Design,Synthesis, NMR‐Solution and X‐Ray Crystal Structure of N‐Acyl‐γ‐dipeptide Amides That Form a βII′‐Type Turn

Conformational analysis of γ‐amino acids with substituents in the 2‐position reveals that an N‐acyl‐γ‐dipeptide amide built of two enantiomeric residues of unlike configuration will form a 14‐membered H‐bonded ring, i.e., a γ‐peptidic turn (Figs. 1 – 3). The diastereoselective preparation of the required building blocks was achieved by alkylation of the doubly lithiated N‐Boc‐protected 4‐aminoalkanoates, which, in turn, are readily available from the corresponding (R)‐ or (S)‐α‐amino acids (Scheme 1). Coupling two such γ‐amino acid derivatives gave N‐acetyl and N‐[(tert‐butoxy)carbonyl] (Boc) dipeptide methyl amides ( 1 and 10 , resp.; Fig. 2, Scheme 2); both formed crystals suitable for X‐ray analysis, which confirmed the turn structures in the solid state (Fig. 4 and Table 4). NMR Analysis of the acetyl derivative 1 in CD₃OH, with full chemical‐shift and coupling assignments, and, including a 300‐ms ROESY measurement, revealed that the predicted turn structure is also present in solution (Fig. 5 and Tables 1 – 3). The results described here are yet another piece of evidence for the fact that more stable secondary structures are formed with a decreasing number of residues, and with increasing degree of predictability, as we go from α‐ to β‐ to γ‐peptides. Implications of the superimposable geometries of the actual turn segments (with amide bonds flanked by two quasi‐equatorial substituents) in α‐, β‐, and γ‐peptidic turns are discussed.     

Helix Formation and Folding in γ‐Peptides and Their Vinylogues

A complete overview of all possible periodic structures with characteristic H‐bonding patterns is provided for oligomers composed of γ‐amino acids (γ‐peptides) and their vinylogues by a systematic conformational search on hexamer model compounds employing ab initio MO theory at various levels of approximation (HF/6‐31G*, DFT/B3LYP/6‐31G*, SCRF/HF/6‐31G*, PCM//HF/6‐31G*). A wide variety of structures with definite backbone conformations and H‐bonds formed in forward and backward directions along the sequence was found in this class of foldamers. All formally conceivable H‐bonded pseudocycles between 7‐ and 24‐membered rings are predicted in the periodic hexamer structures, which are mostly helices. The backbone elongation in comparison to α‐ and β‐peptides allows several possibilities to realize identical H‐bonding patterns. In good agreement with experimental data, helical structures with 14‐ and 9‐membered pseudocycles are most stable. It is shown that the introduction of an (E)‐double bond into the backbone of the γ‐amino acid constituents, which leads to vinylogous γ‐amino acids, supports the folding into helices with larger H‐bonded pseudocycles in the resulting vinylogous γ‐peptides. Due to the considerable potential for secondary‐structure formation, γ‐peptides and their vinylogues might be useful tools in peptide and protein design and even in material sciences.     

Three‐Residue Turns in α/β‐Peptides and Their Application in the Design of Tertiary Structures

A new three‐residue turn was serendipitously discovered in α/β hybrid peptides derived from alternating C‐linked carbo‐β‐amino acids (β‐Caa) and L ‐Ala residues. The three‐residue β‐α‐β turn at the C termini, nucleated by a helix at the N termini, resulted in helix‐turn (HT) supersecondary structures in these peptides. The turn in the HT motif is stabilized by two H bonds—CO(i?2)–NH(i), with a seven‐membered pseudoring (γ turn) in the backward direction, and NH(i?2)–CO(i), with a 13‐membered pseudoring in the forward direction (i being the last residue)—at the C termini. The study was extended to generalize the new three‐residue turn (β‐α‐β) by using different α‐ and β‐amino acids. Furthermore, the HT motifs were efficiently converted, by an extension with helical oligomers at the C termini, into peptides with novel helix‐turn‐helix (HTH) tertiary structures. However, this resulted in the destabilization of the β‐α‐β turn with the concomitant nucleation of another three‐residue turn, α‐β‐β, which is stabilized by 11‐ and 15‐membered bifurcated H bonds. Extensive NMR spectroscopic studies were carried out to delineate the secondary and tertiary structures in these peptides, which are further supported by molecular dynamics (MD) investigations.     

Synthesis and Conformational Analysis of Hybrid α/β‐Dipeptides Incorporating S‐Glycosyl‐β2,2‐Amino Acids

We synthesized and carried out the conformational analysis of several hybrid dipeptides consisting of an α‐amino acid attached to a quaternary glyco‐β‐amino acid. In particular, we combined a S‐glycosylated β^2,2‐amino acid and two different types of α‐amino acid, namely, aliphatic (alanine) and aromatic (phenylalanine and tryptophan) in the sequence of hybrid α/β‐dipeptides. The key step in the synthesis involved the ring‐opening reaction of a chiral cyclic sulfamidate, inserted in the peptidic sequence, with a sulfur‐containing nucleophile by using 1‐thio‐β‐D ‐glucopyranose derivatives. This reaction of glycosylation occurred with inversion of configuration at the quaternary center. The conformational behavior in aqueous solution of the peptide backbone and the glycosidic linkage for all synthesized hybrid glycopeptides was analyzed by using a protocol that combined NMR experiments and molecular dynamics with time‐averaged restraints (MD‐tar). Interestingly, the presence of the sulfur heteroatom at the quaternary center of the β‐amino acid induced θ torsional angles close to 180° (anti). Notably, this value changed to 60° (gauche) when the peptidic sequence displayed aromatic α‐amino acids due to the presence of CH–π interactions between the phenyl or indole ring and the methyl groups of the β‐amino acid unit.     

A Modular Synthesis of Conformationally Preorganised Extended β‐Strand Peptidomimetics

A promising strategy for mediating protein–protein interactions is the use of non‐peptidic mimics of secondary structural protein elements, such as the α‐helix. Recent work has expanded the scope of this approach by providing proof‐of‐principle scaffolds that are conformationally biased to mimic the projection of side‐chains from one face of another common secondary structural element—the β‐strand. Herein, we present a synthetic route that has key advantages over previous work: monomers bearing an amino acid side‐chain were pre‐formed before rapid assembly to peptidomimetics through a modular, iterative strategy. The resultant oligomers of alternating pyridyl and six‐membered cyclic ureas accurately reproduce a recognition domain of several amino acid residues of a β‐strand, demonstrated herein by mimicry of the i, i+2, i+4 and i+6 residues.     

New Open‐Chain and Cyclic Tetrapeptides,Consisting of α‐, β2‐, and β3‐Amino‐Acid Residues,as Somatostatin Mimics – A Survey

Cyclo‐β‐tetrapeptides are known to adopt a conformation with an intramolecular transannular hydrogen bond in solution. Analysis of this structure reveals that incorporation of a β²‐amino‐acid residue should lead to mimics of ‘α‐peptidic β‐turns’ (cf. A, B, C ). It is also known that short‐chain mixed β/α‐peptides with appropriate side chains can be used to mimic interactions between α‐peptidic hairpin turns and G protein‐coupled receptors. Based on these facts, we have now prepared a number of cyclic and open‐chain tetrapeptides, 7 – 20 , consisting of α‐, β²‐, and β³‐amino‐acid residues, which bear the side chains of Trp and Lys, and possess backbone configurations such that they should be capable of mimicking somatostatin in its affinity for the human SRIF receptors (hsst_1–5). All peptides were prepared by solid‐phase coupling by the Fmoc strategy. For the cyclic peptides, the three‐dimensional orthogonal methodology (Scheme 3) was employed with best success. The new compounds were characterized by high‐resolution mass spectrometry, NMR and CD spectroscopy, and, in five cases, by a full NMR‐solution‐structure determination (in MeOH or H₂O; Fig. 4). The affinities of the new compounds for the receptors hsst_1–5 were determined by competition with [¹²⁵I]LTT‐SRIF₂₈ or [¹²⁵I] [Tyr¹⁰]‐CST₁₄. In Table 1, the data are listed, together with corresponding values of all β‐ and γ‐peptidic somatostatin/Sandostatin^® mimics measured previously by our groups. Submicromolar affinities have been achieved for most of the human SRIF receptors hsst_1–5. Especially high, specific binding affinities for receptor hsst₄ (which is highly expressed in lung and brain tissue, although still of unknown function!) was observed with some of the β‐peptidic mimics. In view of the fact that numerous peptide‐activated G protein‐coupled receptors (GPCRs) recognize ligands with turn structure (Table 2), the results reported herein are relevant far beyond the realm of somatostatin: many other peptide GPCRs should be ‘reached’ with β‐ and γ‐peptidic mimics as well, and these compounds are proteolytically and metabolically stable, and do not need to be cell‐penetrating for this purpose (Fig. 5).     

β‐Peptide Conjugates: Syntheses and CD and NMR Investigations of β/α‐Chimeric Peptides,of a DPA‐β‐Decapeptide,and of a PEGylated β‐Heptapeptide

β³‐Peptides consisting of six, seven, and ten homologated proteinogenic amino acid residues have been attached to an α‐heptapeptide (all d‐ amino acid residues; 4 ), to a hexaethylene glycol chain (PEGylation; 5c ), and to dipicolinic acid (DPA derivative 6 ), respectively. The conjugation of the β‐peptides with the second component was carried out through the N‐termini in all three cases. According to NMR analysis (CD₃OH solutions), the (M)‐3₁₄‐helical structure of the β‐peptidic segments was unscathed in all three chimeric compounds (Figs. 2, 4, and 5). The α‐peptidic section of the α/β‐peptide was unstructured, and so was the oligoethylene glycol chain in the PEGylated compound. Thus, neither does the appendage influence the β‐peptidic secondary structure, nor does the latter cause any order in the attached oligomers to be observed by this method of analysis. A similar conclusion may be drawn from CD spectra (Figs. 1, 3, and 5). These results bode well for the development of delivery systems involving β‐peptides.     

Induced Folding of Protein‐Sized Foldameric β‐Sandwich Models with Core β‐Amino Acid Residues

The mimicry of protein‐sized β‐sheet structures with unnatural peptidic sequences (foldamers) is a considerable challenge. In this work, the de novo designed betabellin‐14 β‐sheet has been used as a template, and α→β residue mutations were carried out in the hydrophobic core (positions 12 and 19). β‐Residues with diverse structural properties were utilized: Homologous β³‐amino acids, (1R,2S)‐2‐aminocyclopentanecarboxylic acid (ACPC), (1R,2S)‐2‐aminocyclohexanecarboxylic acid (ACHC), (1R,2S)‐2‐aminocyclohex‐3‐enecarboxylic acid (ACEC), and (1S,2S,3R,5S)‐2‐amino‐6,6‐dimethylbicyclo[3.1.1]heptane‐3‐carboxylic acid (ABHC). Six α/β‐peptidic chains were constructed in both monomeric and disulfide‐linked dimeric forms. Structural studies based on circular dichroism spectroscopy, the analysis of NMR chemical shifts, and molecular dynamics simulations revealed that dimerization induced β‐sheet formation in the 64‐residue foldameric systems. Core replacement with (1R,2S)‐ACHC was found to be unique among the β‐amino acid building blocks studied because it was simultaneously able to maintain the interstrand hydrogen‐bonding network and to fit sterically into the hydrophobic interior of the β‐sandwich. The novel β‐sandwich model containing 25 % unnatural building blocks afforded protein‐like thermal denaturation behavior.     

Synthesis,and Helix or Hairpin‐Turn Secondary Structures of ‘Mixed’ α/β‐Peptides Consisting of Residues with Proteinogenic Side Chains and of 2‐Amino‐2‐methylpropanoic Acid (Aib)

Twelve peptides, 1 – 12 , have been synthesized, which consist of alternating sequences of α‐ and β‐amino acid residues carrying either proteinogenic side chains or geminal dimethyl groups (Aib). Two peptides, 13 and 14 , containing 2‐methyl‐3‐aminobutanoic acid residues or a ‘random mix’ of α‐, β²‐, and β³‐amino acid moieties were also prepared. The new compounds were fully characterized by CD (Figs. 1 and 2), and ¹H‐ and ¹³C‐NMR spectroscopy, and high‐resolution mass spectrometry (HR‐MS). In two cases, 3 and 14 , we discovered novel types of turn structures with nine‐ and ten‐membered H‐bonded rings forming the actual turns. In two other cases, 8 and 11 , we found 14/15‐helices, which had been previously disclosed in mixed α/β‐peptides containing unusual β‐amino acids with non‐proteinogenic side chains. The helices are formed by peptides containing the amino acid moiety Aib in every other position, and their backbones are primarily not held together by H‐bonds, but by the intrinsic conformations of the containing amino acid building blocks. The structures offer new possibilities of mimicking peptide–protein and protein–protein interactions (PPI).     

Synthesis and Conformational Studies of a Hybrid Cyclic Peptide Based on cis‐β‐Furanoid Sugar Amino Acid (FSAA) and Ornithine

The conformational control of a 14‐helix nucleating template, cis‐β‐furanoid sugar amino acid (FSAA), over a flexible δ‐amino acid, ornithine is studied in a FSAA‐ornithine cyclic tetrapeptide. Extensive NMR and MD studies reveal that the cyclic peptide adopts a three‐dimentional bowl‐shape cavity, which promotes six‐ and seven‐membered intra‐ and inter‐residue H‐bonding, in polar and non‐polar solvents, respectively.     

The Design of α/β‐Peptides: Study on Three‐Residue Turn Motifs and the Influence of Achiral Glycine on Helix and Turn

Novel three‐residue helix‐turn secondary structures, nucleated by a helix at the N terminus, were generated in peptides that have ‘β‐Caa‐L ‐Ala‐L ‐Ala,’ ‘β‐Caa‐L ‐Ala‐γ‐Caa,’ and ‘β‐Caa‐L ‐Ala‐δ‐Caa’ (in which β‐Caa is C‐linked carbo‐β‐amino acid, γ‐Caa is C‐linked carbo‐γ‐amino acid, and δ‐Caa is C‐linked carbo‐δ‐amino acid) at the C terminus. These turn structures are stabilized by 12‐, 14‐, and 15‐membered (mr) hydrogen bonding between NH(i)/CO(i+2) (i+2 is the last residue in the peptide) along with a 7‐mr hydrogen bond between CO(i)/NH(i+2). In addition, a series of α/β‐peptides were designed and synthesized with alternating glycine (Gly) and (S)‐β‐Caa to study the influence of an achiral α‐residue on the helix and helix‐turn structures. In contrast to previous results, the three ‘β–α–β’ residues at the C terminus (α‐residue being Gly) are stabilized by only a 13‐mr forward hydrogen bond, which resembles an α‐turn. Extensive NMR spectroscopic and molecular dynamics (MD) studies were performed to support these observations. The influence of chirality and side chain is also discussed.     

Unprecedented Chain‐Length‐Dependent Conformational Conversion Between 11/9 and 18/16 Helix in α/β‐Hybrid Peptides

α,β‐Hybrid oligomers of varying lengths with alternating proteogenic α‐amino acid and the rigid β^2,3,3‐trisubstituted bicyclic amino acid ABOC residues were studied using both X‐ray crystal and NMR solution structures. While only an 11/9 helix was obtained in the solid state regardless of the length of the oligomers, conformational polymorphism as a chain‐length‐dependent phenomenon was observed in solution. Consistent with DFT calculations, we established that short oligomers adopted an 11/9 helix, whereas an 18/16 helix was favored for longer oligomers in solution. A rapid interconversion between the 11/9 helix and the 18/16 helix occurred for oligomers of intermediate length.     

Linear,Peptidase‐Resistant β2/β3‐Di‐ and α/β3‐Tetrapeptide Derivatives with Nanomolar Affinities to a Human Somatostatin Receptor,Preliminary Communication

N‐Acyl‐β²/β³‐dipeptide‐amide somatostatin analogs, 5 – 8 , with β²‐HTrp‐β³‐HLys ('natural' sequence) and β²‐HLys‐β³‐HTrp (retro‐sequence) have been synthesized (in solution). Depending on their relative configurations and on the nature of the terminal N‐acyl and terminal C‐amino group, the linear β‐dipeptide derivatives have affinities for the human receptor hsst 4, ranging from 250 to >10000 nanomolar (Fig. 3). Also, N‐Ac‐tetrapeptide amides 9 and 10 , which contain one α‐ and three β‐amino acid residues (N‐β‐α‐β‐β‐C), have been prepared (solid‐phase synthesis), with the natural (Phe, Trp, Lys, Thr) and the retro‐sequence (Thr, Lys, Trp, Phe) of side chains and with two different configurations, each, of the two central amino acid residues. The novel ‘mixed', linear α/β‐peptides have affinities for the hsst 4 receptor ranging from 23 to >10000 nanomolar (Fig. 4), and, like ‘pure' β‐peptides, they are completely stable to a series of proteolytic enzymes. Thus, the peptidic turn of the cyclic tetradecapeptide somatostatin (Fig. 1) can be mimicked by simple linear di‐ and tetrapeptides. The tendency of β‐dipeptides for forming hydrogen‐bonded rings is confirmed by calculations at the B3LYP/6‐31G(d,p) level (Fig. 2). The reported results open new avenues for the design of low‐molecular‐weight peptidic drugs.     

β‐Hairpins Generated from Hybrid Peptide Sequences Containing both α‐ and β‐Amino Acids

The incorporation of the β‐amino acid residues into specific positions in the strands and β‐turn segments of peptide hairpins is being systematically explored. The presence of an additional torsion variable about the C(α) C(β) bond (θ) enhances the conformational repertoire in β‐residues. The conformational analysis of three designed peptide hairpins composed of α/β‐hybrid segments is described: Boc‐Leu‐Val‐Val‐^DPro‐β Phe ‐Leu‐Val‐Val‐OMe ( 1 ), Boc‐Leu‐Val‐β Val ‐^DPro‐Gly‐β Leu ‐Val‐Val‐OMe ( 2 ), and Boc‐Leu‐Val‐β Phe ‐Val‐^DPro‐Gly‐Leu‐β Phe ‐Val‐Val‐OMe ( 3 ). 500‐MHz ¹H‐NMR Analysis supports a preponderance of β‐hairpin conformation in solution for all three peptides, with critical cross‐strand NOEs providing evidence for the proposed structures. The crystal structure of peptide 2 reveals a β‐hairpin conformation with two β‐residues occupying facing, non‐H‐bonded positions in antiparallel β‐strands. Notably, βVal(3) adopts a gauche conformation about the C(α) C(β) bond (θ=+65°) without disturbing cross‐strand H‐bonding. The crystal structure of 2 , together with previously published crystal structures of peptides 3 and Boc‐β Phe ‐β Phe ‐^DPro‐Gly‐β Phe ‐β Phe ‐OMe, provide an opportunity to visualize the packing of peptide sheets with local ‘polar segments' formed as a consequence of reversal peptide‐bond orientation. The available structural evidence for hairpins suggests that β‐residues can be accommodated into nucleating turn segments and into both the H‐bonding and non‐H‐bonding positions on the strands.     

Fine Tuning of β‐Peptide Foldamers: a Single Atom Replacement Holds Back the Switch from an 8‐Helix to a 12‐Helix

Cyclic homologated amino acids are important building blocks for the construction of helical foldamers. N‐aminoazetidine‐2‐carboxylic acid (AAzC), an aza analogue of trans‐2‐aminocyclobutanecarboxylic acid (tACBC), displays a strong hydrazino turn conformational feature, which is proposed to act as an 8‐helix primer. tACBC oligomers bearing a single N‐terminal AAzC residue were studied to evaluate the ability of AAzC to induce and support an 8‐helix along the oligopeptide length. While tACBC homooligomers assume a dominant 12‐helix conformation, the aza‐primed oligomers preferentially adopt a stabilized 8‐helix conformation for an oligomer length up to 6 residues. The (formal) single‐atom exchange at the N terminus of a tACBC oligomer thus contributes to the sustainability of the 8‐helix, which resists the switch to a 12‐helix. This effect illustrates atomic‐level programmable design for fine tuning of peptide foldamer architectures.     

The Cyclo‐β‐Tetrapeptide (β‐HPhe‐β‐HThr‐β‐HLys‐β‐HTrp): Synthesis,NMR Structure in Methanol Solution,and Affinity for Human Somatostatin Receptors

The known solid‐state structure (Fig. 1, top) of cyclo(β‐HAla)₄ was used to model the structure of the title compound 1 as a prospective somatostatin mimic (Fig. 1, bottom). The synthesis started with the N‐protected natural amino acids Boc‐Phe‐OH, Boc‐Trp‐OH, Boc‐Lys(2‐Cl‐Z)‐OH, and Boc‐Thr(OBn)‐OH, which were homologated to the corresponding β‐amino‐acid derivatives (Scheme 1) and coupled to the β‐tetrapeptide Boc‐β‐HTrp‐β‐HPhe‐β‐HThr(OBn)‐β‐HLys(2‐Cl‐Z)‐OMe ( 16 ); the (N‐Me)‐β‐HThr‐(N‐Me)‐β‐HPhe analog 17 was also prepared. C‐ and N‐terminal deprotection and cyclization through the pentafluorophenyl ester gave the insoluble β‐tetrapeptide with protected Thr and Lys side chains ( 18 ). Solubilization and debenzylation could only be effected in LiCl‐containing THF (ca. 10% yield; with ca. 55% recovery). HPLC Purification provided a sample of the title compound 1 , the structure of which, as determined by NMR‐spectroscopy (Fig. 2, left) was drastically different from the `theoretical' model (Fig. 1). There is a transannular H‐bond dividing the macrocyclic 16‐membered ring, thus forming a ten‐ and a twelve‐membered H‐bonded ring, the former mimicking, or actually being superimposable on, an α‐peptidic so‐called β‐turn. Still, the four side chains occupy equatorial positions on the ring, as planned, albeit with somewhat different geometry as compared to the `original'. The cyclo‐β‐tetrapeptide has micromolar affinities to the human somatostatin receptors (hsst 1 – 5). Thus, we have demonstrated for the first time that it is possible to mimic a natural peptide hormone with a small β‐peptide. Furthermore, we have discovered a simple way to construct the ubiquitous β‐turn motif with β‐peptides (which are known to be stable to mammalian peptidases).     

Improved treatment of cyclic β‐amino acids and successful prediction of β‐peptide secondary structure using a modified force field: AMBER*C

We added parameters to the AMBER* force field to model cyclic β‐amino acid derivatives more accurately within the commonly used MacroModel program. In an effort to generate an improved treatment of cyclohexane and cyclopentane conformational preferences, carbon–carbon torsional parameters were modified and incorporated into a force field we call AMBER*C. Simulation of trans‐2‐aminocyclohexanecarboxylic acid (trans‐ACHC) and trans‐2‐aminocyclopentanecarboxylic acid (trans‐ACPC) derivatives using AMBER*C produces more realistic energy differences between (pseudo)diaxial and (pseudo)diequatorial conformations than does simulation using AMBER*. AMBER*C molecular dynamics simulations more accurately reproduce the experimental hydrogen‐bonding tendencies of simple diamide derivatives of trans‐ACHC and trans‐ACPC than do simulations using the AMBER* force field. More importantly, this modified force field allows accurate qualitative prediction of the helical secondary structures adopted by β‐amino acid homo‐oligomers. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 763–773, 2000     

A microscopic view of a helical poly(γ‐peptide): Molecular dynamics simulations of a 20‐residue un‐ionized poly(γ‐D‐glutamic acid) in water

We present a molecular dynamics study of the helical conformation of the naturally occurring poly(γ‐D ‐glutamic acid) in the un‐ionized state. The study was conducted in both aqueous solution and gas‐phase considering a 20 residue polypeptide. The results indicated that the left‐handed helix with 19‐membered ring hydrogen bonds set between the CO of the amide group i and the NH of amide group i + 3 is very stable in aqueous solution. This conformation was recently proposed for this poly(γ‐amino acid) from a conformational search study. A detailed picture of the most relevant structural details of the helical conformation of poly(γ‐D ‐glutamic acid) is provided.     

Conformational structure of peptides containing dehydroalanine: Formation of β‐bend ribbon structure

α,β‐Unsaturated amino acids (dehydroamino acids) have been found in naturally occurring antibiotics of microbial origin and in some proteins. Due to the presence of the C_αC_β double bond, the dehydroamino acids influence the main‐chain and the side‐chain conformations. The lowest‐energy conformational state of the model tripeptides, Ac–X–ΔAla–NHMe, (X=Ala, Val, Leu, Abu, or Phe) corresponds to ϕ₁=−30°, ψ₁=120° and ϕ₂=ψ₂=30°. This structure is stabilized by the hydrogen bond between CO of the acetyl group and the NH of the amide group, resulting in the formation of a 10‐membered ring. In the model heptapeptide containing ΔAla at alternate position with Ala, Abu, and Leu, the lowest‐energy conformation corresponds to ϕ=−30° and ψ=120° for all the Ala, Abu, and Leu residues and ϕ=ψ=30° for all ΔAla residues. A graphical view of the molecule in this conformation reveals the formation of three hydrogen bonds involving the CO moiety of the ith residue and the NH moiety of the i+3th residue, resulting in a 10‐membered ring formation. In this structure, only alternate peptide bonds are involved in the intramolecular hydrogen‐bond formation unlike the helices and it has been named the β‐bend ribbon structure. The helical structures were predicted to be the most stable structures in the heptapeptide Ac–(Aib–ΔAla)₃–NHMe with ϕ=±30°, ψ=±60° for Aib residues and ϕ=ψ=±30° for ΔAla residues. The computational results reveal that the ΔAla residue does not induce an inverse γ‐turn in the preceding residue. It is the competitive interaction of small solvent molecules with the hydrogen‐bonding sites of the peptide which gives rise to the formation of an inverse γ‐turn (ϕ₁=−54°, ψ₁=82°; ϕ₂=44°, ψ₂=3°) in the preceding residue to ΔAla. The computational studies for the positional preference of ΔAla in the peptide containing one ΔAla and nine Ala residues reveals the formation of a 3₁₀ helical structure in all the cases with the terminal preferences for ΔAla, consistent with the position of ΔAla in the natural antibiotics. The extended structures is found to be the most stable for poly‐ΔAla. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 72: 15–23, 1999     

Conformation of a terminally protected βγ hybrid dipeptide Boc‐Ant‐Gpn‐OMe stabilized by C6/C7 hydrogen bonds

The hybrid βγ dipeptide, methyl 2‐[1‐({2‐[(tert‐butoxycarbonyl)amino]benzamido}methyl)cyclohexyl]acetate (Boc‐Ant‐Gpn‐OMe), C₂₂H₃₂N₂O₅, adopts a folded conformation stabilized by intramolecular six‐ (C₆) and seven‐membered (C₇) hydrogen‐bonded rings, together with weak C—H...O and C—H...π interactions, resulting in a ribbon‐like structure.