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Acta Crystallogr C. Mar 15, 2010; 66(Pt 3): o119–o123.
Published online Feb 3, 2010. doi:  10.1107/S0108270110003094
PMCID: PMC2855584
Two penta­dehydro­peptides with different configurations of the ΔPhe residues
Maciej Makowski,a Marek Lisowski,b* Anna Maciąg,b Maciej Wiktor,b Anna Szlachcic,b and Tadeusz Lisb
aInstitute of Chemistry, University of Opole, 48 Oleska Street, 45-052 Opole, Poland
bFaculty of Chemistry, University of Wrocław, 14 Joliot-Curie Street, 50-383 Wrocław, Poland
Correspondence e-mail: mbl/at/wchuwr.pl
Received December 16, 2009; Accepted January 25, 2010.
Comparison of the crystal structures of two penta­dehydro­peptides containing ΔPhe residues, namely (Z,Z)-N-(tert-butoxy­carbonyl)­glycyl-α,β-phenyl­alanyl­glycyl-α,β-phenyl­alanyl­glycine (or Boc0–Gly1–ΔZPhe2–Gly3–ΔZPhe4–Gly5–OH) methanol solvate, C29H33N5O8·CH4O, (I), and (E,E)-N-(tert-butoxy­carbonyl)­glycyl-α,β-phenyl­alanyl­glycyl-α,β-phenyl­alanyl­glycine (or Boc0–Gly1–ΔEPhe2–Gly3–ΔEPhe4–Gly5–OH), C29H33N5O8, (II), indicates that the ΔZPhe residue is a more effective inducer of folded structures than the ΔEPhe residue. The values of the torsion angles ϕ and ψ show the presence of two type-III′ β-turns at the ΔZPhe residues and one type-II β-turn at the ΔEPhe residue. All amino acids are linked trans to each other in both peptides. β-Turns present in the peptides are stabilized by intra­molecular 4→1 hydrogen bonds. Mol­ecules in both structures form two-dimensional hydrogen-bond networks parallel to the (100) plane.
α,β-Dehydro­amino acid residues contain a double bond between the Cα and Cβ atoms. Due to this structural feature they have the capacity to induce ordered structures in peptides. These structures depend on the type, content and mutual location of Δ-amino acid residues in the peptide sequence. The conformation-stabilizing effect is very pro­nounced in the case of the ΔPhe residue. The presence of one or more ΔPhe residues results in the β-turn conformation in short peptides (Główka et al., 1987 [triangle]; Główka, 1988 [triangle]; Aubry et al., 1984 [triangle]) and the 310 helical arrangement in longer peptides (Rajashankar et al., 1992 [triangle]; Padmanabhan & Singh, 1993 [triangle]; Rajashankar, Ramakumar, Jain & Chauhan, 1995 [triangle]; Rajashankar, Ramakumar, Mal et al., 1995 [triangle]; Jain et al., 1997 [triangle]). The preferred values for the torsion angles ϕ and ψ fall predominantly into the regions of 80 and 0, 60 and 140, and 60 and 30°, respectively, and their enantio­meric values (Singh & Kaur, 1996 [triangle]).
This paper follows previous research on the conformational preferences of ΔPhe residues (Makowski et al., 2006 [triangle], and references therein). We present the structures of two penta­dehydro­peptides with two ΔPhe residues, viz. Boc0–Gly1–ΔZPhe2–Gly3–ΔZPhe4–Gly5–OH, (I), and Boc0–Gly1–ΔEPhe2–Gly3–ΔEPhe4–Gly5–OH, (II). The peptides differ only in the configuration of the ΔPhe residues. Both peptides crystallize in the same space group, P21/c, with one mol­ecule in the asymmetric unit. Additionally, peptide (I) cocrystallizes with one mol­ecule of methanol in the asymmetric unit. A comparison of the crystal structures of both peptides will allow evaluation of the impact of individual ΔPhe isomers on the conformational preferences of the peptides. The atom labelling is the same in both structures.
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Object name is c-66-0o119-scheme1.jpg Object name is c-66-0o119-scheme1.jpg
All amino acids, in both structures, are linked trans to each other. The deviations from ideal ω = 180° do not exceed 10°. Blocking groups adopt transoidal conformations, as indicated by the values of the ω0 (N1—C5—O1—C1) and ϕ0 (C6—N1—C5—O1) torsion angles (Tables 1 [triangle] and 3 [triangle]). The Cα—Cβ distances (C8=C9 and C19=C20) are classical double-bond lengths (Tables 1 [triangle] and 3 [triangle]) and correspond well with the results of other X-ray crystallographic studies of dehydro­peptides (Główka et al., 1987 [triangle]; Ejsmont et al., 2001 [triangle]; Makowski et al. 2005 [triangle]).
Table 1
Table 1
Selected geometric parameters (Å, °) for (I)
Table 3
Table 3
Selected geometric parameters (Å, °) for (II)
Because of the unsaturated character of the Cα—Cβ bond, the side chains of the ΔPhe residues are much closer to the main-chain atoms compared with their saturated counterparts. This feature results in some geometric distortions characteristic of dehydro­peptide structures (Główka et al., 1987 [triangle]). Systematic shortening of the N—Cα (N2—C8 and N4—C19), Cα—Cβ (C8—C16 and C19—C27) and Cβ—Cγ (C9—C10 and C20—C21) single bonds (Tables 1 [triangle] and 3 [triangle]) is observed, which may be caused by extended delocalization of the π electron system. The values of the N2—C8—C16 [118.8 (2) and 114.67 (18)° for (I) and (II), respectively] and N4—C19—C27 [117.1 (2) and 114.04 (18)° for (I) and (II), respectively] bond angles are smaller than the regular trigonal value of 120°, which is clearly understandable owing to the steric inter­actions between the main chain and the side chains of ΔPhe. It is inter­esting that these effects influence analogous angles in both peptides to the same extent, regardless of the location of the aromatic rings.
Another characteristic consequence of the short distance between the aromatic rings and the peptide chain is a considerable opening of the valence angles Cα—Cβ—Cγ to relax the steric strain (Główka, 1988 [triangle]). This trend explains the increased values of the Cα—Cβ—Cγ bond angles for both structures. These angles are the same in both ΔPhe residues in each structure and agree to within one standard deviation between (I) and (II). In the case of (I), these angles for ΔZPhe2 and ΔZPhe4 are C8—C9—C10 = 131.4 (3)° and C19—C20—C21 = 131.4 (3)°, respectively, and for ΔEPhe2 and ΔEPhe4 of (II) they are C8—C9—C10 = 129.9 (2)° and C19—C20—C21 = 129.9 (2)°, respectively. The torsion angles χ2 = −176.9 (2)° and χ4 = −176.0 (2)° between N—Cα and the aromatic system, and χ2,1 = −155.1 (3)°, χ2,2 = 25.4 (4)°, χ4,1 = 20.7 (4)° and χ4,2 = −159.7 (2)°, indicate that in the case of (II) the side chains of both ΔPhe residues are almost planar, while for (I) the torsion angles χ4 = 0.2 (5)°, χ4,1 = −19.8 (5)° and χ4,2 = 162.9 (3)° show that only the side chain of ΔPhe4 is planar. The ΔPhe2 residue side chain adopts a trans-(−)gauche conformation, with torsion angles χ2,1 = −152.6 (3)° and χ2,2 = 30.8 (5)°.
The presence of two ΔZPhe residues in (I) induces the occurrence of two overlapping β-turns. The first is formed by the ΔZPhe2 and Gly3 residues, with torsion angles ϕ2 = 50.4 (4)° and ψ2 = 20.0 (4)°, and ϕ3 = 54.7 (4)° and ψ3 = 26.7 (4)°, respectively. The second turn includes the Gly3 and ΔZPhe4 residues, with torsion angles ϕ3 = 50.4 (4)° and ψ3 = 20.0 (4)°, and ϕ4 = 68.7 (3)° and ψ4 = 17.4 (4)°, respectively. The torsion angles indicate that these β-turns are of type III′ (Lewis et al., 1973 [triangle]). They are stabilized by 4→1 hydrogen bonds between the NH group of ΔZPhe4 and the CO group of Gly1, and between the NH group of Gly5 and the CO group of ΔZPhe2 (Table 2 [triangle]). The two β-turns of type III′ in (I) are the same as in the previously reported crystal structure of the Boc0–Gly1–ΔZPhe2–Gly3–ΔZPhe4–Gly5–OMe penta­peptide, which differs from (I) only in the methanol­ate group at the C terminus (Makowski et al., 2007 [triangle]). The mol­ecular structure of peptide (I) is presented in Fig. 1 [triangle](a) and its packing diagram is shown in Fig. 2 [triangle].
Table 2
Table 2
Hydrogen-bond geometry (Å, °) for (I)
Figure 1
Figure 1
The mol­ecular structures of peptides (a) (I) and (b) (II), showing the atom-numbering schemes. Displacement ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary radii. Hydrogen bonds are shown (more ...)
Figure 2
Figure 2
A packing diagram for peptide (I). Hydrogen bonds are represented by dashed lines. Symmetry codes are as given in Table 2 [triangle].
The situation is somewhat different in the case of (II). There is only one β-turn at the ΔEPhe2 and Gly3 residues, stabilized by a 4→1 hydrogen bond between the NH group of ΔEPhe4 and the CO group of Gly1 (Table 4 [triangle]). This β-turn is additionally stabilized by a C—H(...)π inter­action. The ϕ and ψ angles of these residues are 33.2 (3) and −119.6 (2)°, and −83.2 (3) and −5.3 (3)°, respectively. These values correspond well with a type-II β-turn (Lewis et al., 1973 [triangle]). Deviations from the ideal torsion angles for this β-turn (−60 and 120°, and 80 and 0°) are not larger than 26°, compared with a maximum acceptable deviation of 40° (Lewis et al., 1973 [triangle]). In addition, the C-terminal amino acid residues adopt a conformation similar to a type-IV β-turn. The whole structure is stabilized by inter- and intra­molecular hydrogen bonds of various types, namely O—H(...)O, N—H(...)O and C—H(...)π (Table 4 [triangle]). However, the conformational constraints are not sufficient for a second β-turn to be formed. The mol­ecular structure of peptide (II) is presented in Fig. 1 [triangle](b).
Table 4
Table 4
Hydrogen-bond geometry (Å, °) for (II)
A comparison of (I) and (II) reveals that a ΔZPhe residue is a more effective inducer of folded structures than a ΔEPhe residue. The insertion of two ΔZPhe residues in (I) gives rise to the formation of two β-turns and the structure is stabilized by two intra­molecular 4→1 hydrogen bonds. In the case of (II), there is only one β-turn stabilized by a hydrogen bond and the resulting conformation is more distorted, and this is reflected in the greater deviations from ideal dihedral angles for the β-turns. The previously reported crystal structure of a closely related peptide, viz. Boc–Gly–ΔZPhe–Gly–ΔEPhe–Gly–OMe (Makowski et al., 2006 [triangle]), shows that in the case of a ΔEPhe4 residue the formation of a second β-turn is hindered and deviations from ideal values for the torsion angles ϕ and ψ are increased. A type-II β-turn for the ΔZPhe2 and Gly3 residues, and a type-IV β-turn for Gly3 and ΔEPhe4, was observed. The ΔEPhe4 residue in (II) does not induce a β-turn, as in the case of Boc0–Gly1–ΔZPhe2–Gly3–ΔEPhe4–Gly5–OMe. A β-turn at the ΔEPhe4 residue has been observed for Boc0–Gly1–ΔZPhe2–Gly3–ΔEPhe4–Phe5-p-NA·EtOH (Makowski et al., 2005 [triangle]), due to the presence of the additional H-atom donor, p-nitro­aniline (p-NA), which forms a hydrogen bond with the CO group of Gly3.
The atypical location of the H atom of the C-terminal carboxyl group, H8, merits further discussion. In (II) it is directed to the opposite side compared with the analogous atom in (I). The O8 atoms in both mol­ecules take part in hydrogen bonds. In the case of (II), atom H8 participates in the inter­molecular N2—H2(...)O8(1 − x, y − An external file that holds a picture, illustration, etc.
Object name is c-66-0o119-efi1.jpg, An external file that holds a picture, illustration, etc.
Object name is c-66-0o119-efi1.jpg − z) hydrogen bond (Table 4 [triangle]). The formation of this bond requires a relocation of the H atom. What is more, amide atom H2 of another mol­ecule of (II) in that hydrogen bond corresponds to the position of the carboxyl H atom in (I). Therefore, we suspect some competition between the O8—H8 covalent bond and the N2—H2(...)O8(1 − x, y − An external file that holds a picture, illustration, etc.
Object name is c-66-0o119-efi1.jpg, An external file that holds a picture, illustration, etc.
Object name is c-66-0o119-efi1.jpg − z) hydrogen bond which results in moving atom H8 to the alternative position.
Further information can be derived from a detailed analysis of the packing diagrams of both mol­ecules. The crystal structure stabilizing effect compensates for the energy loss resulting from the unusual position of the H atom in (II). Additionally, the position of atom H8 in (II) is stabilized by the O8—H8(...)O2(x, An external file that holds a picture, illustration, etc.
Object name is c-66-0o119-efi1.jpg − y, An external file that holds a picture, illustration, etc.
Object name is c-66-0o119-efi1.jpg + z) hydrogen bond. This unusual position of the hydroxy H atom is rarely encountered. As reported recently, it occurs when additional stabilization is provided by other inter­actions (Videnova-Adrabinska et al., 2007 [triangle]). In the discussed case, the H atom switches its orientation to approach the lone pair of another hydroxy O atom.
Both title compounds were obtained from their methyl esters. The syntheses of the methyl esters of (I) and (II) have been described by Latajka et al. (2008 [triangle]). For the preparation of (I), Boc–Gly–ΔZPhe–Gly–ΔZPhe–Gly–OMe (0.059 g, 0.1 mmol) was dissolved in MeOH (1.5 ml) and then H2O (0.1 ml) and 1 M NaOH (0.3 ml, 0.3 mmol) were added. The reaction was carried out for 30 min at room temperature. The reaction mixture was then acidified to pH 3 and brine (ca 10 ml) was added. The mixture was extracted with EtOAc (5 × 3 ml). The acetate extracts were washed with 0.5 M HCl (2 × 2 ml) and brine (2 × 2 ml) and dried over anhydrous MgSO4. After removal of EtOAc in vacuo, Boc–Gly–ΔZPhe–Gly–ΔZPhe–Gly–OH was crystallized from EtOAc with addition of hexane to the first turbidity [yield 0.056 g, 97%; m.p. 474–477 K (decomposition)]. Elemental analysis calculated for C29H33N5O8: C 60.09, H 5.74, N 12.08%; found: C 59.89, H 5.98, N 12.12%. Boc–Gly–ΔEPhe–Gly–ΔEPhe–Gly–OH, (II), was obtained from its methyl ester in the same way [yield 0.054 g, 94%; m.p. 474–477 K (decomposition)]. Elemental analysis calculated for C29H33N5O8: C 60.09, H 5.74, N 12.08%; found: C 60.33, H 5.87, N 11.89%. Finally, peptide (II) were recrystallized from a solution in a mixture of MeOH and EtOAc.
Compound (I)
Crystal data
  • C29H33N5O8·CH4O
  • M r = 611.65
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is c-66-0o119-efi7.jpg
  • a = 14.075 (4) Å
  • b = 16.577 (5) Å
  • c = 14.041 (4) Å
  • β = 112.34 (3)°
  • V = 3030.2 (17) Å3
  • Z = 4
  • Cu Kα radiation
  • μ = 0.84 mm−1
  • T = 100 K
  • 0.30 × 0.20 × 0.01 mm
Data collection
  • Oxford Xcalibur PX κ-geometry diffractometer with CCD area detector
  • Absorption correction: analytical [CrysAlis RED (Oxford Diffraction, 2003 [triangle]); analytical numeric absorption correction using a multifaceted crystal model based on the expressions derived by Clark & Reid (1995 [triangle])] T min = 0.842, T max = 0.966
  • 22848 measured reflections
  • 5247 independent reflections
  • 3735 reflections with I > 2σ(I)
  • R int = 0.099
Refinement
  • R[F 2 > 2σ(F 2)] = 0.070
  • wR(F 2) = 0.205
  • S = 1.03
  • 5247 reflections
  • 404 parameters
  • H-atom parameters constrained
  • Δρmax = 0.42 e Å−3
  • Δρmin = −0.39 e Å−3
Compound (II)
Crystal data
  • C29H33N5O8
  • M r = 579.60
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is c-66-0o119-efi7.jpg
  • a = 13.520 (6) Å
  • b = 22.9220 (11) Å
  • c = 9.795 (5) Å
  • β = 97.41 (5)°
  • V = 3010 (2) Å3
  • Z = 4
  • Cu Kα radiation
  • μ = 0.79 mm−1
  • T = 100 K
  • 0.38 × 0.25 × 0.04 mm
Data collection
  • Oxford Xcalibur PX κ-geometry diffractometer with CCD area detector
  • Absorption correction: analytical (CrysAlis RED; Oxford Diffraction, 2003 [triangle]) T min = 0.760, T max = 0.970
  • 24796 measured reflections
  • 5975 independent reflections
  • 3955 reflections with I > 2σ(I)
  • R int = 0.065
Refinement
  • R[F 2 > 2σ(F 2)] = 0.053
  • wR(F 2) = 0.140
  • S = 1.00
  • 5975 reflections
  • 383 parameters
  • H-atom parameters constrained
  • Δρmax = 0.40 e Å−3
  • Δρmin = −0.35 e Å−3
H atoms bonded to C atoms were placed in geometrically optimized positions and treated as riding, with C—H = 0.95 (aromatic), 0.98 (methyl) or 0.99 Å (methyl­ene). H atoms belonging to the amide and hydroxy groups were initially located in difference Fourier maps and in the final refinement their positions were geometrically optimized and treated as riding, with N—H = 0.88 Å and O—H = 0.84 Å. For all H atoms except the methyl groups of (II), U iso(H) = 1.2U eq(C,N,O). For the methyl groups of (II), U iso(H) = 1.5U eq(C).
For both compounds, data collection: CrysAlis CCD (Oxford Diffraction, 2003 [triangle]); cell refinement: CrysAlis RED (Oxford Diffraction, 2003 [triangle]); data reduction: CrysAlis RED; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]). Molecular graphics: XP in SHELXTL (Sheldrick, 2008 [triangle]) for (I); Mercury (Macrae et al., 2006 [triangle]) and SHELXTL for (II). For both compounds, software used to prepare material for publication: SHELXL97.
Supplementary Material
Crystal structure: contains datablocks global, I, II. DOI: 10.1107/S0108270110003094/sk3358sup1.cif
Structure factors: contains datablocks I. DOI: 10.1107/S0108270110003094/sk3358Isup2.hkl
Structure factors: contains datablocks II. DOI: 10.1107/S0108270110003094/sk3358IIsup3.hkl
Footnotes
Supplementary data for this paper are available from the IUCr electronic archives (Reference: SK3358). Services for accessing these data are described at the back of the journal.
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