPLC (Figure S1b). The m/z values for [M + Fe]2+ (Fe(II)−2: 451.4; Fe(II)−2L: 480.6) and [M + Fe]+ (Fe(II)−2: 902.37; Fe(II)−2L: 961.41) were detected by ESI-MS and MALDI-TOF MS analyses, respectively (Figure S2), suggesting that 1:1 complexation between Fe(II) and each peptide led to a single species for each of Fe(II)−2 and Fe(II)− 2L. As such, the three Bpa4 residues in hexapeptides 1 and 1L preferred intermolecular association with other peptides via Fe(II), while the Bpa5 residues in peptides 2 and 2L favored intramolecular assembly with a single Fe(II) ion to form a mononuclear complex. These results suggested that the position of the bipyridine attachment on the hexapeptide side chains had a large effect on the coordination geometry, thereby contributing to the mode of assembly between Fe(II) and the bipyridines on the hexapeptides. Investigation of the Possible Stereoisomers of Fe(II)− Peptide Complexes by NMR Spectroscopy. To determine the solution structure of the Fe(II)−peptide complexes, NMR analyses were carried out in CD3CN/D2O (1:1). An octahedral metal complex composed of three asymmetric bipyridine ligands can form four stereoisomers by the combination of two optical isomers (Δ and Λ) and two geometrical isomers [facial ( fac) and meridional (mer)].37−39 These possible interchangeable stereoisomers (Δ/Λ and fac/mer) of the complexes can be detected as separate signals in NMR analysis,23,26−28 according to the previous reports of the Fe(II) complexes of three chiral substituted-bipyridine ligands. The 1H NMR spectrum of a mixture of peptide 2 and Fe(II) suggested that the complex appeared to consist of a single species. The single sets of D-Bpa5 and Gly signals indicated that the Fe(II)−2 complex is present as a single C3-symmetric isomer with fac configuration (Figure 5b). Indeed, a mer geometrical configuration of Fe(II)−2 would be unlikely, because the short methylene tethers between the bipyridine

Figure 3. Structures of 2,2′-bipyridine-containing D-amino acid (DBpa) residues and the sequences of D-Bpa-containing hexapeptides.

(1 and 2) was mixed with an equimolar amount of Fe(II) ions (as FeSO4) in CH3CN/H2O (1:1), the mixtures exhibited UV−visible spectra characteristic of the [FeII(bpy)3] complex with a broad absorption band with maximum absorbance around 520−530 nm. The open-chain congeners (1L and 2L) also had spectra similar to those of cyclic peptides 1 and 2, respectively. These results indicated that three bipyridine moieties in the side chains of all four peptides coordinated with Fe(II) to form some sort of Fe(II)−peptide complex, although the stoichiometry remains unknown. Next, we investigated the component species in these Fe(II)−peptide complexes using several separation techniques. The HPLC chromatograms of Fe(II)−1 and Fe(II)−1L, which contain three Bpa4 residues, showed a large number of peaks (Figure S1a). In the ultrafiltration experiment of Fe(II)−1 and Fe(II)−1L mixtures using an ultrafilter (100 kDa cutoff), the UV−visible absorbance of the filtrates was significantly decreased (Figure S3). These results suggested that the Fe(II) complexes of Bpa4-peptides 1 and 1L consisted of multiple components, in which the molecular size was estimated to be more than 100 000 Da. These species are likely to be derived from the heterogeneous aggregation of Fe(II) and Bpa4 residues on the peptides into large supramolecular assemblies. C


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Inorganic Chemistry

Figure 5. 1H NMR spectra of peptide 2 (a) and its Fe(II) complex (b) in CD3CN/D2O (1:1).

Metal-Centered Chirality of the Fe(II)−Peptide Complexes. Next, we focused on the metal-centered chirality of the Fe(II)−peptide complexes. It is known that the two stereoisomers (Δ and Λ configurations) of Fe(II)−tris(bipyridine) ligand complexes can be distinguished using CD analysis. The CD spectrum of the Fe(II)−2 complex showed the characteristic sign of the exciton couplet of π−π* transitions (250−350 nm) and CD signals in the MLCT region (450−600 nm) (Figure 6), indicating that the complex predominantly existed

ligands and the peptide macrocyclic scaffold to favor the edge configuration 83.37,40 Compared with the 1H NMR spectrum of uncoordinated peptide 2 (Figure 5a), a remarkable upfield shift of the bipyridine 6-H and 6′-H signals on addition of Fe(II) was observed, which confirms the coordination between Fe(II) and the side-chain bipyridines.25 Upfield shifts of the bipyridine 4-H, 4′-H, and 5′-H, as well as downfield shifts of the bipyridine 3-H and 3′-H signals in the spectrum of 2 were also observed. 1H-diffusion ordered spectroscopy (1H-DOSY) spectra were recorded to estimate the molar ratio of the Fe(II)−2 complex (Figure S4). The diffusion coefficient value of the Fe(II)−2 complex was essentially identical with that of the uncoordinated cyclic peptide 2 [D[Fe(II)−2]: 10−9.55 (m2/ sec); D(2): 10−9.57 (m2/sec)], suggesting that the molecular size was not changed upon Fe(II)-coordination indicating a 1:1 Fe(II)−peptide 2 complex. The 1H NMR spectrum of a mixture of linear peptide 2L and Fe(II) was considerably different from that of Fe(II)−2 (Figure S5). The observed multiple signals indicated that the Fe(II)− 2L mixture included multiple components, which appeared inconsistent with the single peak observed in HPLC analysis. A comparison of the 1H-DOSY spectra of Fe(II)−2L and uncoordinated peptide 2L suggested that most of the peptides formed a 1:1 complex with Fe(II), while a small but significant amount of molecules were present as higher oligomeric forms of Fe(II)−2L complexes (Figure S6). These minor component(s) might reflect the lower affinity and/or lower specificity of peptide 2L, compared with cyclic peptide 2, in the formation of the 1:1 complex with Fe(II). The 1H NMR spectra of the DBpa4-containing peptides 1 and 1L were also measured (Figures S7 and S9). In the absence of Fe(II), the line shape and overall complexity of the spectra of 1 and 1L were very similar to those of the isomeric counterparts 2 and 2L, respectively. However, substantial line broadening was observed on addition of Fe(II), suggesting the formation of species with a large molecular weight. This is supported by the results of ultrafiltration experiments (Figure S3, >100 000 Da) and the 1 H-DOSY spectra of Fe(II)−1 and Fe(II)−1L (Figures S8 and S10).

Figure 6. CD spectra of D-Bpa5-containing peptide−Fe(II) complexes in H2O/CH3CN (1:1).

in the Λ configuration.23−28,41 Taken with the results of the NMR investigations, Fe(II)−2 should only form a complex with the fac-Λ configuration. An identical CD signal was observed in the mixture of linear peptide 2L and Fe(II), suggesting that peptide 2L also formed Fe(II)-complexes with an Λ configuration, although both fac and mer isomers might be present. The observed common metal-centered chirality of Fe(II)−2 and Fe(II)−2L was in contrast with that of the tripodal tris(triazolylpyridine) ligand, in which different Fe(II)centered chirality was observed depending on the scaffold peptide structure.35 The Fe(II) complexes of D-Bpa4containing peptides 1 and 1L showed significantly weaker CD intensity compared with the Fe(II)−2 complex (Figure S11a). While the D-Bpa4-containting peptides (1 and 1L) had favorable coordination ability with Fe(II), as shown by the similar UV−vis absorbance to that of Fe(II)−2 (Figure 4), the arrangements of the three bipyridine ligands is not conducive D


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Inorganic Chemistry

Figure 7. Conformation analysis of fac-Λ-Fe(II)−2 by MD simulations. PCA map (a); peptide backbones of representative structures in each cluster (b); and graphical image of conformation exchange (c).

Figure 8. Representative structures in clusters A1 and B and overlay of representative structures in A1−A3.

for the predominant formation of either Δ or Λ configurational stereoisomers. These results suggested that the Fe(II)-centered chirality of the Fe(II)−2 complex can be attributed to the coordinating ligand structure, the substitution position, and the peptide scaffold. To the best of our knowledge, the Fe(II)−2 complex is the smallest-sized octahedral Fe(II)−ligand complex with a single configuration at the chiral metal center. Conformational Exchange of the Cyclic Hexapeptide Scaffold with Maintenance of Metal-Centered Chirality. Taking into account the C3-symmetric structure of the Fe(II)− 2 complex with the fac-Λ configuration suggested by NMR and CD analysis, the conformation(s) in solution was further investigated using Amber 10:EHT in Molecular Operating

Environment (MOE). Since the 1H NMR spectrum of Fe(II)− 2 showed only single sets of signals for D-Bpa5 and Gly, C3 symmetrical conformation(s), in which both the sets of three DBpa5 and three Gly residues are chemically identical, were anticipated to be most stable. However, contrary to our expectations, some of calculated structures after the conformational search were not C3 symmetrical (Figure S12). We suspect that multiple asymmetric conformations of the Fe(II)− 2 complex might be chemically exchanging in fast regime on the NMR time scale.42 To explore the conformational exchange of the fac-ΛFe(II)−2 complex, a replica exchange molecular dynamics (REMD) simulation was performed (see the Experimental E


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Inorganic Chemistry

Figure 9. Dihedral angles of fac-Λ-Fe(II)−2 by MD simulation. Ramachandran plots (a); and χ1/χ2 plots (b).

Section for details of the procedure).43−45 Because the conformational space of the Fe(II)−2 complex is too large to intuitively describe its characteristics, principle component analysis (PCA) can be useful to classify the sampled conformations.46−48 PCA classifies conformations using as few principal component (PC) axes as possible, and the PC coordinates correspond to the conformations of the molecules. The contributions of PC-1, PC-2, and PC-3 were 34.7, 31.1, and 3.5%, respectively, which showed that PC-1 and PC-2 mainly contributed to the conformational space description. Thus, we described the free energy landscape by the twodimensional PCA. The free energy values (F) in the PC space are related to the population density of the conformations. All structures obtained from MD simulations were classified into four conformational clusters: A1, A2, A3, and B (Figure 7a). The superimposed structures showed that the conformations within the same clusters were similar to each other (Figure S13), suggesting the effectiveness of the two-dimensional PCA analysis. The most representative structures from each cluster are shown in Figures 8 and S14. In the structure belonging to cluster A1, a characteristic intramolecular hydrogen bond in the cyclic hexapeptide scaffold was observed between the Gly carbonyl oxygen (CO) and the D-Bpa5 amide hydrogen (N−H), which indicated the presence of a β-turn substructure with Gly and D-Bpa5 at the i and i+3 positions, respectively. The conformations in clusters A2 and A3 also contained a β-turn but between a different set of Gly and D-Bpa5 residues than in the structure belonging to A1. When these macrocyclic structures of A1−A3 were turned 120°, the structures were completely overlapped (Figure 8, right). The conformation in cluster B had a single C3-symmetric structure. The projections of the three Gly carbonyl groups (CO) in B are all directed away from the Fe(II) center. While no hydrogen bond to form a β-turn was observed, three γ-turn-like structures appeared in the cage space of the

conformation in cluster B, in which the carbonyl groups of DBpa5 (i) were located in close proximity to the amide hydrogens (N−H) of the next D-Bpa5 (i+2). One of these γturn-like structures was preserved in the conformations of A1− A3, in which one D-Bpa5 residue occupies both the β-turn i+3 position and the γ-turn i position. These conformational characteristics of clusters A1−A3 and B were also supported by Ramachandran plots, which were calculated from the component structures in highly populated regions in PCA. In the conformations belonging to cluster A1 as representative of clusters A1−A3, three separate clusters of φ and ψ dihedral angles for each Gly or D-Bpa5 residue were observed (Figure 9a). Among them, the φ/ψ plots around −37.3 ± 8.7°/−55.5 ± 8.3° for D-Bpa5(2) and −79.3 ± 11.2°/ 3.7 ± 13.2° for Gly(3) in A1 suggested that these sequential residues occupied the i+1 and i+2 positions of the mirror-image type I′ β-turn. Additionally, the φ/ψ dihedral angles of Gly(5) [φ: −68.7 ± 18.5°; ψ: 57.1 ± 25.3°] were close to the theoretical values for a mirror-image γ-turn i+1 position. The φ/ψ charts of conformations in A2 and A3 were similar in shape to A1, but the arrangements of the component amino acids were shifted, indicating that the conformations in A1−A3 were well-overlapped, but independent, conformations. In contrast, the φ and ψ plots of the three Gly residues of structures in cluster B overlapped to form one cluster in the region of −68.9 ± 12.2°/37.1 ± 23.8°, indicating that the three Gly residues are at the i+1 positions of three mirror-image γ-turn-like structures. The φ and ψ plots of the three D-Bpa5 residues in the conformations in cluster B also converged to one cluster in the region of 119.1 ± 26.5°/−83.2 ± 18.6°. These uniform dihedral angles for the component amino acids support the presence of C3-symmetrical structures in B. Interestingly, the χ1 and χ2 plots for D-Bpa5 were well overlapped in all the conformations in A1−A3 and B (Figure 9b), indicating that restricted χ1 and χ2 dihedral angles contribute to stabilization of Fe(II)-centered F


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Inorganic Chemistry chirality with the Λ configuration, even over the relatively flexible cyclic peptide conformations. This apparently paradoxical induction of metal-centered chirality with a single configuration using a flexible scaffold is similar to that observed in the Fe(III)-coordination of enterobactin, in which the Fe(III)-centered chirality is dictated by the relatively flexible trilactone scaffold.49 These results suggest that the structure of Fe(II)−2 exists in rapid equilibrium between three asymmetric β/γ conformations in A1−A3 via one apparently C3-symmetric γ/γ/γ conformations in B (Figure 7b,c and Table S1). In the interchange process, the interaction of the D-Bpa5 N−H group with the Gly CO group in the β-turn of conformations in A1−A3 was switched to an interaction of the D-Bpa5 N−H group with the 50−52 D-Bpa5 CO group in a γ-turn of the conformations in B. We speculated that the observation of only one set of Gly and 1 D-Bpa5 signals in the H NMR spectrum of the Fe(II)−2 complex is derived from the averaged signals through conformational exchange between these conformations. This theory is supported by several NMR observations. In the 1H NMR spectrum of Fe(II)−2, several protons (D-Bpa5 α-H, DBpa5 β-H, bipyridine 6-H, and bipyridine 6′-H) appeared as broad signals at room temperature, whereas they became much sharper at a high temperature (Figure S15). Similarly, in the 13 C NMR spectra, all of peptide backbone (α-C, CO) and several side-chain (D-Bpa5 β-C and bipyridine 6-C) signals were detected only at a high temperature (Figure S16). We assumed that these temperature dependencies of the line shape in the Fe(II)−2 complex were caused by chemical exchange line broadening, in which the environment around the nuclei (and thus the chemical shift values) varied at the intermediate rate of the NMR chemical shift time scale (micro- to millisecond). Furthermore, in the relaxation dispersion experiments, chemical exchange was observed for the signals from the 53 D-Bpa5 β-H and bipyridine 6-H (Figure S17). On the basis of these NMR analyses, chemical exchange occurred over several microseconds or longer, which is far beyond the time scale accessible by conventional MD simulations. In fact, when we performed 1 μs standard MD simulations, conformational exchange to other clusters in the PC space was not observed during the simulation (data not shown). Chiral Ru(II) Complex with a Bpa5-Containing Cyclic Hexapeptide. Three 2,2′-bipyridines coordinate with Ru(II) to form a [RuII(bpy)3] complex. This type of ruthenium(II) complexes can be used in luminophore materials,54 as well as visible-light-mediated photoredox catalysis.55 Because the Ru(II) complex is substitutionally inert, two mirror-image isomers of Δ-[RuII(bpy) 3] and Λ-[RuII(bpy) 3] can be isolated.56 This is in contrast to the interconvertible Δ[FeII(bpy)3] and Λ-[FeII(bpy)3] complexes. We next investigated the chemical properties of a chiral Ru(II) complex with cyclic peptide 2. The reaction of peptide 2 with RuCl2(dmso)4 in MeOH/ H2O (1:1) at 80 °C provided the expected 1:1 complex of orange-colored Ru(II)−2 as a major product (Figure S18), which was characterized by ESI-MS (m/z: 474.4 for [M + Ru]2+) and MALDI-TOF MS (m/z: 947.40 for [M + Ru − H]+) analyses (Figure S19). In the UV−vis spectrum, an absorption maxima around 450 nm was observed, which is characteristic of MLCT bands of the [RuII(bpy)3] complex (Figure 10a).57 Additionally, the fluorescence spectrum of Ru(II)−2 had an identical emission maximum around 625 nm to that of [RuII(bpy)3] (Figure 10b).57 These spectroscopic

Figure 10. Spectral data of Ru(II)−2 complex. UV−vis absorption spectrum (a); fluorescence spectrum (b); and CD spectrum (c).

data support the formation of an octahedral Ru(II)−2 complex. The metal-centered chirality in Ru(II)−2 was determined to be the Λ configuration based on the characteristic intense CD exciton couplet around 290 nm in the CD spectrum (Figure 10c).58,59 As the Λ configuration is common to both the Fe(II)−2 and Ru(II)−2 complexes, this induction of metalcentered chirality regardless of the metal ion species can be attributed to the bipyridine arrangements on the macrocyclic scaffold of peptide 2. Although irradiation of Λ-Ru(II)−(bpy)3 with light-emitting diode (LED) light led to racemization of the complex,60 the metal-centered chirality of the Ru(II)−2 complex was stable even after 6.5 W LED light irradiation for 24 h in CH3CN/H2O (1:1) at room temperature (Figure S20).61 The 1H NMR and 1H-DOSY spectra of the Ru(II)−2 complex were recorded to estimate the impact of the substitution of Fe(II) with Ru(II) on the structure of the complexes (Figures S21 and S22). Overall, the spectra of Ru(II)−2 were essentially similar to those of Fe(II)−2, including the characteristic downfield shift of the bipyridine 6-H and 6′-H signals.25 Interestingly, broad D-Bpa5 α-H and DBpa5 β-H signals were found in both the Fe(II)−2 and Ru(II)−2 complexes. These results indicated that the Fe(II)−2 and Ru(II)−2 complexes exhibit similar overall conformations. Considering that the metal-centered chirality of inert Ru(II)− bipyridine complexes cannot be converted to the other G


Article

Inorganic Chemistry

the force field. The exterior dielectric constant was set to the dielectric constant of CH3CN/H2O (1:1, ε = 60).63 To simulate the Fe(II) coordination, Fe(II) and each N atom of the bipyridines were restricted to be arranged within 1.8−2.3 Å. Replica Exchange MD Simulation. The peptide was solvated with 589 H2O molecules, 210 CH3CN molecules, 1 Fe(II) ion, and 2 chloride ions, which corresponded to the conditions when the peptide was dissolved in CH3CN/H2O (1:1). Peptide 2 was described by the AMBERff14SB force field,64 CH3CN molecules were described by the general amber force field (GAFF),65 and water molecules were described by the TIP3P model.66 The partial charges of D-Bpa5 and CH3CN molecules were assigned as restrained electrostatic potential (RESP) charges (Figure S23).67 The chloride ion parameters were from the Joung and Cheatham model,68,69 and Li/Merz ion parameters were used for the Fe(II) ion.70 The bonded interaction between the Fe(II) ion and the side chain of D-Bpa5 was modeled by the parameters for the heme molecule.71 We simulated the system with dodecahedron periodic boundary conditions and used the particlemesh Ewald method.72 The bond lengths that include hydrogen atoms in the peptide were constrained by the p-LINC73 and SETTLE was used for the bond lengths of H2O molecules.74 The cutoff distance for nonbonded interactions were 10 Å. To enhance sampling, we used the Replica Exchange MD method in the NPT ensemble.43−45 We used 32 replicas; the temperatures of replicas were distributed in the range of T = 300−550 K (T = 300.0, 305.1, 310.4, 315.7, 321.2, 326.9, 332.6, 338.6, 344.4, 350.5, 356.9, 363.2, 369.9, 376.8, 383.7, 390.8, 398.0, 406.3, 414.5, 423.2, 432.1, 441.4, 450.9, 460.7, 471.0, 481.5, 492.2, 502.9, 514.6, 525.9, 538.2, and 550.0 K). The pressure of each replica was 1.0 atm. Exchange attempts were made after every 1 ps. The acceptance ratios were between 29 and 36%, which showed the conformational space of the system was well sampled. The replica temperatures were maintained by the Langevin dynamics, and the pressures were maintained by the Parrinello−Rahman barostat.75 As an initial structure for simulation, the structure of the 1:1 complex of Fe(II)−2 fixed to the fac-Λ form was used (Figure 3). The initial state was prepared by the steepest descent minimization, followed by a 200 ps MD simulation at 300 K/1 atm with the constraint for the solute heavy atoms and continuing 200 ps MD simulation without constraint. The REMD simulation time was 500 ns for each replica for all simulations. The total simulation time was 32 000 ns. The simulation was carried out by GROMACS 2016 simulator.76,77 PCA was employed to analyze the free energy landscape.46−48 First, we selected 5000 configurations of the peptide and the Fe(II) ion from a snapshot of the 500 ns of the simulation from the trajectory at 300 K. These conformations were superimposed onto a reference conformation. Subsequently, the variance−covariance matrix of the ensemble was diagonalized to obtain the eigenvectors (PC axes) and eigenvalues (λi) (which are the standard deviations of the conformational distribution along the ith PC axis). Here, λi/Σiλi was regarded as the relative contribution of the distribution along the ith PC. Selection of the Representative Structures. First, the coordinates of every atom, including hydrogen and side-chain atoms, were averaged over all structures within the same group classified by the PCA analysis (800, 1018, 978, and 259 structures, for A1, A2, A3, and B, respectively) to calculate the four “averaged” coordinates. Next, the root-mean-square deviations from these “averaged” coordinates were calculated for each structure, and the coordinate with the smallest deviation was selected as the most representative structure for that group.

configuration, these peak broadenings of D-Bpa5 residues in the 1 H NMR spectra of Fe(II)−2 and Ru(II)−2 are likely to be derived from conformational exchange, especially in the relatively flexible peptide backbone, in the NMR time scale.

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CONCLUSIONS We have designed and synthesized an optically pure Fe(II)coordinated, cage-shaped complex of tripodal tris(bipyridine) ligands. The alternating arrangement of D-Bpa5 and Gly in a cyclic hexapeptide scaffold predominantly formed a 1:1 Fe(II)− peptide 2 complex with only a single configuration at the chiral metal center. In contrast, D-Bpa4-containing congener 1 preferred a heterogeneous assembly via intermolecular Fe(II)−bipyridine coordinations, suggesting that the three bipyridine moieties in 2 complexed with a single Fe(II) ion because of the suitable spatial dispositions of the cyclic hexapeptide scaffold, as well as the bipyridine substitution position. Spectroscopic analyses revealed that the Fe(II)− peptide 2 complex was a single isomer of a C3-symmetric structure with the fac-Λ configuration. MD simulations of the Fe(II)−2 complex suggested that the cyclic peptide backbone undergoes dynamic conformational changes between three βturn conformations and one C3-symmetric conformation. Peptide 2 also coordinated with an inert Ru(II) ion to form a photoluminescent complex with a C3-symmetric fac-Λ configuration, which may be useful as a chiral photocatalyst. In total, this semirigid cyclic hexapeptide is a suitable small scaffold for the facile induction of metal-centered chirality with a single configuration, even with the labile Fe(II) ion.

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EXPERIMENTAL SECTION

UV−Vis Spectra, CD Spectra, and LC-MS Analysis. Peptide (0.05 mM) [or 2,2′-bipyridine (0.15 mM)] and FeSO4 (0.05 mM) were dissolved in CH3CN/H2O (1:1). Ru(II)−peptide 2 (0.05 mM) was also dissolved in CH3CN/H2O (1:1). UV−vis spectra were recorded on a Shimadzu UV-2450 UV−vis spectrophotometer at room temperature. CD spectra were recorded on a JASCO J-720 circular dichroism spectrometer at 20 °C. After recording the spectra, the samples were analyzed with a Waters 2795 Separations Module. Fluorescence Spectra. Each Ru(II) complex (5 μM) was dissolved in H2O. The excitation light was set to 450 nm and the emission spectra were recorded on a Shimadzu RF-5300PC spectrofluorophotometer at 25 °C. The quantum yield of Ru(II)−2 was calculated to be Φ = 0.030 using Ru(II)−(bpy)3 as a standard.62 Ultrafiltration Experiment. A mixture of Fe(II) and peptide [0.05 mM each in CH3CN/H2O (1:1)] was diluted five times with H2O. The solution was centrifuged through a 100 kDa ultrafilter (Microcon centrifugal filter unit YM-100) for 3 min at 7000 × g. The UV−vis spectra of the solutions before and after ultrafiltration were measured. 1 H-DOSY Spectra. 1H-DOSY experiments were performed on a Bruker Avance I 600 spectrometer using a standard stimulated echo pulse sequence with bipolar gradient pulses at 25 °C. The pseudo-2D spectra were analyzed by a DOSY analysis module integrated in topspin 2.1 software. Relaxation Dispersion Experiments. Relaxation dispersion experiments were performed using a standard Carr−Purcell− Meiboom−Gill (CPMG) spin−echo sequence with presaturation for water-suppression. The spectra were recorded on a Bruker Avance I 600 spectrometer at 25 °C. The total relaxation period during CPMG pulsing was implemented in a constant time manner with T = 80 ms. Peak intensities were compared between the spectra recorded with a different set of τcp intervals, the time between successive 180° pulses of 80, 180, 480, and 980 μs. Conformational Search by MOE. Amber 10:EHT in MOE (Chemical Computing Group Inc., Montreal, Canada) was selected as

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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.inorgchem.8b00416. Experimental procedures, characterization data, and NMR spectra of newly synthesized compounds; 1H H


Article

Inorganic Chemistry NMR, 13C NMR, and 1H-DOSY NMR spectra, mass spectra, UV−vis absorption, CD spectra, and HPLC chromatograms of peptides, peptide−Fe(II) complexes, and peptide−Ru(II) complexes; structures obtained by simulation experiments; charges and atom types for MD simulation (PDF)

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Accession Codes

CCDC 1824844−1824845 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +81-75-753-4561. Fax: +81-75-753-4570. E-mail: [email protected]. ORCID

Tomoshi Kameda: 0000-0001-9508-5366 Hiroaki Ohno: 0000-0002-3246-4809 Shinya Oishi: 0000-0002-2833-2539 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by Grants-in-Aid for Scientific Research from JSPS, Japan (24659004 and 26-7879); the Platform Project for Supporting Drug Discovery and Life Science Research funded by Japan Agency for Medical Research and Development (AMED), Japan; and Takeda Science Foundation. Y.K. is grateful for JSPS Research Fellowships for Young Scientists. In this research work, we used the supercomputer of ACCMS, Kyoto University. We are grateful to Dr. Yoshiaki Yano and Dr. Toru Nakatsu (Kyoto University) for their generous supports of this research.

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REFERENCES

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Use of a Compact Tripodal Tris(bipyridine) Ligand to Stabilize a Single

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