Core directed self-assemblies in the solid state of retro aib bis-peptide dicarboxylic acids: A design strategy for control of molecular orientation in peptides

Self-assembly patterns as a function of the central core insert in the retro bis-peptide dicarboxylic acids HO? Aib? X? Aib? OH, containing oxalyl (-CO? CO? 1), fumaryl (? O? CH?CH ? CO ? ;2), and adipoyl [? CO? (CH₂)₄ ? CO? 3], have been characterized by single crystal x-ray diffraction analyses. Extensive hydrogen bonding occurs in each crystal but there are no OH…O bonds between acid groups. Only two types of hydrogen bonds occur in all the crystals:NH…O (acid terminal),2.84-2.98 Åand OH (acidterminal)…O (corecarbonyl),2.55–2.67 Å (exceptfor an additional intramolecular C₅ type bond in the oxalyl moiety in 1). The self-assembly patterns are a β-network in1, separate layer assemblies (β-networks) for two independent molecules in 2 that combine into a three-dimensional γnetwork, and separate ribbon assembles (αnetworks) for two independent molecules in 3 that combine into an extended β-network sheet withhydrophobic faces. © 1995 John Wiley & Sons, Inc.     

Structural versatility of peptides from Cα, α-disubstituted glycines: Crystal-state conformational analysis of homopeptides from Cα-methyl,Cα-benzylglycine [(αMe)Phe]n

The molecular and crystal structures of one derivative and three homopeptides (from the di-to the tetrapeptide level) of the chiral, C^{α, α}-disubstituted glycine C^α-methyl, C^α-benzylglycine [(αMe)Phe], have been determined by x-ray diffraction. The derivative is mClAc-D -(αMe)Phe-OH, and the peptides are pBrBz-[D -(αMe)Phe]₂-NHMe, pBrBz-[D -(αMe)Phe]₃-OH hemihydrate, and pBrBz-[D -(αMe)Phe]₄-OtBu sesquihydrate. All (αMe)Phe residues prefer ?,ψ torsion angles in the helical region of the conformational map. The dipeptide methylamide and the tripeptide carboxylic acid adopt a β-turn conformation with a 1 ← 4 C?O…?H? N intramolecular H bond. The structure of the tripeptide carboxylic acid is further stabilized by a 1 ← 4 C?O…?H? O intramolecular H bond, forming an “oxy-analogue” of a β-turn. The tetrapeptide ester is folded in a regular (incipient) 3₁₀-helix. In general, the relationship between (αMe)Phe chirality and helix screw sense is opposite to that exhibited by protein amino acids. A comparison is made with the conclusions extracted from published work on homopeptides from other C^α-methylated α-amino acids. © 1993 John Wiley & Sons, Inc.     

Crystal and molecular structure of benzyloxycarbonyl-α-aminoisobutyryl-L-prolyl methylamide: The observation of an X2-Pro3 Type III β-Turn

The crystal and molecular structure of N-benzyloxycarbonyl-α-aminoisobutyryl-L -prolyl methylamide, the amino terminal dipeptide fragment of alamethicin, has been determined using direct methods. The compound crystallizes in the orthorhombic system with the space group P2₁2₁2₁. Cell dimensions are a = 7.705 Å, b = 11.365 Å, and c = 21.904 Å. The structure has been refined using conventional procedures to a final R factor of 0.054. The molecular structure possesses a 4 → 1 intramolecular N-H—O hydrogen bond formed between the CO group of the urethane moiety and the NH group of the methylamide function. The peptide backbone adopts the type III β-turn conformation, with ?₂ = ?51.0°, ψ₂ = ?39.7°, ?₃ = ?65.0°, ψ₃ = ?25.4°. An unusual feature is the occurrence of the proline residue at position 3 of the β-turn. The observed structure supports the view that Aib residues initiate the formation of type III β-turn conformations. The pyrrolidine ring is puckered in C^γ-exo fashion.     

X-Pro peptides: Solution and solid-state conformation of benzyloxycarbonyl-(Aib-Pro)2methyl ester,a type I β-turn

The synthesis of the tetrapeptide benzyloxycarbonyl(α-aminoisobutyryl-L -prolyl)₂-methyl ester (Z-(Aib-Pro)₂-OMe) and an analysis of its conformation in solution and the solid state are reported. Stepwise synthesis using dicyclohexylcarbodiimide leads to racemization at Pro(2). Evidence for the presence of diastereomeric tetrapeptides is obtained from 270-MHz¹H-nmr and 67.89-MHz ¹³C-nmr. The all-L tetrapeptide is obtained by fractional crystallization from ethyl acetate. The NH of Aib(3) is shown to be involved in an intramo-lecular hydrogen bond by variable-temperature ¹H-nmr and the solvent dependence of NH chemical shifts. The results are consistent with a β-turn conformation with Aib(1) and Pro(2) at the corners stabilized by a 4 → 1 hydrogen bond. The molecule crystallizes in the space group P2₁2₁2₁, with a = 8.839, b = 14.938, and c = 22.015 Å. The structure has been refined to an R value of 0.051. The peptide backbone is all-trans, and a 4 → 1 hydrogen bond, between the CO group of the urethane moiety and Aib(3) NH, is observed. Aib(1) and Pro(2) occupy the corner positions of a type I β-turn with ? = ?55.4°, Ψ = ?31.3° for Aib(1) and ? = ?71.6°, Ψ = ?38° for Pro(2). The tertiary amide unit linking Pro(2) and Aib(3) is significantly distorted from planarity (Δω = 14.3°).     

Crystal Structure and Molecular Conformation of the Cyclic Hexapeptide cyclo-(Gly-Aib-Gly)2

We have synthesized and crystallized the cyclic peptide (Gly-Aib-Gly) ₂. Its structure has been determined by conventional X-ray diffracti on methods. In the crystal it adopts a conformation with one β-turn (type I) and its mirror image at the other side of the ring. All conformation al angles are similar to those reported for these amino acid residues. In particular the Aib residue has a conformation intermediate between α- and 3₁₀-helical conformations. The ring is an adequate model for the β-turn conformation. A molecule of formic acid is found in the crystal which shows a very short hydrogen bond with one of the glycine carbonyl groups.     

Solid state and solution conformations of a helical peptide with a central gly-gly segment

The influence of amino acids with contrasting conformational tendencies on the stereochemistry of oligopeptides has been investigated using an octapeptide Boc-Leu-Aib-Val-Gly-Gly-Leu-Aib-Val-OMe, which contains two helix-promoting Aib residues and a central helix-destabilizing Gly-Gly segment. Single crystal x-ray diffraction studies reveal that a 3 ₁₀-helix is formed up to the penultimate Aib residue, at which point there is a helix reversal in the backbone, reminiscent of a C-terminal 6 → I hydrogen bond. The curious feature in the crystal is the solvation of the possible 6 → 1 bond by a CH₃OH molecule, where the OH is inserted between O(3) and N(8) and participates in hydrogen bonds with both. The cell parameters are as follows: space group P2₁2₁2₁, a = 10.649(4) Å, b = 15.694(5) Å, c = 30.181(8) Å, R = 6.7% for 3427 data (| F₀| > 3σF) observed to 0.9 Å. Nuclear magnetic resonance studies in CDCl₃ using NH group solvent accessibility and nuclear Overhauser effects as probes are consistent with a 3 ₁₀-helical conformation. In contrast, in (CD₃)₂SO, unfolding of the central segment results in a multiple β-turn structure, with β-turn conformations populated at residues 1–2, 3–4, and 6–7. CD studies in methanol-2,2,2-trifluoroethanol (TFE) mixtures also provide evidence for a solvent-dependent structural transition. Helical conformations are populated in TFE, while type II β-turn structures are favored in methanol. © 1996 John Wiley & Sons, Inc.     

Chymotrypsin inhibitory conformation of dipeptides constructed by side chain–side chain hydrophobic interactions

A complete series of configurationally isomers (L -L , L -D , D -L AND D -D ) of a dipeptide Leu-Phe benzyl ester have been synthesized and assayed for chymotrypsin. In the conformational analysis by 400 MMz ¹H NMR, the L -D and D -L isomers, but not hte L -L and D -D isomers, showed fairly large up field shifts (0.2–0.4 ppm) of Leu-βCH₂ and γCH proton signals, indicating the presence of shielding effects from the benzene ring. In addition to distinct signal splitting of Phe-βCH₂, the NOE enhancement observed between Leu-δCH₃ and Phe-phenyl groups revealed that these groups are in close proximity. These data indicated that L -D and D -L isomers from a hydrophobic core between side chains of adjacent Leu and Phe residues. When the dipeptides were examined for inhibition of chymotrypsin using Ac-Try-OEt as a substrate, the L -L isomer showed no inhibition, itself becoming a substrate. However, the other three isomers inhibited chymotrypsin in a competitive manner, and the D -L isomer was strongest with K_i of 2.2 × 10_?5 M . It was found that the D -L isomer was only slowly hydrolysed but the L (or D )-D isomer was not. H-D -Phe-L -Leu-OBzl with the inverse sequence of H-D -Leu-L -Pre-OBzl inhibited chymotrypsin more strongly (K_i = 6.3 × 10^?6 M ). Since the free acid analogue of the D -L isomer exhibited no inhibition, the benzyl ester moiety itself was thought to be involved in the enzyme inhibition. It is assumed that in the inhibitory conformation the ester-benzyl group fits the S₁ site of chymotrypsin, while the side chain-side chain complexing hydrophobic core fits the S₂ site.     

Insulin analogues with modifications in the β-turn of the B-chain

The β-turn formed by the amino acid residues 20–23 of the B-chain of insulin has been implicated as an important structural feature of the molecule. In other biologically active peptides, stabilization of β-turns has resulted in increases in activity. We have synthesized three insulin analogues containing modifications which would be expected to increase the stability of the β-turn. In two analogues, we have substituted α-aminoisobutyric acid (Aib) for the Glu residue normally present in position B21 or for the Arg residue normally present in position B22; in a third compound, we have replaced the Glu residue with its D-isomer. Biological evaluation of these compounds showed that [B21 Aib]insulin displays a potencyca. one-fourth that of natural insulin, while [B22 Aib]insulin is less than 10% as potent. In contrast, [B21 D-Glu]insulin is equipotent with natural insulin. We conclude that the β-turn region of the insulin molecule normally possesses considerable flexibility, which may be necessary for it to assume a conformation commensurate with high biological activity. If this is the case, [B21 D-Glu]insulin may exhibit a stabilized geometry similar to that of natural insulin when bound to the insulin receptor.     

X-Pro peptides: Synthesis and solution conformation of benzyloxycarbonyl-(Aib-Pro)4methyl ester. Evidence for a novel helical structure

The synthesis of the octapeptide, benzyloxycarbonyl-(α-aminoisobutyryl-L-prolyl)₄-methyl ester [Z-(Aib-Pro)₄-OMe] and an analysis of its solution conformation is reported. The octapeptide is shown to possess three strong intramolecular hydrogen bonds on the basis of studies of the solvent and temperature dependence of NH chemical shifts and rates of hydrogen–deuterium exchange. ¹³C studies are consistent with a structure involving only trans Aib-Pro bonds, while ir experiments support a hydrogen-bonded conformation. The Aib 3, 5, and 7 NH groups are shown to participate in hydrogen bonding. A 3₁₀ helical conformation compatible with the spectroscopic data is suggested. The proposed conformation consists of three type III β-turns with Aib and Pro at the corners and stabilized by 4 → 1 intramolecular hydrogen bonds.     

NMR studies of a free and protected tetrapeptide glycyl-L-prolylglycylglycine in beta-turn-supporting environment

Nmr studies of the protected and free tetrapeptide Gly-Pro-Gly-Gly were carried out in β-turn-supporting solvents, that is, in CDCl₃ for Z-Gly-Pro-Gly-Gly-OMe and in Me₂SO-d₆ for H-Gly-Pro-Gly-Gly-OH. Comparisons with specifically α-deuterated analogs gave complete assignments of the NH and methylene regions. Analysis of chemical shifts, coupling constants, and the temperature dependence of chemical shifts show that the peptide adopts a type II β-turn conformation. This turn is stabilized for the protected tetrapeptide by two hydrogen bonds between (i) C?O (Gly₁) and NH(Gly₄), and (ii) urethane function NH and methyl ester C?O.     

A nonhelical,multiple β-turn conformation in a glycine-rich heptapeptide fragment of trichogin A IV containing a single central α-aminoisobutyric acid residue

The conformational properties of the protected seven-residue C-terminal fragment the lipopeptaibol antibiotic Trichogin A IV (Boc-Gly-Gly-Leu-Aib-Gly-Ile-Leu-OMe) has been examined in CDCl₃ and (CD₃)₂SO by ¹H-nmr. Evidence for a multiple β-turn conformation [type I′ at Gly(1)-Gly(2), type II at Leu(3)-Aib(4), and a type I′ at Aib(4)-Gly(5)] suggests that Leu(3) has preferred an extended or semiextended conformation over a helical conformation in CDCl₃. This structure is thus in contrast to earlier observations of seven-residue peptides containing a single central Aib preferring helical conformations in both solution and crystalline slates. A structural transition to a frayed right-handed helix is absented in (CD₃)₂SO. These results suggest that nonhelical conformations may be important in Gly-rich peptides containing Aib. Further, the presence of amino acids with contradictory influences on backbone conformational freedom can lead to well-defined conformational transitions even in small peptides. © 1995 John Wiley & Sons, Inc.     

Synthesis and conformational analysis of aib-containing peptide modelling for N-glycosylation site in N-glycoprotein

A tetrapetide containing an Aib residue, Boc-Asn-Aib-Thr-Aib-OMe, was synthesized as a peptide model for the N-glycosylation site in N-glycoproteins. Backbone conformation of the peptide and possible intramolecular interaction between the Asn and Thr side chains were elucidated by means of n.m.r. spectroscopy. Temperature dependence of NH proton chemical shift and NOE experiments showed that Boc-Asn-Aib-Thr-Aib-OMe has a tendency to form a β-turn structure with a hydrogen bond involving Thr and Aib⁴ NH groups. Incorporation of Aib residues in the peptide model promotes folding of the peptide backbone. With folded backbone conformation, carboxyamide protons of the Asn residue are not involved in hydrogen bond network, while the OH group of the Thr residue is a candidate for a hydrogen bond in DMSO-d₆ solution.     

Experimental investigations on the backbone folding of proline-containing model tripeptides

Some proline-containing tripeptides with the general formulas R⁰CO-L -Pro-X-NHR³ (X = Gly,Sar,L -Ala,D -Ala) and R⁰CO-X-L -Pro-NHR³ (X = Gly,L -Ala,D -Ala) have been investigated in solution by ir and ¹H-nmr spectroscopies. Their favored conformational states depend mainly on both the primary structure and the chiral sequence of the molecules. In inert solvents the βII-folding mode is the most favored conformation for the L -Pro-D -Ala and L -Pro-Gly tripeptides, while the βII′-turn is largely preferred by D -Ala-L -Pro derivatives. Under the same conditions only about one-third of the whole conformers of L -Pro-L -Ala molecules adopts the βI-folding mode. Semiopened C₇C₅ and C₅C₇ conformations are appreciably populated in the L -Pro-L -Ala sequence, on the one hand, and in the Gly-L -Pro and L -Ala-L -Pro derivatives, on the other hand. In L -Pro-Sar and X-L -Pro models, the cis–trans isomerism around the middle tertiary amide function is observed. Thus cis L -Pro-Sar and L -Ala-L -Pro conformers are folded by an intramolecular i + 3 → i hydrogen bond, whereas cis D -Ala-L -Pro and Gly-L -Pro molecules accommodate an open conformation. In dimethylsulfoxide the βII- and βII′-folding modes are not essentially destabilized, as contrasted with the βI conformation, which is less populated. In water solution all the above-mentioned conformations, with the possible exception of the βII′-folding mode for D -Ala-L -Pro molecules, seem to vanish. Solute conformations are also compared with the crystal structures of four proline-containing tripeptides.     

Comparison of conformation and antimicrobial activity of synthetic analogs of gramicidin S: Stereochemical consideration of the role of D-phenylalanine in the antibiotic.

In order to study the role of D -amino acid residues in keeping the stable β-sheet conformation and in the antimicrobial activity of gramicidin S (GS), the four analogs of GS containing D -Ala, L -Ala, Gly, and Aib (α-aminoisobutyric acid) in place of D -Phe were synthesized. D -Ala-and Gly-containing analogs showed antimicrobial activity, while those containing L -Ala and Aib showed no activity. Conformation of these analogs and their derivatives were studied by comparison of ORD and CD spectra and by slective methylation method. It is concluded that the biologically active analogs have β-sheet conformation while inactive analogs have a much different conformation from that of GS. This indicates that D -Ala-Pro and Gly-Pro sequences favor taking a β-bend form but L -Ala-Pro and Aib-Pro sequences do not because the presence of L -side methyl group on the α-carbon atom of L Ala and Aib residues destabilizes the β-bend form. This would explain why the inactive analogs which take a different conformation from that of the active ones result in the loss of activity.     

Conformational interconversions in peptide β-turns: Discrimination between enantiomeric conformations by chiral perturbation

The crystal structure of the model tripeptide Boc-Aib-Gly-Leu-OMe ( 1 ) reveals two independent molecules in the asymmetric unit that adopt “enantiomeric” type I and type I′ β-turn conformations with the Aib and Gly residues occupying the corner (i + 1 and i + 2) positions. ¹³C cross polarization and magic angle sample spinning spectra in the solid state also support the coexistence of two conformational species. ¹³C-nmr in CDCl₃ establishes the presence of a single species or rapid exchange between conformations. 400 MHz ¹H-nmr provides evidence for conformational exchange involving a major and minor species, with β-turn conformations supported by the low solvent exposure of Leu(3) NH and the observation of N_iH ↔ N_i+1H nuclear Overhauser effects. CD bands in the region 190–230 nm are positive, supporting a major population of type I′ β-turns. The isomeric peptide, Boc-Gly-Leu-Aib-OMe ( 2 ), adopts an “open” type II′ β-turn conformation in crystals. Solid state and solution nmr support population of a single conformational species. Chiral perturbation introduced outside the folded region of peptides may provide a means of modulating screw sense in achiral sequences. © 1998 John Wiley & Sons, Inc. Biopoly 45: 191–202, 1998     

Conformational preferences and self-association modes of two diastereomeric statine derivatives

The conformational preferences and self-association modes of the two diastereomeric N-acetyl, methylamides of 3-hydroxy, 4-amino, 6-methylheptanoic acid (statine) with (R, S) and (S, S) configurations at the 3-hydroxy and 4-amino carbons, respectively, have been determined in solution as well as in the solid state by infrared absorption, 1H nuclear magnetic resonance, and X-ray diffraction. Conformational energy computations have also been performed in parallel. In the crystal state, the change in chirality of the hydroxyl group induces different intermolecular H-bonding schemes in the (R, S) isomer compared to the two structurally distinct molecules in the asymmetric unit of the (S, S) isomer. Different propensities to self-aggregate are seen in solvents of low polarity. In solvents of high polarity, however, the molecules of both isomers are largely solvated, while still keeping some local conformational restriction. Conformational energy computations indicate that in vacuo the two diastereomers exhibit different flexibility, and a preferred conformation with a different type of intramolecular H-bond.     

Solvent and side-chain contributions to the two-cis ⇄ all-trans equilibria of cyclic hexapeptides,cyclo(Xxx-Pro-D-Yyy)2

Cyclic hexapeptides of the type cyclo(L -Xxx-L -Pro-D -Yyy)₂ or cyclo(L -Xxx-L -Pro-Gly)₂ exist in solution predominantly in two forms of C₂ average symmetry, one with all-trans peptide bonds and generally well-established conformation, and another with both Xxx-Pro peptide bonds cis. We have been measuring the thermodynamic parameters of this equilibrium using carbon and proton nmr spectroscopy. Data have been obtained for peptides in which Yyy = Gly, D -Ala, or D -Phe, and Xxx = Gly, L -Ala, L -Leu, and L -Val. In a given solvent, stability of the all-trans form decreases (ΔG⁰ increases) as Xxx is changed through the series Gly, L -Ala-, L -Leu, and L -Val, consistent with expected increasing repulsion between the Xxx side chain and the proline δ methylene across the trnas Xxx-Pro bond. Also, for a given set of side chains, the stability of the all-trnas form increases as the polarity of the solvent decreases, consistent with models in which all C?O and N? H groups are accessible for solvation in the two-cis form, but two C?O and two N? H groups are somewhat sequestered in the all-trans form. With the available data it is not possible to identify pure intramolecular (solvent-independent) or pure peptide-bond solvation (side chain-independent) terms in ΔH° or ΔS°, although trends are discernible.     

A CD and an nmr study of multiple bradykinin conformations in aqueous trifluoroethanol solutions

CD and nmr studies have been carried out on aqueous trifluoroethanol (TFE) solutions of bradykinin (BK) and a bradykinin antagonist. The CD results exhibit a striking effect of TFE on the spectra of BK, with sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg, and the BK antagonist, with sequence D -Arg-Arg-Pro-Hyp-Gly-Thi-D -Ser-D -Cpg-Cpg-Arg [where Hyp is 4-hydroxy-L -proline; Thi refers to β-(2-thienyl)-L -alanine and Cpg refers to α-cyclopentylglycine]. The effect of increasing concentration of TFE in water on the difference ellipticity at 222 nm was examined and showed that BK may be a mixture of at least two different conformers, one of which largely forms when the TFE concentration is increased beyond 80%. The linear extrapolation of 100% of the difference ellipticity of BK at low TFE concentrations yields a value in agreement with that shown by the BK antagonist, indicating that the conformation of BK at the lower TFE concentrations is similar to that of the BK antagonist. The conformational analysis was carried out using both one-dimensional and two-dimensional ¹H-nmr techniques. The total correlation spectroscopy (TOCSY) spectrum of BK in a 60/40% (v/v) TFE/H₂O solution at 10°C and a nuclear Overhauser effect spectroscopy (NOESY) spectrum that shows only sequential H_α(i) – NH(i + 1) or the H_α(i) – H_δδ′(i + 1) NOEs indicate that the majority of the molecules adopt an all-trans extended conformation. The TOCSY for BK in the 95/5% (v/v) TFE/H₂O solution shows that there are two major conformations in the solution with about equal population. The NOESY experiment shows two new important cross peaks for one conformation, namely Pro²(α)-Pro³ (α) and the Pro²(α)-Gly⁴(NH), indicating a cis Pro²-Pro³ bond and a type VI β-turn between residues Arg¹ and Gly⁴ involving cis proline at position 3, respectively. The low temperature coefficient of Gly⁴ for this conformation suggests the presence of an intramolecular hydrogen bond, therefore a type VIa β-turn is present. The other conformation is all trans and extended. The BK antafonist shows difference CD spectra in TFE solutions referred to H₂O that are superficially indicative of a β-bend. However, nmr speaks against this possibility, as only one set of peaks were observed in the TOCSY and NOESY experiments, indicating an all-trans extended confirmation over the range of TFE concentrations. The BK-antagonist CD data suggest that solvent perturbation of the CD of an extended confirmation perturbation of the optical activity of the thienyl moiety of the peptide since the CD spectrum of N-acetyl-β-thienyl-L -alanine N-methylamide is strongly perturbed by TFE. The present results again demonstrate the complementary relationship between CD and nmr. © 1994 John Wiley & Sons, Inc.     

Sequential polypeptides containing arginine as histone models: synthesis and conformational studies

The sequential polypeptides (L -Arg-X-Gly)_n, where X represents amino acid residues Ala, Val, and Leu, were prepared as models of arginine-rich histones to be used in studying their structure and their interactions with DNA. The polymerization was carried out on the pentachlorophenyl active esters of the appropriate tripeptides, while the toluene-4-sulfonyl group was used for protecting the arginine guanido group. CD was employed to investigate the conformation of (L -Arg-X-Gly)_n polymers in aqueous solutions, at different pH, as well as in trifluoroenthanol and hexafluoroisopropyl alcohol solutions. In aqueous solutions (at pH 7 and 12) the prepared sequential polymers behaved as a random coil. The CD spectra in various trifluoroethanol–water or hexafluoroisopropyl alcohol–water mixtures indicated that the degree of helical conformation of the studied polytripeptides increased in the order of Ala → Val → Leu. The opposite was true for the β-structure. Characteristics of β-turn are excluded from the poly(L -Arg-L -Leu-Gly), which assumed the most pronounced helical conformation. The poly(L -Arg-L -Val-Gly) exerts a significant preference to the β-turn structure compared to that of poly(L -Arg-L -Ala-Gly). Thus the probability for helical, β-structure or β-turn conformations of the polymers was analyzed in relation to the bulkiness and length, and to the special features of the X-residue side chain (β-branching). We concluded that the prepared sequential arginine-containing polypeptides are plausible models for histone fractions, f₃ and f₂α₁.     

β-Turn conformations in crystal structures of model peptides containing α,α-Di-n-propylglycine and α,α-Di-n-butylglycine

The crystal state conformations of three peptides containing the α,α-dialkylated residues. α,α-di-n-propylglycine (Dpg) and α,α-di-n-butylglycine (Dbg), have been established by x-ray diffraction. Boc-Ala-Dpg-Alu-OMe (I) and Boc-Ala-Dbg-Ala-OMe (III) adopt distorted type II β-turn conformations with Ala (1) and Dpg/Dbg (2) as the corner residues. In both peptides the conformational angles at the Dxg residue (I: ? = 66.2°, ψ = 19.3°; III: ? = 66.5°. ψ = 21.1°) deviate appreciably from ideal values for the i + 2 residue in a type II β-turn. In both peptides the observed (N…O) distances between the Boc CO and Ala (3) NH groups are far too long (1: 3.44 Å: III: 3.63 Å) for an intramolecular 4 → 1 hydrogen bond. Boc-Ala-Dpg-Ata-NHMe (II) crystallizes with two independent molecules in the asymmetric unit. Both molecules HA and HB adopt consecutive β-turn (type III-III in HA and type III-I in IIB) or incipient 3₁₀-helical structures, stabilized by two intramolecular 4 → 1 hydrogen bonds. In all four molecules the bond angle N-C^α-C′ (τ) at the Dxg residues are ≥ 110°. The observation of conformational angles in the helical region of ?,ψ space at these residues is consistent with theoretical predictions. © 1995 John Wiley & Sons, Inc.