Empirical rules predicting conformation of cyclic tetrapeptides from primary structure

A useful set of empirical rules is put forward to predict the conformations of cyclic tetrapeptides and cyclic tetradepsipeptides on the basis of primary structure, briefly presented as follows: 1. A conformation allowing an intramolecular hydrogen bond (IMHB) of γ-turn is preferred, and an ester bond always adopts a trans form. 2. On a right-handed peptide ring, the carbonyl group acylating a D residue is oriented to the upper side of the main ring. 3. The carbonyl group acylating a d proline or an N-methyl-d -amino acid residue is oriented to the lower side of the ring, forming a cis bond. 4. The lddl configurational sequence adopts a cis-trans-cis-trans backbone with C_i symmetry. 5. A glycine residue behaves as a d residue in an l -peptide. Conformations of cyclotetrapeptides containing two glycine residues at diametric positions or containing an N-methyl-dehydroamino acid residue are predicted by use of appendices of rule 5. Almost all conformations of cyclic tetrapeptides are predicted by these rules. Energetical rationalization of the rules and prediction of possible new conformations are described. Conformations of cyclo (-l -Pro-l -Leu-d -Tyr(Me)-l -Ile-)(1) and cyclo (-l -Pro-d -Leu-d -Tyr(Me)-l -Ile)(2) are compared. Results of n.m.r. experiments showed that compound 1 adopts a unique cis-trans-trans-trans backbone with a γ-turn IMHB, and 2 has a cis-trans-cis-trans backbone with C_i symmetry. These observations confirmed the rules described above. Peptides 1 and 2 are the first diastereomeric peptides with trans (ld ) and cis (dd ) secondary amide bonds.     

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.     

Conformational investigation of αβ-dehydropeptides

Solution conformations of three series of model peptides, homochiral Ac-Pro-L-Xaa-NHCH₃ and heterochiral Ac-Pro-D-Xaa-NHcH₃ (Xaa = Val, Phe, Leu, Abu. Ah) as well as αβ-unsaturated Ac-Pro-ΔXaa-NHCH₃ [Δ Xaa =ΔVal, (Z)-ΔPhe, (Z)-ΔLeu, (Z)-ΔAbu] were investigated in CDCl₃ and CH₂Cl₂ by ¹H-, ¹³C-NMR, and FTIR spectroscopy. NH stretching absorption spectra, solvent shifts Δδ for NH (Xaa) and NHCH₃ on going from CDCl₃ to (CD₃)₂SO, diagnostic interresidue proton NOEs, and trans-cis isomer ratios were examined. These studies performed showed the essential difference in conformational propensities between homochiral peptides (L-Xaa) on the one hand and heterochiral (D-Xaa) and αβ-dehydropeptides (ΔXaa) on the other. Former compounds are conformationally flexible with an inverse γ-bend, a β-turn, and open forms in an equilibrium depending on the nature of the Xaa side chain. Conformational preferences of heterochiral and αβ-dehydropeptides are very similar, with the type-II β-turn as the dominating structure. There is no apparent correlation between conformational properties and the nature of the Xaa side chain within the two groups. The β-turn formation propensity seems to be somewhat greater in αβ-unsaturated than in heterochiral peptides, but an estimation of β-folded conformers is risky.     

Conformational investigation of α,β-dehydropeptides

Conformations of three series of model peptides: homochiral Ac-Pro-L-Xaa-NHCH₃ and heterochiral Ac-Pro-D-Xaa-NHCH₃ (Xaa=Phe, Val, Leu. Abu. Ala) as ivell as α,β-dehydro Ac-Pro-ΔXaa-NHCH_s [ΔXaa = (Z)-ΔPhe, ΔVal. (Z)-ΔLeu, (Z)-ΔAbu] were investigated by CD spectroscopy in 2 % dichloromethanecyclohexane, trifluoroethanol. water. and occasionally in other solvents. The spectra of homochiral peptides show a significant solvent dependence. Folded structures are present in 2% dichloromethane-cyclohexane and unordered ones occur in water. The folded conformers are of the inverse γ-turn type for all the peptides but Ac-Pro-L-Phe-NHCH₃ for which the type-I β-turn is preferred. The changes in the spectra of the heterochiral peptides are limited. The compounds adopt the typc-II β–turn in 2% dichloromethanecyclohexane, represented by class B spectra, and retain this conformation in water as well as in fluorinated alcohols but not always to a full extent. The CD spectra of the unsaturated peptides in 2%, dichloromethanecyclohexane, although they cannot be assigned to any common spectral class, must be attributed to the βII-turn conformation as determined for these coinpounds by NMR and IR spectroscopy. The CD spectra of dehydropeptides exhibit a considerable solvent dependence and suggest unordered structures in water.     

Motifs and conformational analysis of amino acid residues adjoining β-turns in proteins

Using a data set of 250 non-homologous high-resolution globular proteins, a systematic analysis of the conformations that precede and succeed (positions i and i+3) the various classical β-turn types has been carried out. The collective conformation of a specific β-turn type, including the flanking positions, termed motif, has been studied. In all the four turn types, the majority of examples are preceded and succeeded by extended conformation. Some of the other observations are: (1) In a type I β-turn, Gly at position i+ 3 has a higher favorability to occur with positive ø and does not prefer the major motif βα_R-α_R-β. (2) The left-handed alpha;-helical conformation (alpha;_L) is not preferred at both the flanking positions for type I'and II β-turns, (3) The β–β motif is favourable for all the turn types and the motif β–α_L very highly favourable for type I. © Munksgaard 1996.     

Conformational studies on β-bend containing a cis peptide unit

Conformational studies have been carried out on the X-cis-Pro tripeptide system (a system of three linked peptide units, in the trans-cis-trans configuration) using energy minimization techniques. For X, residues Gly, L-Ala, D-Ala and L-Pro have been used. The energy minima have been classified into different groups based upon the conformational similarity. There are 15, 20, 18 and 6 minima that are possible for the four cases respectively arid these fall into 11 different groups. A study of these minima shows that, (i) some minima contain hydrogen bonds - either 4→1 or 1→2 type, (ii) the low energy minima qualify themselves as bend conformations, (iii) cis′ and trans′ conformations are possible for the prolyl residue as also the C^γ-endo and C^γ-exo puckerings, and (iv) for Pro-cis-Pro, cis′ at the first prolyl residue is ruled out, due to the high energy. The available crystal structure data on proteins and peptides, containing cis-Pro segment have been examined with a view to find the minima that occur in solid state. The data from protein show that they fall under two groups. The conformation at X in X-cis-Pro is near extended when it is a non-glycyl residue. In both peptides and proteins there exists a preference for trans′ conformation at prolyl residue over cis′ when X is a non-glycyl residue. The minima obtained can be useful in modelling studies.     

Synthesis and conformational analysis of two 2-oxopiperazine-containing tetrapeptide analogues

One unsubstituted and one stereoselectively prepared 3-(S)-substituted-2-oxopiperazine have been used as dipeptide templates to generate tetrapeptide analogues. NMR analysis shows that these tetrapeptide analogues present an inverse γ-turn conformation in chloroform.     

Synthesis and solution structure of an S-glycosylated cyclic hexapeptide

Synthesis and conformational analysis of the S-glycosylated cyclic hexapeptide cyclo(-d -Pro¹-Phe²-Cys³(tetra-O-acetyl-β-d -galactopyranosyl)-Trp⁴-Lys(Z)⁵-Phe⁶-) I was carried out to examine the influence of a saccharide residue in position i of a standard β-turn on the formation of reverse turns and on the biological activity. Synthesis was carried out in the liquid phase employing a galactosylated cysteine building block. The cyclization reagents DPPA/NaHCO₃ avoided high dilution conditions. Spectroscopic data were extracted from homo- and heteronuclear 2D-NMR techniques (TOCSY, NOESY, HMQC, HMQC-TOCSY, HMBCS-270). For structural refinement restrained molecular dynamics (MD) simulations in vacuo and with explicit DMSO as solvent were performed. Finally, simulations in DMSO without experimental restraints provided insight in stability and dynamics of the structural model. A comparison of the S-glycosylated Cys³ peptide with the analogous Thr³ peptide exhibits a similar overall conformation of the hexapeptide [βII’d -Pro-Phe and another β-turn about Trp⁴-Lys⁵(Z)]. However, the latter shows a distinct dynamic flip βI, βII in the glycopeptide, whereas the Thr-analogue only populates βI. This influence is attributed to a βI stabilizing effect of a hydrogen bridge of Thr-O, in position i to the NH of the amino acid in position i+ 2, which is lacking in the glycosylated compound.     

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.     

Conformationally restrained peptides: crystal structure of tert-butyloxycarbonyl-L-alanyl-D-alanyl-D-aminosuccinyl-glycyl-L-alanine methyl ester

The solid-state structure of a heterochiral peptide embodying a D-aminosuccinyl peptide (D-ASU) and a D-Ala was studied in order to analyse the effects of Asu and amino acids with inverse chirality on peptide conformation. The crystal structure has been determined by X-ray diffraction techniques and refined to a final R factor of 0.043. The molecule adopts an unusual overall 'S-shape’ conformation due to two consecutive type II β-turns. In this molecule it is possible to compare a type II β-bend conformation (L-Ala¹-D-Ala²) favoured by the presence of a D-residue at second corner to a type II β-turn (D-Asu³-Gly⁴) favoured by the presence of a D-ASU residue at first corner. In agreement with previous studies, this structure confirms that the Asu has a high propensity to adopt a type II or II′β-bend conformation and that it may be used as a strong determinant of these structural motifs. © Munksgaard 1996.     

N-Methyl peptides

The natural occurrence of N-methyl peptides in various plant metabolites has made N-methylation a subtle and attractive possible modification for structure-activity relationship studies of endogeneous peptides. However, little is known about the conformational specificity induced by the N-methylation of a given peptide, and particularly concerning the β-turn conformation. A spectroscopic investigation (i.r., n.m.r., CD) and X-ray diffraction experiments have been carried out on tBuCO-X-Me-Y-NHMe blocked dipeptides (X = Gly, L-Ala, L-Pro, and Y = Gly, and L- or D-Ala, Leu, Phe) with reference to the homologous desmethylated species. The influence of the N-methylation on conformation depends to a large extent on the chirality of the X and Y residues. Homochiral sequences are the most affected, with a strong preference for the βVI-folded conformation containing a middle cis amide bond. Heterochiral sequences are essentially unaffected and retain the βII-folded conformation with a trans middle amide bond. Glycine-containing sequences undergo a more complex perturbation according to the X or Y position of the Gly residue. The available data for larger N-methyl peptides are consistent with our observations, suggesting that these simple dipeptides well reflect the conformational perturbations induced by N-methylation on the β-turn conformation.     

Simulations of conformers of tuftsin and a cyclic tuftsin analog

The conformational properties of the configurational isomers of tuftsin, a linear tetrapeptide with the sequence Thr-Lys-Pro-Arg, were investigated with six 1 ns molecular dynamics simulations in explicit water and in a 1.0 M NaCl solution. The average conformation of the cis isomer is a type VI β-turn. Our results indicate that water-peptide hydrogen bonding, in addition to intramolecular hydrogen bonds, stabilizes the cis conformer. The trans isomer is neither a β- nor a γ-turn. Results are compared with parallel studies on a cyclic analog of tuftsin, cyclo(Thr-Lys-Pro-Arg-Gly). The addition of salt does not influence the backbone conformation of the peptide. Differences between the structures are confined to the side-chain orientations of the Lys and Arg residues. © Munksgaard 1995.     

Esters of choline and beta-trimethylammoniopropionic acid: geometrical isomerism and anti-acetylcholinesterase activity

The preparation of the choline esters of cis- and trans-4-t-butylcyclohexanecarboxylic acid is reported. The similar inhibitory potency displayed by these isomers towards the acetylcholinesterase catalysed hydrolysis of acetylcholine is explained on the basis of the binding of a thermodynamically unstable conformation of the cis-isomer to the active site. Similar studies employing the β-trimethylammoniopropionate esters of cis- and trans-4-t-butylcyclohexanol suggest that the “reverse esters” do not bind to the active site in an identical manner to the acylcholines.     

Structure of cyclic peptides: the crystal and solution conformation of cyclo(Phe-Phe-Aib-Leu-Pro)

A solid-state and solution conformation analyses of the cyclopentapeptide cyclo(Phe-Phe-Aib-Leu-Pro) has been carried out by X-ray diffraction and nuclear magnetic resonance techniques. The structure of the hexagonal crystals, grown from a methanol solution [a=b= 16.530(4) Å, c= 21.356(9) Å, space group P6₅, Z = 6], shows the presence of one intramolecular N-H?O=C hydrogen bond with the formation of a γ-turn (C₇). The Aib³ residue, at the center of the γ-turn, presents unexpected values of the torsion angles [φ= 70.5° and ψ= -73.8°], which have been observed only once before for this helicogenic residue. A cis peptide bond occurs between Leu⁴ and Pro⁵; all other peptide bonds are trans. The overall conformation for the cyclopentapeptide with one cis-peptide bond on one side and an intramolecular γ-turn on the opposite side results in an equatorial topology of the side-chains of the Phe¹, Phe² and Leu⁴ residues. Indeed, the C^α-C^βand C^β-C^γ bonds of these residues lie approximately in the mean plane of the cyclic ring system. The structure is compared with data in the literature on cyclic pentapeptides. In addition the Pro-Phe-Phe moiety shows a conformation similar to that observed in other larger cyclic bioactive peptides, which indicates a reduced number of conformations for this sequence. The solution study was carried out in three different solvent systems: chloroform, acetonitrile and methanol in the temperature interval 220–300 K. In all three solvents the room temperature spectra show that the peptide is conformationally nonhomogeneous. In acetonitrile at low temperatures it is possible to reduce the conformational equilibrium to two predominant conformers which differ for the cis-trans isomerism of the Leu⁴-Pro⁵ peptide bond.     

Influence of serine in position i on conformation and dynamics of reverse turns

NMR spectroscopy has been employed for the conformational analysis of the cyclic hexapeptide cycle(-d -Pro¹-Ala²-Ser³(Bzl)-Trp⁴-Orn⁵(Z)-Tyr⁶-) with and without protecting groups on Ser³ and Orn⁵. This peptide sequence was derived from the active loop sequence of the α-amylase inhibitor Tendamistat (HOE 467). The aim was to investigate the role of serine in position i of a standard β-turn on the conformation and stabilization of this turn. Based on distance and torsion constraints from 2D NMR spectroscopic measurements in DMSO-d₆ solution, structure refinement was accomplished by restrained molecular dynamics (MD) simulations in vacuo and in DMSO. The analysis of both structures in solution reveals a considerable effect of the unprotected serine sidechain on the adjacent β-turn conformation. While in the protected peptide with Ser³(Bzl) a βII-turn is observed between Trp⁴ and Orn⁵, the deprotected compound reveals a βI-turn in this region. The βI-turn is stabilized by a backbone-sidechain hydrogen bond from Orn⁵N_αH to Ser³O_γ. Comparisons with other NMR-derived solution structures of cyclic model peptides and in some protein structures from literature reveal a general structural motif in the stabilization of βI-turns by serine in the i position through backbone-sidechain interactions. © Munksgaard 1995.     

Derivate des 2-Amino-1,2,3,4-tetrahydronaphthalins, 6. Mitt. IR-Spektroskopische Konformationsermittlung einiger 2-Amino-3-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthaline

Derivatives of 2-Amino-1,2,3,4-tetrahydronaphthalene, VI: IR-Spectroscopic Determination of the Conformational Equilibrium of Some 2-Amino-3-hydroxy-1,2,3,4-tetrahydronaphthalenes. The conformational characteristics of cis- and trans-2-amino-3-hydroxy-5,8-dimethoxytetralins and some N-substituted derivatives were investigated by analysing their IR spectra. A high degree of hydrogen bonding for the trans compounds and a preferred diequatorial conformation were established. The spectra of the cis isomers show the presence of a larger population of the rotamer with axial OH group. The scheme for the synthesis of cis-AT is presented.     

Solution conformations of the peptide backbone for DPDPE and its β-MePhe4-substituted analogs

The solution structures of DPDPE, a conformationally restricted pentapeptide with the sequence H-Tyr¹-d -Pen²-Gly³-Phe⁴-d -Pen⁵-OH, and its four β-MePhe⁴-substituted analogs were examined by a combined approach including the NMR measurements in DMSO and water as well as independent energy calculations. It was concluded that several low energy conformers of DPDPE backbone satisfy the NMR data obtained in this study as well as in previous studies by other authors. These possible solution conformers of DPDPE in both DMSO and water share virtually the same type of cyclic backbone structure, with the Gly³ residue in a conformation close to a γ-turn, and the Phe⁴ residue in a conformation close to α-helical torsion angles. They differ in the space arrangements of the flexible Tyr¹ moiety. The solution structures of the β-MePhe⁴-substituted analogs of DPDPE are interesting. For analogs with an S-configuration at the C^α atom in the Phe⁴ residue, the cyclic backbone conformations resemble those of DPDPE itself, whereas for analogs with an R-configuration at the C^α atom, the backbone conformation is somewhat different. This observation is in line with the high biological potencies and selectivities displayed by the former compounds but not by the latter ones. It was noted also that as far as the peptide backbone conformers are concerned, some of the possible DPDPE conformers in water are similar to the previously suggested model for the δ-receptor-bound conformation of DPDPE, becoming virtually identical to this conformation by rotating the side chains of the Tyr¹ and the Phe⁴ residues.     

s-cis,s-trans Isomerism about the Ala-Pro peptide bond in Nα-phospho- and Nα-phosphono-l-alanyl-l-prolines by 31P n.m.r.

Nα-(Phenethylphosphono)-l -alanyl-l -proline 1, a potent inhibitor of angiotensin converting enzyme, exhibits two ³¹P n.m.r. resonances (intensity ratio one to one), which exchange with a constant (k₁) of about 1 s^?1 and a free energy of activation ΔG*=～ 20kcal/mol at 23° in deuterated dimethylsulfoxide. Two resonances in exchange are also observed in deuterium oxide at pH 7.5. Thus the exchanging ³¹P resonances report the s-cis, s-trans conformational equilibrium about the alanyl-proline peptide bond. Similar results were observed with Nα-[(O-phenyl)-phenethylphosphono]-l -alanyl-l -proline 2. Nα -(O-phenylphospho)-l -alanyl-l -proline, 3 Nα-(O, O′-diphenylphospho)-l -alanyl-l -proline 4, and Nα-[2-(2-oxo-1, 3, 2-dioxaphosphiranyl)]-l -alanyl-l -proline 5 in deuterated dimethyl sulfoxide, deuterium oxide, and deuterochloroform. A ¹³C n.m.r. spectrum of 5 confirmed the presence of s-cis and s-trans resonances for the proline carbons in the same intensity ratio observed by ³¹P n.m.r.     

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.     

Structural features of thePip/AzPip couple in the crystalline state: influence of the relative AzPip location in an azadipeptide sequence upon the induced chirality and conformational characteristics

Abstract: Azapipecolic (AzPip) is a pipecolic (Pip) residue analogue containing a nitrogen atom in place of the C^αH group. AzPip was introduced into two reverse dipeptide sequences,Piv‐AzPip‐l ‐Ala‐NHiPr I and Boc‐l ‐Ala‐AzPip‐NHiPr II in order to evaluate, in the crystalline state, the influence of thel ‐Ala‐induced chirality upon the prochiral AzPip residue, and therefore the resulting conformational characteristics, according to the relative position of the AzPip residue. Piv‐dl ‐Pip‐NHMe III served as a control derivative for comparison between the properties of the two different heterocycles of Pip and AzPip residues. Piperidine and hexahydropyridazine rings have a few characteristics in common: chair conformation, axial disposition of the C‐terminal backbone substituent and the cisoid form of the N‐terminal tertiary amide function. An almost pure sp³ hybridization state is observed for the substituted nitrogen atom N^α, so that l ‐Ala induces an AzPip (R) or (S) chirality when it follows or precedes, respectively, the azaresidue in such a pseudodipeptide sequence. If both I and II compounds present a short NH…N contact between the sp² tertiary amide nitrogen atom and the NH of the next secondary amide function, whatever the chiral nature of the sequence, the heterochiral azadipeptide I adopts a rather totally extended conformation while the homochiral azadipeptide II is folded by a β‐VI turn‐like structure stabilized by a classical 4→1 intramolecular hydrogen bond.