Conformational investigation of α, β-dehydropeptides

The crystal structure of Ac-Pro-ΔVal-NHCH₃ was examined to determine the influence of the α,β-dehydrovaline residue on the nature of peptide conformation. The peptide crystallizes from methanol-diethyl ether solution at 4° in needle-shaped form in orthorhombic space group P2₁2₁2₁ with a= 11.384(2) Å, b = 13.277(2) Å, c = 9.942(1) Å. V = 1502.7(4) ų Z = 4, D_m= 1.17 g cm^?3 and D_c=1.18 g cm^?3 The structure was solved by direct methods using SHELXS-86 and refined to an R value of 0.057 for 1922 observed reflections. The peptide is found to adopt a β-bend between the type I and the type III conformation with φ₁=?68.3(4)°, ψ₁=? 20.1(4)°, φ₂=?73.5(4)°= and Ψ₂=?14.1(4)°=. An intramolecular hydrogen bond between the carbonyl oxygen of ith residue and the NH of (i+ 3)th residue stabilizes the β-bend. An additional intermolecular N.,.O hydrogen bond joins molecules into infinite chains. In the literature described crystal structures of peptides having a single α,β-dehydroamino acid residue in the (i+ 2) position and forming a β-bend reveal a type II conformation.     

Synthesis,crystal structure and molecular conformation of the tBuCO-D,L-Ala-Δz-Phe-NhiPr α,β-unsaturated dipeptide

The crystal structure of the tBuCO-d,l -Ala-Δ^z-Phe-NHiPr dipeptide has been solved by X-ray diffraction. The peptide crystallizes in monoclinic space group P2JC with a = 13.445 (3) Å, b = 35.088 (4) Å, c = 14.755(3) Å, β= 116.73(1)°, Z = 12 and d_c= 1.151 g.cm^?3. The three independent molecules per asymmetric unit accommodate a βII-folded conformation, but only one of them contains the typical i + 3 → i interaction characterizing a β-turn. In the other two molecules, the N…O distance exceeds 3.2 Å, a value generally considered the upper limit for hydrogen bonds in peptides. In solution, the βII-turn conformation is largely predominant.     

Structure of N-Boc-L-Pro-dehydro-Leu-NHCH3

The peptide N-Boc-L-Pro-dehydro-Leu-NHCH₃ was synthesized to examine the nature of β-bend as a result of dehydro-Leu in the sequence. The peptide crystallizes from methanol-water mixture at 4° in orthorhombic space group P22₁2₁ with a = 5.726(1)Å, b = 14.989(4) Å, c = 24.131(9) Å, V = 2071(1) ų, Z = 4, dm = 1.064(5)gcm^-3 and dc = 1.0886(5)gcm^-3. The structure was solved by direct methods using SHELXS 86 and it was refined by full-matrix least-squares procedure to an R value of 0.059 for 957 observed reflections. The peptide is found to adopt a β-bend type II conformation with φ₁=– 51(1)°, ψ₁= 133(1)°, φ₂= 74(2)° and ψ₂= 8(2)°. The β-bend is stabilized by an intra-chain hydrogen bond between the carbonyl oxygen of ith residue and the NH of (i + 3)th residue. The five-membered pyrrolidine ring of Pro-residue adopts an ideal C^γ-exo conformation with torsion angles of χ₁¹=– 25(1)°, χ₁²= 38(1)°, χ₂=– 34(1)°, χ₁⁴= 20(1)° and χ₁⁰= 2(1)°. The side chain conformation angles of dehydro-Leu residue are χ₂= 12(2)°, χ₂^2.1=– 112(2)° and χ₂^2.2= 136(2)°. The crystal structure is stabilized by a network of hydrogen bonds and van der Waals interactions.     

Crystal and molecular structure of tert.-butyloxycarbonyl-L-hydroxy-prolyl-α-aminoisobutyryl-α-aminoisobutyryl-L-phenylalaninol

The crystal structure of the synthetic tetrapeptide, Boc-Hyp-Aib-Aib-Phol, an analogue of the C-terminal tetrapeptide in the antibiotic Antiamoebin I, was determined as part of a study of the conformation of peptaibophol antibiotics. The crystals are orthorhombic, space group P2₁2₁2₁, with cell parameters a = 16.576 (1) Å, b= 17.657 (1) Å, c = 10.435 (1) Å, V = 3053.9 (2) ų, Z = 4, D_c= 1.163 g · cm^-3. The three amino acids form a single turn of a 3₁₀-helix, stabilized by two intramolecular hydrogen bonds. The Aib residues adopt the usual conformation in the region between the 3₁₀- and α-helices. The terminal hydroxy methyl group of the phenylalaninol residue is disordered. The position of the benzyl side chain of the amino alcohol relative to the backbone corresponds to a conformation also observed in phenylalanine residues.     

Conformational investigation of α,β-dehydropeptides VII*. Conformation of Ac-Pro-ΔAla-NHCH3 and Ac-Pro-(E)-ΔAbu-NHCH3: comparison with (Z)-substituted α,β-dehydropeptides†

The crystal structure and solution conformation of Ac-Pro-ΔAla-NHCH₃ and the solution conformation of Ac-Pro-(E)-ΔAbu-NHCH₃ were investigated by X-ray diffraction method and NMR, FTIR and CD spectroscopies. Ac-Pro-ΔAla-NHCH, adopts an extended-coil conformation in the crystalline state, with all-trans peptide bonds and the ΔAla residue being in a C₅ form, φ₁=– 71.4(4), ψ₁=– 16.8(4), φ₂=– 178.4(3) and ψ₂= 172.4(3)°. In inert solvents the peptide also assumes the C₅ conformation, but a γ-turn on the Pro residue cannot be ruled out. In these solvents Ac-Pro-(E)- ΔAbu-NHCH₃ accommodates a βII-turn, but a minor conformer with a nearly planar disposition of the CO—NH and C=C bonds (φ₂～0°) is also present. Previous spectroscopic studies of the (Z)-substituted dehydropeptides Ac-Pro-(Z)- ΔAbu-NHCH, and Ac-Pro-ΔVal-NHCH₃ reveal that both peptides prefer a βII-turn in solution. Comparison of conformations in the family of four Ac-Pro-ΔXaa-NHCH₃ peptides let us formulate the following order of their tendency to adopt a β-turn in solution: (Z)- ΔAbu > (E)- δAbu > ΔVal; ΔAla does not. None of the folded structures formed by the four compounds is stable in strongly solvating media. © Munksgaard 1996.     

Crystal structures of a nonapeptide helix containing α, α-di-n-butylglycine (Dbg), Boc-G1y-Dbg-Ala-Val-Ala-Leu-Aib-Val-Leu-OMe

Two crystal structures of a nonapeptide (anhydrous and hydrated) containing the amino acid residue α,α-di-n-butylglycyl, reveal a mixed 3₁₀-α-helical conformation. Residues 1-7 adopt φ, ψ values in the helical region, with Val(8) being appreciably distorted. The Dbg residue has φ, ψ values of -40, -37° and -46, -407° in the two crystals with the two butyl side chains mostly extended in each. Peptide molecules in the crystals pack into helical columns. The crystal parameters are: C₅₀ H₉₁ N₉ O₁₂, space group P2₁, with a= 9.789(1)Å;, b= 20.240(2) Å. c= 15.998(3) Å. β= 103.97(1): Z= 2, R=10.3% for 1945 data observed < 3σ(F) and C₅₀H₉₁N₉O₁₂· 3H₂O, space group P2₁ with a= 9.747(3)Å, b= 21.002(8) Å, c= 15.885(6) Å, β= 102.22(3). Z= 2. R=13.6% for 2535 data observed < 3σ(F) The observation of a helical conformation at Dbg suggests that the higher homologs in the α,α-dialkylated glycine series also have a tendency to stabilize peptide helices. © Munksgaard 1996.     

Crystal structure of tert.-butyloxycarbonyl-L-prolyl-D-alanyl-D-alanyl-N-methylamide Dimeric β-sheet formation

The crystal structure of the tripeptide t-Boc-L-Pro-D-Ala-D-Ala-NHCH₃, monohydrate, (C₁₇H₃₀N₄O₅·H₂O, molecular weight = 404.44) has been determined by single crystal X-ray diffraction. The crystals are mono-clinic, space group P2₁, a = 9.2585(4), b = 9.3541(5). c = 12.4529(4) Å, β= 96.449(3)°, Z = 2. The peptide units are in the trans and the tBoc-Pro bond in the cis orientation. The first and third peptide units show significant deviations from planarity (Δω=5.2° and Δω=3.7°, respectively). The backbone torsion angles are: φ¹, = -60°, ψ_1/= 143.3°, ω₁= -174.8°, φ₂= 148.4°, ψ₂= -143.1°, ω₂= -179.7°, φ₃= 151.4°, ψ₃= -151.9°, ω₃= -176.3°. The pyrrolidine ring of the proline residue adopts the C₂— C^γ conformation. The molecular packing gives rise to an antiparallel β-sheet structure formed of dimeric repeating units of the peptide. The surface of the dimeric β-sheet is hydrophobic. Water molecules are found systematically at the edges of the sheets interacting with the urethane oxygen and terminal amino groups. Surface catalysis of an L-Ala to D-Ala epimerization process by water molecules adsorbed on to an incipient β-sheet is suggested as a mechanism whereby crystals of the title peptide were obtained from a solution of tBoc-Pro-D-Ala-Ala-NHCH₃.     

Synthesis and crystal structures of Boc-L-Asn-L-Pro-OBzl·CH3OH and dehydration side product,Boc-β-cyano-L-alanine-L-Pro-OBzl

Boc-L-Asn-L-Pro-OBzl:C₂₁H₂₉O₆N₃·CH³OH, M_r= 419.48 + CH₃OH, monoclinic, P2₁, a= 10.049(1), b= 10.399(2), c= 11.702(1)Åβ= 92.50(1)°, V = 1221.7(3)ų, d_x= 1.14g cm^-3, Z = 2, CuKα (λ= 1.54178 Å), F(000) = 484 (with solvent), 23°, unique reflections (I > 3σ(I)) = 1745, R = 0.043, R_w= 0.062, S = 1.66. Boc-β-cyano-L-alanine-L-Pro-OBzl: C₂₁H₂₇O₅N₃, M_r= 401.46, orthorhombic, P2₁2₁2₁, a= 15.741(3), b= 21.060(3), c= 6.496(3)ÅV= 2153(1)ų, d_x= 1.24g·cm^-3, Z = 4, CuKα (λ= 1.54178 Å), F(000) = 856, 23°, unique reflections (I > 3σ(I)) = 1573, R = 0.055, R_w= 0.078, S = 1.86. The tert.-butyloxycarbonyl (Boc) protected dipeptide benzyl ester (OBzl), BOC-L-Asn-L-Pro-OBzl, prepared from a mixed anhydride reaction using isobutylchloroformate, BOC-L-asparagine, and HCI·L-proline-OBzl, crystallized with one methanol per asymmetric unit in an extended conformation with the Asn-Pro peptide bond trans. Intermolecular hydrogen bonding occurs between the methanol and the Asn side chain and between the peptide backbone and the Asn side chain. A minor impurity due to the dehydration of the Asn side chain to a β-CNaia crystallized with a similar extended conformation and a single intermolecular hydrogen bond.     

Molecular design of peptides

The peptide N-Boc-l -Phe-dehydro-Abu-NH-CH₃ was synthesized by the usual workup procedure. The crystals grown from methanol at 4°C belong to the space group P2₁2₁2₁ with a= 7.589(2), b= 13.690(4), c= 21.897(6) Å, Z= 4 and d_c= 1.149(5) g cm^?3 for C₁₉H₂₉N₃O₅·CH₃OH. The peptide crystals were highly sensitive to radiation. The final agreement factor R was 0.055 for 1109 observed reflections (I > 2σ) with data extending to a 2θ value of 103°. The methanol oxygen atom is split into two occupancies. Both sites are involved in identical hydrogen bonding. As a result of substitution of a dehydro-Abu residue at the (i+ 2) position the peptide adopts an ideal β-turn II′ conformation with torsion angles of corner residues as φ₁=63(1)°, ψ₁= - 127(1)°, φ₂= -66(1)° and ψ₂= - 10(1)°, and an intramolecular hydrogen bond N—H ? O of length 3.01(1) Å. This shows that the conformational constraints produced by dehydro-Abu are similar in nature to but different in magnitude than those produced by dehydro-Phe and dehydro-Leu. The methanol–peptide interactions show characteristic features of multiple hydrogen-bond formations involving polar sites of participating peptide and methanol molecules. The packing of the molecules in the unit cell is stabilized by interactions through methanol molecules with the help of several hydrogen bonds.     

Design of peptides withα,β-dehydro-residues: synthesis,and crystal and molecular structure of a310-helical tetrapeptide Boc-l-Val-ΔPhe-ΔPhe-l-Ile-OCH3

Abstract: The peptide Boc-l -Val-ΔPhe-ΔPhe-l -Ile-OCH₃ was synthesized using the azlactone method in the solution phase, and its crystal and molecular structures were determined by X-ray diffraction. Single crystals were grown by slow evaporation from solution in methanol at 25°C. The crystals belong to an orthorhombic space group P2₁2₁2₁ with a = 12.882(7) Å, b = 15.430(5) Å, c = 18.330(5) Å and Z = 4. The structure was determined by direct methods and refined by a least-squares procedure to an R-value of 0.073. The peptide adopts a right-handed 3₁₀-helical conformation with backbone torsion angles: φ₁ = 56.0(6)°, ψ₁ = –38.0(6)°, φ₂ = –53.8(6)°, ψ₂ = 23.6(6)°, φ₃ = –82.9(6)°, ψ₃ = –10.6(7)°, φ₄ = 124.9(5)°. All the peptide bonds are trans. The conformation is stabilized by intramolecular 4→1 hydrogen bonds involving Boc carbonyl oxygen and NH of ΔPhe³ and CO of Val¹ and NH of Ile⁴. It is noteworthy that the two other chemically very similar peptides: Boc-Val-ΔPhe-ΔPhe-Ala-OCH₃ (i) and Boc-Val-ΔPhe-ΔPhe-Val-OCH₃ (ii) with differences only at the fourth position have been found to adopt folded conformations with two overlapping β-turns of types II and III′, respectively, whereas the present peptide adopts two overlapping β-turns of type III. Thus the introduction of Ile at fourth position in a sequence Val-ΔPhe-ΔPhe-X results in the formation of a 3₁₀-helix. The crystal structure is stabilized by intermolecular hydrogen bonds involving NH of Val¹ and carbonyl oxygen of a symmetry related (–x, y – 1/2, 1/2 + z) ΔPhe² and NH of ΔPhe² with carbonyl oxygen of a symmetry related (x, y1/2, 1/2 + z) Ile⁴. This gives rise to long columns of helical molecules linked head to tail running along [010] direction.     

Peptide crystal growth via vapor diffusion

The structure of a dihydrated form of glycyl-L-tyrosyl-L-alanine (GYA) has been determined as part of a series of peptide structural investigations and development of microscale vapor diffusion experiments for peptide crystal growth. Crystals were grown by the hanging-drop method against sodium acetate. The tripeptide is a zwitterion in the crystal, adopting an extended conformation through glycine, a nearly perpendicular bend attyrosine and a reverse turn for the C-terminal carboxylate. Principal backbone torsion angles are ψ₁ 175(1)°, ω₂ 173(1)°, φ₂ -119(1)°, ψ₂ 120(1)°, ω₃3 172(1)°, φ₃ -73(1)°,ψ₃₁ -9(1)°, ψ₃₂ 171(1)°. The tyrosyl side chain adopts an unusual orientation (χ^1/2= -86(1)°). The relationship of the GYA.2H₂O structure to GYA sequences in proteins is examined, particularly as regards its helix-forming potential. Crystal data: C₁₄H₁₉N₃O₄.2H₂O, Mr = 345.36, orthorhombic, P2₁2₁2₁, a = 4.810 (4), b= 11.400(7), c = 30.162(23)Å, V=1653.8(24)Å^?3, Z = 4, Dx= 1.387 Mgm^?3, λ(CuK_α^?)= 1.540 Åμ= 9.053 mm^?1, F(000) = 736, T = 199K, R = 0.041 for 1458 observations with I ≥ 3σ(I).     

Conformations of peptides containing 1-aminocyclohexanecarboxylic acid (Acc6). Crystal structures of two model peptides

The crystal structures of two peptides containing 1-aminocyclohexanecarboxylic acid (Acc⁶) are described. Boc-Aib-Acc⁶-NHMe · H₂O adopts a β-turn conformation in the solid state, stabilized by an intramolecular 4 → 1 hydrogen bond between the Boc CO and methylamide NH groups. The backbone conformational angles (φ_Aib = – 50.3°, ψ_Aib = – 45.8°; φ_Acc6 = – 68.4°, ψ_Acc6 = – 15°) lie in between the values expected for ideal Type I or III β-turns. In Boc-Aib-Acc⁶-OMe, the Aib residue adopts a partially extended conformation (φ_Aib = – 62.2°, ψ_Aib = 143°) while the Acc⁶residue maintains a helical conformation (φ_Acc6 = 48°, ψ_Acc⁶= 42.6°). ¹H n.m.r. studies in CDCl₃ and (CD₃)₂SO suggest that Boc-Aib-Acc⁶-NHMe maintains the β-turn conformation in solution.     

Observation of a mixed antiparallel and parallel β-sheet motif in the crystal structure of Boc-Ala-Ile-Aib-OMe

A diastereomeric mixture of the tripeptide Boc-Ala-Ile-Aib-OMe crystallized in the space group Pl from CH₃OH/H₂O. The unit cell parameters are a= 10.593(2) Å, b= 14.377(3) Å, c= 17.872(4) Å, α= 104.41(2)°, β= 90.55(2)°, γ= 106.91(2)°, V= 2512.4 ų, Z=4. X-Ray crystallographic studies shows the presence of four molecules in the asymmetric unit consisting of two pairs of diastereomeric peptides, Boc-l -Ala-l -Ile-Aib-OMe and Boc-l -Ala-d -Ile-Aib-OMe. The four molecules in the asymmetric unit form a rarely found mixed antiparallel and parallel β-sheet hydrogen bond motif. The Ala and (l ,d )-Ile residues in all the four molecules adopt the extended conformations, while the φ, ψ values of the Aib residues are in the right-handed helical region. In one of the molecules the Ile sidechain adopts the unusual gauche conformation about the C^β-C^γ bond. © Munksgaard 1996.     

Structure and conformation of linear peptides

The crystal structure of a dipeptide tert-butyloxycarbonyl-l -alanylglycine monohydrate (C₁₀H₁₈N₂O₅·H₂O), molecular weight 264, has been determined. The crystals are monoclinic, space group P2₁, with a= 10.767(1), b= 6.317(1), c= 10.981(2) Å, β= 109.15(2)°, and Z= 2, D_c= 1.24 g cm^?3. The structure was solved by direct methods and refined to 3 final R-index of 0.045 for 856 reflections (sin θ/λ < 0.55 Å^?1) with I > 2 σ. The N-terminus of the molecule blocked with the t-Boc group is uncharged and the C-terminus exists in an unionized state. The peptide unit is trans and shows slight deviations from planarity. (Δω= 3.1°). The peptide backbone is folded, with torsion angles of φ₁= -76.0(5), ψ₁= 164.3(4), ω₁= 176.9(5), φ₂= 116.1(5), ψ₂₁= - 2.8(7) and ψ₂₂= 177.8(4)°. The conformation about the urethane bond (C5–N1) is trans. The urethane group is essentially planar. The conformation of the boc group is trans–trans.     

Cystine peptides Antiparallel β-sheet conformation of the cyclic biscystine pep tide [Boc-Cys-Ala-Cys-NHCH3]2

The crystal structure analysis of the cyclic biscystine peptide [Boc-Cys¹-Ala²-Cys³-NHCH₃]₂ with two disulfide bridges confirms the antiparallel β-sheet conformation for the molecule as proposed for the conformation in solution. The molecule has exact twofold rotation symmetry. The 22-membered ring contains two transannular NH ? OC hydrogen bonds and two additional NH ? OC bonds are formed at both ends of the molecule between the terminal (CH₃)₃COCO and NHCH₃ groups. The antiparallel peptide strands are distorted from a regularly pleated sheet, caused mainly by the L-Ala residue in which φ=– 155° and ψ= 162°. In the disulfide bridge C^α (1)-C^β (1)-S(1)-(3′)-C^β(3′)-C^α(3′), S—S = 2.030 Å, angles C^β SS = 107° and 105°, and the torsional angles are –49, –104, +99, –81, –61°, respectively. The biscystine peptide crystallizes in space group C2 with a = 14.555(2) Å, b = 10.854(2) Å, c = 16.512(2)Å, and β= 101.34(1) with one-half formula unit of C₃₀H₅₂N₈O₁₀S₄· 2(CH₃)₂SO per asymmetric unit. Least-squares refinement of 1375 reflections observed with |F| > 3σ(F) yielded an R factor of 7.2%.     

Crystal and molecular structure of tert. -butyloxycarbonyl-L-prolyl-α-aminoisobutyryl-L-alanyl-α-aminoisobutyrate methyl ester

Boc-Pro-Aib-Ala-Aib-OMe crystallizes in the orthorhombic space group P2₁2₁2 with cell dimensions a = 17.701 (3)Å, b = 17.476 (4)Å, c = 9.686 (2)Å, V = 2996.3 ų. The first three residues form a single turn of a 3₁₀-helix stabilized by two intramolecular hydrogen bonds. Comparison of the conformation of the methyl ester of the tetrapeptide with that of its benzyl ester shows differences in the individual torsion angles of up to 29°, although the overall conformation is conserved.     

Peptides from chiral Cα,α-disubstituted glycines

The molecular and crystal structures of one derivative and three model peptides (to the pentapeptide level) of the chiral C^α,α-disubstituted glycine Cα-methyl, Cα-isopropylglycine [(αMe)Val] have been determined by X-ray diffraction. The derivative is mClAc-l -(α Me)Val-OH, and the peptides are Z-l -(αMe)Val-(l -Ala)₂-OMe monohydrate, Z-Aib-L-(αMe)Val-(Aib)₂-OtBu, and Ac-(Aib)₂-l -(αMe)Val-(Aib)₂OtBu acetonitrile solvate. The tripeptide adopts a type-I β-turn conformation stabilized by a 1 ← 4N-H . O=C intramolecular H-bond. The tetra- and pentapeptides are folded in regular right-handed 3₁₀-helices. All four L-(αMe)Val residues prefer φ, Ψ angles in the right-handed helical region of the conformational map. The results indicate that: (i) the (αMe)Val residue is a strong type-I/III β-turn and helix former, and (ii) the relationship between (αMe)Val chirality and helix screw sense is the same as that of Cα-monosubstituted protein amino-acids. The implications for the use of the (αMe)Val residue in designing conformationally constrained analogues of bioactive peptides are briefly discussed.     

Hydration and distortion of peptide helices in crystals. α-Helical structure of a dodecapeptide,Boc-(Ala-Leu-Aib)4-OMe

The dodecapeptide Boc-(Ala-Leu-Aib)₄-OMe crystallized with two independent helical molecules in a triclinic cell. The two molecules are very similar in conformation, with a 3₁₀-helix turn at the N-terminus followed by an α-helix, except for an elongated N(7)…O(3) distance in both molecules. All the helices in the crystal pack in a parallel motif. Eleven water sites have been found in the head-to-tail region between the apolar helices that participate in peptide-water hydrogen bonds and a network of water-water hydrogen bonds. The crystal parameters are as follows: 2(C₅₈H₁₀₄N₁₂O₁₅) +ca. 10H₂O, space group P1 with a= 12.946(2), b= 17.321(3), c= 20.465(4)Å, α=103.12(2), β= 105.63(2), γ= 107.50(2)?, Z= 2, R= 10.9% for 5152 data observed > 3σ(F), resolution 1.0 Å. In contrast to the shorter sequences [Karle et al. (1988) Proc. Natl. Acad. Sci. USA 85 , 299–3031 and Boc-(Ala-Leu-Aib)₂-OMe [Karle et al. (1989) Biopolymers 28 , 773–781], no insertion of a water molecule into the helix is observed. However, the elongated N—O distance between Ala⁷ NH and Aib³ CO in both molecules (molecule A, 3.40 Å; molecule B, 3.42 Å) is indicative of an incipient break in the helices.     

Crystal structure of a dipeptide Boc-Aib-Phe-OMe

In order to understand the effect of the restrictions posed by the Aib residue on peptide conformation we studied the crystal structure of a dipeptide tBoc-Aib-Phe-OMe. Crystals of this compound are triclinic, space group PI with a= 9.600(1) Å, b=10.262(1) Å, c= 10.799(1) Å, α= 98.43°(1), β=99.18°(1), °=98.87°(1), V= 1021.69(18) ų and Z=2. The structure was solved by direct methods and refined to an R-factor of 4.98%. The backbone conformational angles for the Aib residue in molecule A are in the left-handed helical region, while in molecule B they are in the right-handed helical region. The Phe residue in molecule A is in the right-handed helical conformation, while in molecule B it is in the β-region. The peptide units are trans and show significant deviation from planarity [(ω₁= 166.67(5)° and ω₂=–177.9(5)]. © Munksgaard 1997.     

Design of peptides with αβ-dehydro residues: Synthesis,crystal structure and molecular conformation of N-Boc-L-Ile-ΔPhe-L-Trp-OCH3

The dehydro-peptide Boc-L-Ile-ΔPhe-L-Trp-OCH₃ was synthesized by the azlactone method in the solution phase. The peptide was crystallized from methanol in an orthorhombic space group P2₁2₁2₁ with a = 10.777(2), b= 11.224(2), c= 26.627(10) Å. The structure was determined by direct methods and refined to an R value of 0.069 for 3093 observed reflections [l≥ 2σ(l)].The peptide failed to adopt a folded conformation with backbone torsion angles: φ₁, = 90.8(8)°, ψ₁= -151.6(6)°, φ₂= 89.0(8)°, ψ₂= 15.9(9)°, φ₃= 165.7(7)°, ψ^T₃= -166.0(7)°. A general rule derived from earlier studies indicates that a three-peptide unit sequence with a ΔPhe at the (i+ 2) position adopts a β-turn II conformation. Because the branched β-carbon residues such as valine and isoleucine have strong conformational preferences, they combine with the ΔPhe residue differently to generate a unique set of conformations in such peptides. The presence of β-branched residues simultaneously at both (i+ 1) and (i+ 3) positions induces unfolded conformations in tetrapeptides, but a β-branched residue substituted only at (i+ 3) positron can not prevent the formation of a folded β-turn II conformation. On the other hand, the present structure shows that a β-branched residue substituted at the (i+ 1) position prevents the formation of a β-turn II conformation. These observations indicate that a β-branched residue at the (i+ 1) position prevents a folded conformation whereas it cannot generate the same degree of effect from the (i+ 3) position. This may be because of the trans disposition of the planar ΔPhe side-chain with respect to the C=O group in the residue. The molecules are packed in an anti-parallel manner to generate N₂-H₂…O₂ (-x,y-1/2, -z+ 3/2) and N^ε1₃-H^ε1₃…O₁(-x,y -1/2, -z+ 3/2) hydrogen bonds.