Ac10c: a medium‐ring,cycloaliphatic Cα,α‐disubstituted glycine. Incorporation into model peptides and preferred conformation

Abstract: Two complete series of N‐protected oligopeptide esters to the pentamer level from 1‐amino‐cyclodecane‐1‐carboxylic acid (Ac₁₀c), an α‐amino acid conformationally constrained through a medium‐ring C^α_i ? C^α_i cyclization, and either the l ‐Ala or Aib residue, along with the N‐protected Ac₁₀c monomer and homo‐dimer alkylamides, were synthesized using solution methods and fully characterized. The preferred conformation of these model peptides was assessed in deuterochloroform solution using FT‐IR absorption and ¹H NMR techniques. Furthermore, the molecular structures of two derivatives (Z‐Ac₁₀c‐OH and Fmoc‐Ac₁₀c‐OH) and two peptides (the dipeptide ester Z‐Ac₁₀c‐l ‐Phe‐OMe and the tripeptide ester Z‐Aib‐Ac₁₀c‐Aib‐OtBu) were determined in the crystal state using X‐ray diffraction. The experimental results support the view that β‐bends and 3₁₀‐helices are preferentially adopted by peptides rich in Ac₁₀c, the third largest cycloaliphatic C^α,α‐disubstituted glycine known. This investigation allowed us to complete a detailed conformational analysis of the whole 1‐amino‐cycloalkane‐1‐carboxylic acid (Ac_nc, with n = 3–12) series, which represents the prerequisite for our recent proposal of the ‘Ac_nc scan’ concept.     

Crystallographic characterization of conformation of 1-aminocyclopropane-1-carboxylic acid residue (Ac3c) in simple derivatives and peptides*

The molecular and crystal structures of the C^α,α-dialkylated α-amino acid residue 1-aminocyclopropane-1-carboxylic acid hemihydrate (H₂^⊕-Ac₃c-O^?·½ H₂O) and nine derivatives and dipeptides have been determined by X-ray diffraction. The derivatives are pBrBz-Ac₃c-OH, Piv-Ac₃c-OH, Z-Ac₃c-OH, the α- and β-forms of t-Boc-Ac₃c-OH, Z-Ac₃c-OMe, and the 5(4H)-oxazolone from pBrBz-Ac₃c-OH; the dipeptides are H-(Ac₃c)₂-OMe and c(Ac₃c)₂. The values determined for the torsion angles about the N-C^α (φ) and C^α-C′ (φ) bonds for the single Ac₃c residue of Piv-Ac₃c-OH, the α- and β-forms of t-Boc-Ac₃-OH and Z-Ac₃c-OMe, and the C-terminal Ac₃c residue of H-(Ac₃c)₂-OMe correspond to folded conformations in the “bridge” region of the Ramachandran map. The structures of pBrBz-Ac₃c-OH and Z-Ac₃c-OH, however, are unusual in having a semi-extended conformation for the φ,ψ angles. The N-terminal Ac₃c residue of H-(Ac₃c)₂-OMe adopts a novel type of C₅ conformation, characterized inter alia by an (amino) N ? H-N (peptide) intramolecular hydrogen bond. While the acyl N^α-blocking groups form trans amides (pBrBz-Ac₃c-OH and Piv-Ac₃c-OH), the urethane groups may adopt either the trans [Z-Ac₃c-OH and t-Boc-Ac₃c-OH(α-form)] or the cis amide conformations [t-Boc-Ac₃c-OH(β-form) and Z-Ac₃c-OMe]. The five- and six-membered rings of the 5(4H)-oxazolone and the 2,5-dioxopiperazine, respectively, are planar. The four independent molecules in the asymmetric unit of the free α-amino acid are zwitterionic.     

Stereochemistry of peptides containing 1-aminocycloheptane-1-carboxylic acid (Ac7c)

The crystal structures of four peptides incorporating l-aminocycloheptane-l-carboxylic acid (Ac₇c) are described. Boc-Aib-Ac₇c-NHMe and Boc-Pro-Ac₇c-Ala-OMe adopt β-turn conformations stabilized by an intramolecular 4 × 1 hydrogen bond, the former folding into a type-I/III β-turn and the latter into a type-II β-turn. In the dipeptide esters, Boc-Aib-Ac₇c-OMe and Boc-Pro-Ac₇c-OMe, the Ac₇c and Aib residues adopt helical conformations, while the Pro residue remains semi-extended in both the molecules of Boc-Pro-Ac₇c-OMe found in the asymmetric unit. The cycloheptane ring of Ac₇c residues adopts a twist-chair conformation in all the peptides studied. ¹H-NMR studies in CDCl₃ and (CD₃)₂SO and IR studies in CDCl₃, suggest that Boc-Aib-Ac₇c-NHMe and Boc-Pro-Ac₇c-Ala-OMe maintain the β-turn conformations in solution.     

A solution NMR study of the selectively 13C, 15N-labeled peptaibol chrysospermin C in methanol

Abstract: The conformation of the 19-residue peptaibol chrysospermin C in methanol has been investigated by NMR spectroscopy using selective ¹⁵N and ¹³C labeling of the α-aminoisobutyric acid (Aib) residues. Complete ¹H and ¹³C sequential assignments, including stereospecific assignments for the heavily overlapped resonances from the two C^β methyl groups of the eight Aib residues, are reported for a peptaibol for the first time. An Aib residue followed by a Pro is an exception to previous suggestions regarding stereospecific assignment of the two C^β methyl groups of Aib residues. Local nuclear Overhauser effects and ³J_HNC and ³J_HNCβ scalar couplings indicate that the φ angles of the Aib residues are restricted sterically to local conformations consistent with right-handed helices. Despite these constraints on the eight Aib residues, the NMR data for chrysospermin C in methanol are generally most consistent with an ensemble of transient conformations, including backbone conformations inconsistent with helical structures. Initial NMR measurements for chrysospermin C bound to micelles suggest structural and dynamic differences relative to alamethicin bound to micelles which may be related to differences in gating voltages for formation of ion channels.     

Conformational preferences of oligopeptides rich in α-aminoisobutyric acid. III. Design,synthesis and hydrogen bonding in 310-helices

Two sterically constrained peptides {ⁱBoc-Aib-Aib-Aib-DkNap-Leu-Qx-Ala-Aib-Aib-F1, (Dk⁴Qx⁶[7/9]) and ⁱBoc-Aib-Aib-Aib-DkNap-Leu-Aib-Ala-Aib-Aib-Fl, (Dk⁴7/9)} containing α-aminoisobutyric acid (Aib) and Aib-class amino acids in conjunction with selected mono-α-alkyl amino acids were synthesized by an optimized TBTU/HOBt procedure. The use of Aib-class amino acids (e.g. DkNap and Qx), defined and discussed here, gives rise to the same overwhelmingly 3₁₀-helical backbone conformation as that provided by simpler Aib-rich peptides and homopeptides. The synthetic α,α-dialkylamino acids (DkNap, Qx) are aromatic homologues of the known alicyclic variants of Aib, the Ac₅c and Ac₆c amino acids. Two new organic solubilizing groups for peptides, ⁱBoc and 2-methoxyethylamine, are introduced. The ¹H nuclear magnetic resonance analyses of the Dk⁴s/p[7/9] and Dk⁴Qx⁶[7/9] peptides demonstrate the unambiguous 310s/b-helical hydrogen bonding pattern of these peptides, confirming the design objective of these sequence patterns containing greater than 50% Aib and Aib-class composition. © Munksgaard 1994.     

Bioactive N‐terminal undecapeptides derived from parathyroid hormone: the role of α‐helicity*

Abstract: The N‐terminal 1–34 segment of parathyroid hormone (PTH) is fully active in vitro and in vivo and it can reproduce all biological responses in bone characteristic of the native intact PTH. Recent studies have demonstrated that N‐terminal fragments presenting the principal activating domain such as PTH(1–11) and PTH(1–14) with helicity‐enhancing substitutions yield potent analogues with PTH(1–34)‐like activity. To further investigate the role of α‐helicity on biological potency, we designed and synthesized by solid‐phase methodology the following hPTH(1–11) analogues substituted at positions 1 and/or 3 by the sterically hindered and helix‐promoting C^α‐tetrasubstituted α‐amino acids α‐amino isobutyric acid (Aib), 1‐aminocyclopentane‐1‐carboxylic acid (Ac₅c) and 1‐aminocyclohexane‐1‐carboxylic acid (Ac₆c): Ac₅c‐V‐Aib‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( I ); Aib‐V‐Ac₅c‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( II ); Ac₆c‐V‐Aib‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( III ); Aib‐V‐Ac₆c‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( IV ); Aib‐V‐Aib‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( V ); S‐V‐Aib‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( VI ), S‐V‐Ac₅c‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( VII ); Ac₅c‐V‐S‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( VIII ); Ac₆c‐V‐S‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( IX ); Ac₅c‐V‐Ac₅c‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( X ); Ac₆c‐V‐Ac₆c‐E‐I‐Q‐L‐M‐H‐Q‐R‐NH₂ ( XI ). All analogues were biologically evaluated and conformationally characterized in 2,2,2‐trifluoroethanol (TFE) solution by circular dichroism (CD). Analogues I – V , which cover the full range of biological activity observed in the present study, were further conformationally characterized in detail by nuclear magnetic resonance (NMR) and computer simulations studies. The results of ligand‐stimulated cAMP accumulation experiments indicated that analogues I and II are active, analogues III , VI and VII are very weakly active and analogues IV , V , VIII–XI are inactive. The most potent analogue, I exhibits biological activity 3500‐fold higher than that of the native PTH(1–11) and only 15‐fold weaker than that of the native sequence hPTH(1–34). Remarkably, the two most potent analogues, I and II , and the very weakly active analogues, VI and VII , exhibit similar helix contents. These results indicate that the presence of a stable N‐terminal helical sequence is an important but not sufficient condition for biological activity.     

Structural versatility of peptides from Cα,α-disubstituted glycines: crystal-state conformational analysis of peptides from Cα-methylhomophenylalanine, (αMe)Hph

The molecular and crystal structures of the C^α-tetrasubstituted, δ-branched α-amino acid C^α-methyl-homophenylalanine, H-d -(αMe)Hph-OH, and three peptides (to the pentamer level), including the homotripeptide, have been determined by X-ray diffraction. The peptides are Z-l -(αMe)Hph-(l -Ala)₂-OMe, pBrBz-[d -(αMe)Hph]₃-OtBu and Ac-(Aib)₂-l -(αMe)Hph-(Aib)₂-OtBu. All the (αMe)Hph residues prefer φ,ψ torsion angles in the helical region of the conformational map. The two terminally blocked tripeptides adopt a β-bend conformation stabilized by a 1→4 C = O?H-N intramolecular H-bond. The terminally blocked pentapeptide is folded in a regular 3₁₀-helix. In general, the relationship between (αMe)Hph α-carbon chirality and helix handedness is the same as that exhibited by protein amino acids. A comparison is also made with the conclusions extracted from published work on peptides from other types of C^α-alkylated aromatic α-amino acids. © Munksgaard 1996.     

(αMe)Aun: a highly lipophilic,chiral, Cα‐tetrasubstituted α‐amino acid. Incorporation into model peptides and preferred conformation

Abstract: Using a chemo‐enzymatic approach we prepared the highly lipophilic, chiral, C^α‐methylated α‐amino acid (αMe)Aun. Two series of terminally protected model peptides containing either d ‐(αMe)Aun in combination with Aib or l ‐(αMe)Aun in combination with Gly were synthesized using solution methods and fully characterized. A detailed solution conformational analysis, based on FT‐IR absorption, ¹H NMR and CD techniques, allowed us to determine the preferred conformation of this amino acid and the relationship between chirality at its α‐carbon atom and screw sense of the helix that is formed. The results obtained strongly support the view that d ‐(αMe)Aun favors the formation of the left‐handed 3₁₀‐helical conformation.     

Conformation—activity correlations for chemotactic tripeptide analogs incorporating dialkyl residues with linear and cyclic alkyl sidechains at position 2

Five stereochemically constrained analogs of the chemotactic tripeptide incorporating l-aminocycloalkane-l-carboxylic acid (Ac_nc) and α, α-dialkylglycines (Deg, diethylglycine; Dpg, N, N-dipropylglycine and Dbg, N, N-dibutylglycine) at position 2 have been synthesized. NMR studies of peptides For-Met-Xxx-Phe-OMe (Xxx = Ac₇c. I: Ac₈c. II: Deg, III; Dpg, IV and Dbg, V; For, formyl) establish that peptides with cycloalkyl residues, I and II, adopt folded β-turn conformations in CDCl₃, and (CD³)₂SO. In contrast, analogs with linear alkyl sidechains, III-V, favour fully extended (C₅) conformations in solution. Peptides I-V exhibit high activity in inducing β-glucosaminidase release from rabbit neutrophils, with ED₅₀ values ranging from 1.4–8.0 × 10–¹¹. M. In human neutrophils the Dxg peptides III-V have ED₅₀ values ranging from 2.3 × 10^?8 to 5.9 × 10^?10 M, with the activity order being V>IV>III. While peptides I-IV are less active than the parent. For-Met-Leu-Phe-OH, in stimulating histamine release from human basophils, the Dbg peptide V is appreciably more potent, suggesting its potential utility as a probe for formyl peptide receptors. © Munksgaard 1996.     

Amphipathic control of the 310‐/α‐helix equilibrium in synthetic peptides

Abstract: A series of short, amphipathic peptides incorporating 80% C^α,C^α‐disubstituted glycines has been prepared to investigate amphipathicity as a helix‐stabilizing effect. The peptides were designed to adopt 3₁₀‐ or α‐helices based on amphipathic design of the primary sequence. Characterization by circular dichroism spectroscopy in various media (1 : 1 acetonitrile/water; 9 : 1 acetonitrile/water; 9 : 1 acetonitrile/TFE; 25 mm SDS micelles in water) indicates that the peptides selectively adopt their designed conformation in micellar environments. We speculate that steric effects from ith and ith + 3 residues interactions may destabilize the 3₁₀‐helix in peptides containing amino acids with large side‐chains, as with 1‐aminocyclohexane‐1‐carboxylic acid (Ac₆c). This problem may be overcome by alternating large and small amino acids in the ith and ith + 3 residues, which are staggered in the 3₁₀‐helix.     

Solution conformations of oligomers of α -aminoisobutyric acid°

The N-acetyl(Aib)nN' -methylamides (with n= 1, 2 and 3) and the N-acetyl-(Aib)3 methyl ester have been synthesized using an oxazolone procedure. An experimental conformational analysis of this series of oligomers has been carried out in water, DMSO-d6 and CDCI3 using n.m.r. techniques, and in chloroform using i.r. spectroscopy. Deuterium exchange rates of amide protons in DMSO-d6 and the rates of change of these proton chemical shifts with temperature in water, DMSO-d6 and CDCI3 indicate that the oligomeric N'-methylamides adopt conformations that have no hydrogen bonds when n = 1, one hydrogen bond when n = 2, and two hydrogen bonds when n = 3, and that Ac(Aib)3OMe has a conformation with one hydrogen bond. An analysis of the N-H stretching region of the i.r. spectra of these compounds in CHCI3 also suggests the existence of these conformational states. These data imply that the peptides adopt the 310-helical and not the α-helical conformation in solution. This conclusion supports the hypothesis that the Aib residue has asymmetric geometry at the C^α atom in solution, similar to that reported in the literature for the crystalline state.     

Improved solid‐phase synthesis of α,α‐dialkylated amino acid‐rich peptides with antimicrobial activity*

Abstract: A homologous series of nonapeptides and their acetylated versions were successfully prepared using solid‐phase synthetic techniques. Each nonapeptide was rich in α,α‐dialkylated amino acids [one 4‐aminopiperidine‐4‐carboxylic acid (Api) and six α‐aminoisobutyric acid (Aib) residues] and also included lysines or lysine analogs (two residues). The incorporation of the protected dipeptide 9‐fluorenylmethyloxycarbonyl (Fmoc)‐Aib‐Aib‐OH improved the purity and overall yields of these de novo designed peptides. The helix preference of each nonapeptide was investigated in six different solvent environments, and each peptide's antimicrobial activity and cytotoxicity were studied. The 3₁₀‐helical, amphipathic design of these peptides was born out most prominently in the N‐terminally acetylated peptides. Most of the peptides exhibited modest activity against Escherichia coli and no activity against Staphylococcus aureus. The nonacetylated peptides (concentrations ≤100 μm ) and the acetylated peptides (concentrations ≤200 μm ) did not exhibit any significant cytotoxicity with normal (nonactivated) murine macrophages.     

The β-bend ribbon spiral

The synthesis and conformational analysis in solution (by FTIR absorption and ¹H NMR) and in the crystal state (by X-ray diffraction) of three Hib-containing depsipeptides have been performed. In the crystal state Z-Aib-Hib-Aib-OMe is folded into a type-III β-bend, while the conformation adopted by Z-(Aib-Hib)₂-Aib-OMe is a β-bend ribbon spiral, characterized by two type-III β-bends with Aib(1)-Hib(2) and Aib(3)-Hib(4) as corner residues, respectively. Both independent molecules in the asymmetric unit of t-Boc-L-Ala-Hib-L-Ala-OMe crystals are folded into a type-II β-bend. For the Aib-Hib depsipeptides the conformation adopted in the crystal state is also that largely prevailing in solution, whereas for t-Boc-L-Ala-Hib-L-Ala-OMe the β-bend conformation is significantly less populated in solution. A comparison is also made with: (i) the published crystal-state conformations of fully protected -(Aib)₃^?, -(Aib)₅^?, and -L-Ala-Aib-L-Ala- sequences and the β-bend ribbon spiral generated by (Aib-L-Pro)_n oligomers, and (ii) with the herewith described solution preferred conformation of Z-L-Ala-Aib-L-Ala-OMe. The possible use of Hib as an isosteric replacement for Aib in the design of conformation ally constrained depsipeptides is briefly discussed.     

Solution structure of the phosphorylated sites of ribosomal protein S6 by 1H NMR spectroscopy

An increase in the rate of protein synthesis is found to be accompanied by phosphorylation of the 40S ribosomal protein S6. Treatment of S6 by cyanogen bromide produced three fragments, and one of the fragments of S6, which is a C-terminal portion of S6 (M_r? 4000), contains all phosphorylation sites of S6. The C-terminal fragment of S6 contains seven serines. S6 kinase phosphorylates S6 specifically, i.e. five serines in the C-terminal of S6 are phosphorylated. The three-dimensional structure of S6 peptide was studied in 50% trifluoroethanol/50% H₂O solution by ¹H NMR with combined use of distance geometry and restrained molecular dynamics calculations. NMR results indicated that it takes an α-helix between Glu5 and Arg21 and a distorted helical structure for the following three residues, but no rigid structure was present from Ser25 through the C-terminus and for the N-terminal region (Lys1-Lys4). The specificity of the phosphorylation of the peptide is discussed from a structural aspect. © Munksgaard 1996.     

CD-n.m.r. study of the solution conformation of bradykinin analogs containing α-aminoisobutyric acid

The conformation in aqueous solution of several α-aminoisobutyric acid (AIB)-containing analogs of bradykinin (BK) has been probed by complementary CD and ¹H n.m.r. measurements. The conclusion reached is that substitution of AIB for Pro² and/or Pro³ in BK stabilizes a degree of β-turn conformation in the N-terminal tetrapeptide moiety of the resulting analogs. Changing the solvent from water to DMSO or TFE further enhances the contribution of particular hydrogen bonded structures to the time-averaged conformation of these peptides. Bradykinin and [AIB⁷]-BK adopt similar hydrogen bonded conformations in TFE, apparently with a contribution from a β-turn involving their common Arg¹-Pro²-Pro³-Gly⁴ moiety. The contrasting biological activities of BK and its AIB-analogs are considered in terms of the conformational analogy between the AIB-residue and cis¹ Pro and the propensity for a β-turn at the N-terminus of the peptide.     

A concise methodology for the stereoselective synthesis of O-glycosylated amino acid building blocks: complete 1HNMR assignments and their application in solid-phase glycopeptide synthesis

A facile strategy for the stereoselective synthesis of suitably protected O-glycosylated amino acid building blocks, namely, N^α-Fmoc-Ser-[Ac₄-β-d -Gal-(1-3)-Ac₂α or β-d -GalN₃]-OPfp and N^α-Fmoc-Thr-[Ac₄-β-d -Gal-(1-3)-Ac₂-α or β-d -GalN₃]-OPfp is described. What is new and novel in this report is that Koenigs-Knorr type glycosylation of an aglycon serine/threonine derivative (i.e. N^α-Fmoc-Ser-OPfp or N^α-Fmoc-Thr-OPfp) with protected β-d -Gal(1-3)-d -GalN₃ synthon mediated by silver salts resulted in only α-and/or β-isomers in excellent yields under two different reaction conditions. The subtle differences in stereoselectivity were demonstrated clearly when glycosylation was carried out using only AgClO₄ at -40°C which afforded α-isomer in a quantitative yield (α:β= 5:1). On the other hand, the β-isomer was formed exclusively when the reaction was performed in the presence of Ag₂CO₃AgClO₄ at room temperature. A complete assignment of ¹H resonances to individual sugar ring protons and the characteristic anomeric α-1H and β-1H in Ac₄Galβ(1-3)Ac₂GalN₃α and/or β linked to Ser/Thr building blocks was accomplished unequivocally by two-dimensional double-quantum filtered correlated spectroscopy and nuclear Overhauser enhancement and exchange spectroscopy NMR experiments. An unambiguous structural characterization and documentation of chemical shifts, including the coupling constants for all the protons of the aforementioned a- and p-isomers of the O-glycosylated amino acid building blocks carrying protected β-d -Gal(1-3)-d -GalN₃, could serve as a template in elucidating the three-dimensional structure of glycoproteins. The synthetic utility of the building blocks and versatility of the strategy was exemplified in the construction of human salivary mucin (MUC7)-derived, O-linked glycopeptides with varied degrees of glycosylation by solid-phase Fmoc chemistry. Fmoc/tert-butyl-based protecting groups were used for the peptidic     

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.     

A crystal-state,solution and theoretical study of the preferred conformation of linear Cα,α-diphenylglycine derivatives and dipeptides with potential anticonvulsant activity

Several linear molecules containing the C^α,α-diphenylglycine residue were prepared as potential anticonvulsants. The conformational preferences of the C^α,α-diphenylglycine residue were assessed in these synthetic derivatives and dipeptides by X-ray diffraction, FTIR absorption and ¹H NMR techniques, and by conformational energy computations. Five (out of six) derivatives adopt the fully extended C₅ conformation in the crystal state. This intramolecularly H-bonded form is largely populated in chloroform solution in all the derivatives investigated. Conformational energy computations in vacuo support the view that the intramolecularly H-bonded C₇-ring form is the most stable structure for these compounds. Only one linear derivative exhibits a (modest) anticonvulsant activity.     

A combined extended and helical backbone for Boc‐(Ala‐Leu‐Ac7c‐)2‐OMe*

Abstract: The structure of the peptide Boc‐Ala‐Leu‐Ac₇c‐Ala‐Leu‐Ac₇c‐OMe (Ac₇c,1‐aminocycloheptane‐1‐carboxylic acid) is described in crystals. The presence of two Ac₇c residues was expected to stabilize a 3₁₀‐helical fold. Contrary to expectation the structural analysis revealed an unfolded amino terminus, with Ala(1) adopting an extended β‐conformation (φ = ?93°,ψ = 112°). Residues 2–5 form a 3₁₀‐helix, stabilized by three successive intramolecular hydrogen bonds. Notably, two NH groups Ala(1) and Ac₇c(3) do not form any hydrogen bonds in the crystal. Peptide assembly appears to be dominated by packing of the cycloheptane rings that stack against one another within the molecule and also throughout the crystal in columns.     

Intramolecular water bridge and a distorted trans peptide bond in the crystal structure of α-L-glutamyl-L-aspartic acid hydrate

The crystal structure of the monohydrated form of α-L-glutamyl-L-aspartic acid, C₁₉H₁₄N₂O₇ · H₂O, has been determined from three-dimensional X-ray diffractometer data. The dipeptide crystallizes in the triclinic space group P1 with one formula unit in a cell of dimensions a = 7.806(3), b = 8.473(5), c = 4.965(2)Å, α = 101.50(3), β = 100.81(3), γ = 104.72(3)°. The structure was solved by direct methods and refined by full-matrix least-squares methods to a final value of the weighted R factor (on F) of 0.047 based on 1647 unique observations with I ≥ 0.01 (I). The dipeptide crystallizes as a zwitterion with the amino terminus protonated and the main chain carboxyl group ionized. The peptide bond conformation is trans, though the ω angle of 161.3° is highly distorted from the ideal 180° value. The adoption of an unusual 13-membered “intramolecularly” hydrogen bonded ring structure with resulting α-turn character is responsible for distortion of the peptide bond. The solid-state conformation of the hydrate thus differs considerably from the previously reported unhydrated pseudopolymorphic structure of α-L-Glu-L-Asp.