Incorporation of phenylcarbonyl groups in the sidechain: A tool to induce ordered assembly of peptides on surfaces.

The possibility of introducing various functionalities on peptides with relative ease allows them to be used for molecular applications. However, oligopeptides prepared entirely from proteinogenic amino acids seldom assemble as ordered structures on surfaces. Therefore, sidechain modifications of peptides that can increase the intermolecular interactions without altering the constitution of a given peptide become an attractive route to self-assembling them on surfaces. We find that replacing phenylalanine residues with unusual amino acids that have phenylcarbonyl sidechains in oligopeptides increases the formation of ordered self-assembly on a highly ordered pyrolytic graphite surface. Peptides containing the modified amino acids provided extended long-range ordered assemblies, while the analogous peptides containing phenylalanine residues failed to form long-range assemblies. X-ray crystallographic analysis of the bulk structures of these peptides and the analogous peptides containing phenylalanine residues reveal that such modifications do not alter the secondary structure in crystals. It also reveals that the secondary hydrogen bonding interaction through phenylcarbonyl sidechains facilitates extended growth of the peptides on graphite.

Synthesis of 2,2-dimethyl-chroman-based stereochemically flexible and constrained anti-breast cancer agents.

Receptors are proteinous macromolecules which remain in the apo form under normal/unliganded conditions. As the ligand approaches, there are specific stereo-chemical changes in the apo form of the receptor as per the stereochemistry of a ligand. Accordingly, a series of substituted dimethyl-chroman-based stereochemically flexible and constrained Tamoxifen analogs were synthesized as anti-breast cancer agents. The synthesized compounds 19a-e, 20a-e, 21, and 22a-e, showed significant antiproliferative activity against estrogen receptor-positive (ER+, MCF-7) and negative (ER-, MDA MB-231) cells within IC50 value 8.5-25.0 µM. Amongst all, four potential molecules viz 19b, 19e, 22a, and 22c, were evaluated for their effect on the cell division cycle and apoptosis of ER+ and ER- cancer cells (MCF-7 & MDA MB-231cells), which showed that these compounds possessed antiproliferative activity through triggering apoptosis. In-silico docking experiments elucidated the possible affinity of compounds with estrogen receptors-α and -ß.

Ambidexterity and Left-Handedness Induced by Geminally Disubstituted γ Amino Acid Residues in Chiral 310 Helices.

Chirality is an omnipresent feature in nature's architecture starting from simple molecules like amino acids to complex higher-order structures viz. proteins, DNA, and RNA. The L configuration of proteinogenic amino acids gives rise to right-handed helices. Ambidexterity is as rare in organisms as in molecules. There are only a few reports of ambidexterity in single-peptide molecules composed of either mixed L and D or achiral residues. Here, we report, for the first time, the ambidextrous and left-handed helical conformations in the chiral nonapeptides P1-P3 (Boc-LUVUγx,xULUV-OMe where U = Aib, x,x = 2,2/3,3/4,4), containing chiral L α amino acid residues, in addition to the usually observed right-handed helical conformation. The centrally located achiral γ residue, capable of adopting both left and right-handed helical conformations, induces its handedness on the neighboring chiral and achiral residues, leading to the observation of both left and right-handed helices in P2 and P3. The presence of a single water molecule proximal to the γ residue induces the reversal of helix handedness by forming distinct and stable water-mediated hydrogen bonds. This gives rise to ambidextrous helices as major conformers in P1 and P2. The absence of the observation of ambidexterity in P3 might be due to the inability of γ4,4 in the recruitment of a water molecule. Experiments (NMR, X-ray, and CD) and density functional theory (DFT) calculations suggest that the position of geminal disubstitution is crucial for determining the population of the amenable helical conformations (ambidextrous, left and right-handed) in these chiral peptides.

Interaction Patterns of Pyrazolopyrimidines with Receptor Proteins.

Heterocyclic compounds have a prominent role in medicinal chemistry and drug design. They are not only useful as medicinally active compounds but also as a modular structural scaffold for drug design. Therefore, heterocycles are present in many ligands that exhibit a broad spectrum of biological activities. Pyazolopyrimidines are nitrogen heterocycles and are part of many biologically active compounds and marketed drugs. This study examines the non-covalent interactions between the pyrazolopyrimidine rings and receptor proteins through data mining and analysis of high-resolution crystal structures deposited in the Protein Data Bank. The Protein Data Bank contains 471 crystal structures with pyrazolopyrimidine derivatives as ligands, among which 50% contains 1H-pyrazolo[3,4-d]pyrimidines (Pyp1), while 38% contains pyrazolo[1,5-a] pyrimidines (Pyp2). 1H-Pyrazolo[4,3-d]pyrimidines (Pyp3) are found in 11% of the structures, and no structural data is available for pyrazolo[1,5-c]pyrimidine isomers (Pyp4). Among receptor proteins, transferases are found in most examples (67.5%), followed by hydrolases (13.4%) and oxidoreductases (8.9%). Detailed analysis of structures to identify the most prevalent interactions of pyrazolopyrimidines with proteins shows that aromatic π···π interactions are present in ∼91% of the structures and hydrogen bonds/other polar contacts are present in ∼73% of the structures. The centroid-centroid distances (dcent) between the pyrazolopyrimidine rings and aromatic side chains of the proteins have been retrieved from crystal structures recorded at a high resolution (data resolution <2.0 Å). The average value of dcent in pyrazolopyrimidine-protein complexes is 5.32 Å. The information on the geometric parameters of aromatic interactions between the core pyrazolopyrimidine ring and the protein would be helpful in future in silico modeling studies on pyrazolopyrimidine-receptor complexes.

MYB transcription factors and their role in Medicinal plants.

Transcription factors are multi-domain proteins that regulate gene expression in eukaryotic organisms. They are one of the largest families of proteins, which are structurally and functionally diverse. While there are transcription factors that are plant-specific, such as AP2/ERF, B3, NAC, SBP and WRKY, some transcription factors are present in both plants as well as other eukaryotic organisms. MYB transcription factors are widely distributed among all eukaryotes. In plants, the MYB transcription factors are involved in the regulation of numerous functions such as gene regulation in different metabolic pathways especially secondary metabolic pathways, regulation of different signalling pathways of plant hormones, regulation of genes involved in various developmental and morphological processes etc. Out of the thousands of MYB TFs that have been studied in plants, the majority of them have been studied in the model plants like Arabidopsis thaliana, Oryza sativa etc. The study of MYBs in other plants, especially medicinal plants, has been comparatively limited. But the increasing demand for medicinal plants for the production of biopharmaceuticals and important bioactive compounds has also increased the need to explore more number of these multifaceted transcription factors which play a significant role in the regulation of secondary metabolic pathways. These studies will ultimately contribute to medicinal plants' research and increased production of secondary metabolites, either through transgenic plants or through synthetic biology approaches. This review compiles studies on MYB transcription factors that are involved in the regulation of diverse functions in medicinal plants.

Effect of Differential Backbone Di-substitution of Gamma Amino Acid Residues on the Conformation and Assembly of their Fmoc Derivatives in Solid and Solution States.

We studied the effect of variable backbone dimethyl-substitution of γ amino acid residues (γ2,2 , γ3,3 and γ4,4 ) on the conformation and assembly, in crystals and solution of their Fmoc derivatives. The crystal structure of γ2,2 and γ4,4 derivatives showed distinct conformations (open/close for γ2,2 /γ4,4 ) that differed in torsion angles, hydrogen-bonding and most importantly the π-π Fmoc-stacking interactions (relatively favourable for γ4,4 -close). Fmoc derivatives existed in an equilibrium between major-monomeric (low energy, non-hydrogen bonded) and minor-dimeric (high energy, hydrogen bonded) populations in solution. The rate of major/minor population exchange was dependent on the position of substitution, highest being for γ4,4 derivative. In solution, assembly of Fmoc derivatives was solvent dependent, but it was independent of the position of geminal substitution. Crystallization was primarily governed by the stabilization of high-energy dimer by favourable π-π stacking involving Fmoc moieties. High free-energy of the dimers (γ2,2 -close, γ3,3 -open/close) offset favourable stacking interactions and hindered crystallization.

Crystal structure and self-assembly on graphite of a pyrazolo[1,5-c]pyrimidine derivative.

The crystal structure of the heterocyclic compound 2-(4-methoxyphenyl)-7-phenylpyrazolo[1,5-c]pyrimidine, C19H15N3O, has been determined and its self-assembly on the surface of graphite has been examined using atomic force microscopy (AFM). The title compound crystallized in the monoclinic space group P21/c, with two independent molecules in the asymmetric unit. The packing of the L-shaped molecules in the crystal is governed by arene interactions, in the absence of any conventional hydrogen-bonding interactions. The packing arrangement reveals four types of dimeric motifs stabilized by π-π and C-H...π interactions. At low coverage, molecules assemble into long needle-like islands on the graphite surface. High-resolution AFM images reveal that the molecules interact through weak noncovalent interactions between the aromatic H atoms and the methoxy O atoms.

Insecticidal fern protein Tma12 is possibly a lytic polysaccharide monooxygenase.

MAIN CONCLUSION: Amino acid sequence and crystal structure analyses of Tma12, an insecticidal protein isolated from the fern Tectaria macrodonta, identify it as a carbohydrate-binding protein belonging to the AA10 family of lytic polysaccharide monooxygenases, and provide the first evidence of AA10 proteins in plants. Tma12, isolated from the fern Tectaria macrodonta, is a next-generation insecticidal protein. Transgenic cotton expressing Tma12 exhibits resistance against whitefly and viral diseases. Beside its insecticidal property, the structure and function of Tma12 are unknown. This limits understanding of the insecticidal mechanism of the protein and targeted improvement in its efficacy. Here we report the amino acid sequence analysis and the crystal structure of Tma12, suggesting that it is possibly a lytic polysaccharide monooxygenase (LPMO) of the AA10 family. Amino acid sequence of Tma12 shows 45% identity with a cellulolytic LPMO of Streptomyces coelicolor. The crystal structure of Tma12, obtained at 2.2 Å resolution, possesses all the major structural characteristics of AA10 LPMOs. A H2O2-based enzymatic assay also supports this finding. It is the first report of the occurrence of LPMO-like protein in a plant. The two facts that Tma12 possesses insecticidal activity and shows structural similarity with LPMOs collectively advocate exploration of microbial LPMOs for insecticidal potential.

Synthesis of peptides containing oxo amino acids and their crystallographic analysis.

An isolated uncharged hydrogen bond acceptor such as the carbonyl functionality of an aldehyde or a keto group is absent in natural amino acids. Although glutamine and asparagine are known to hydrogen bond through the amide carbonyl group in their side chains, they also possess the amide NH2 group, which can act as a hydrogen bond donor. This makes the structural study of peptides containing an oxo residue, with an isolated carbonyl group in the side chain, interesting. Here, we report the synthesis of δ- and ε-oxo amino acids and their incorporation into oligopeptides as the N-terminal residue. The resultant oxo peptides were extensively studied using X-ray crystallography to understand the interactions offered by the oxo group in peptide crystals. We find that the oxo groups are capable of providing additional hydrogen bonding opportunities to the peptides, resulting in increased intermolecular interactions in crystals. The study thus offers avenues for the utilization of oxo residues to introduce intermolecular interactions in synthetic peptides.

Structure-Activity Relationship Studies on Holy Basil (Ocimum sanctum L.) Based Flavonoid Orientin and its Analogue for Cytotoxic Activity in Liver Cancer Cell Line HepG2.

O. sanctum L. (O. tenuiflorum) is an important sacred medicinal plant of India known as Holy Basil or Tulsi. The chemical composition of volatile oil is highly complex and comprises high ratio of phenylpropanoids and terpenes, and some phenolic compound or flavonoids such as orientin and vicenin. These minor flavonoids are known to be antioxidant and anticancer in nature. Orientin reported as potential anticancer agent due to anti-proliferative activity on human liver cancer cell line HepG2, but its mechanism of action is not fully explored. In the present work an in-silico structure-activity relationship study on orientin was performed and built a pharmacophore mapping and QSAR model to screen out the potential structurally similar analogues from chemical database of Discovery Studio (DSv3.5, Accelrys, USA) as potential anticancer agent. Analogue fenofibryl glucuronide was selected for in vitro cytotoxic/anticancer activity evaluation through MTT assay. Binding affinity and mode of action of orientin and its analogue were explored through molecular docking studies on quinone oxidoreductase, a potential target of flavonoids. Contrary to the assumption, in vitro results showed only 41% cell death at 202.389 µM concentration (at 96 hrs). Therefore, we concluded that the selected orientin analogue fenofibryl glucuronide was non-cytotoxic/non-anti-carcinogenic up to 100 µg/ml (202.389 µM) concentrations for a long term exposure i.e., till 96 hrs in human cancer cells of HepG2. We concluded that orientin and its analogue fenofibryl glucuronide as pure compound showed no activity or less cytotoxicity activity on liver cancer cell line HepG2.

Crystal structure of a tripeptide containing aminocyclododecane carboxylic acid: a supramolecular twisted parallel ß-sheet in crystals.

The crystal structure of a tripeptide Boc-Leu-Val-Ac12 c-OMe (1) is determined, which incorporates a bulky 1-aminocyclododecane-1-carboxylic acid (Ac12 c) side chain. The peptide adopts a semi-extended backbone conformation for Leu and Val residues, while the backbone torsion angles of the C(α,α) -dialkylated residue Ac12 c are in the helical region of the Ramachandran map. The molecular packing of 1 revealed a unique supramolecular twisted parallel ß-sheet coiling into a helical architecture in crystals, with the bulky hydrophobic Ac12 c side chains projecting outward the helical column. This arrangement resembles the packing of peptide helices in crystal structures. Although short oligopeptides often assemble as parallel or anti-parallel ß-sheet in crystals, twisted or helical ß-sheet formation has been observed in a few examples of dipeptide crystal structures. Peptide 1 presents the first example of a tripeptide showing twisted ß-sheet assembly in crystals.

Multicomponent One-pot Reactions Towards the Synthesis of Stereoisomers of Dipicolylamine Complexes.

Reported are multi-component one-pot syntheses of chiral complexes [M(L(R) OR')Cl2 ] or [M(L(R) SR')Cl2 ] from the mixture of an N-substituted ethylenediamine, pyridine-2-carboxaldehyde, a primary alcohol or thiol and MCl2 utilizing in-situ formed cyclized Schiff bases where a C-O bond, two stereocenters, and three C-N bonds are formed (M=Zn, Cu, Ni, Cd; R=Et, Ph; R'=Me, Et, nPr, nBu). Tridentate ligands L(R) OR' and L(R) SR' comprise two chiral centers and a hemiaminal ether or hemiaminal thioether moiety on the dipicolylamine skeleton. Syn-[Zn(L(Ph) OMe)Cl2 ] precipitates out readily from the reaction mixture as a major product whereas anti-[Zn(L(Ph) OMe)Cl2 ] stays in solution as minor product. Both syn-[Zn(L(Ph) OMe)Cl2 ] and anti-[Zn(L(Ph) OMe)Cl2 ] were characterized using NMR spectroscopy and mass spectrometry. Solid-state structures revealed that syn-[Zn(L(Ph) OMe)Cl2 ] adopted a square pyramidal geometry while anti-[Zn(L(Ph) OMe)Cl2 ] possesses a trigonal bipyramidal geometry around the Zn centers. The scope of this method was shown to be wide by varying the components of the dynamic coordination assembly, and the structures of the complexes isolated were confirmed by NMR spectroscopy, mass spectrometry, and X-ray crystallography. Syn complexes were isolated as major products with Zn(II) and Cu(II) , and anti complexes were found to be major products with Ni(II) and Cd(II) . Hemiaminals and hemiaminal ethers are known to be unstable and are seldom observed as part of cyclic organic compounds or as coordinated ligands assembled around metals. It is now shown, with the support of experimental results, that linear hemiaminal ethers or thioethers can be assembled without the assistance of Lewis acidic metals in the multi-component assembly, and a possible pathway of the formation of hemiaminal ethers has been proposed.

Crystal structures of four δ-keto esters and a Cambridge Structural Database analysis of cyano-halogen interactions.

The revived interest in halogen bonding as a tool in pharmaceutical cocrystals and drug design has indicated that cyano-halogen interactions could play an important role. The crystal structures of four closely related δ-keto esters, which differ only in the substitution at a single C atom (by H, OMe, Cl and Br), are compared, namely ethyl 2-cyano-5-oxo-5-phenyl-3-(piperidin-1-yl)pent-2-enoate, C19H22N2O3, (1), ethyl 2-cyano-5-(4-methoxyphenyl)-5-oxo-3-(piperidin-1-yl)pent-2-enoate, C20H24N2O4, (2), ethyl 5-(4-chlorophenyl)-2-cyano-5-oxo-3-(piperidin-1-yl)pent-2-enoate, C19H21ClN2O3, (3), and the previously published ethyl 5-(4-bromophenyl)-2-cyano-5-oxo-3-(piperidin-1-yl)pent-2-enoate, C19H21BrN2O3, (4) [Maurya, Vasudev & Gupta (2013). RSC Adv. 3, 12955-12962]. The molecular conformations are very similar, while there are differences in the molecular assemblies. Intermolecular C-H...O hydrogen bonds are found to be the primary interactions in the crystal packing and are present in all four structures. The halogenated derivatives have additional aromatic-aromatic interactions and cyano-halogen interactions, further stabilizing the molecular packing. A database analysis of cyano-halogen interactions using the Cambridge Structural Database [CSD; Groom & Allen (2014). Angew. Chem. Int. Ed. 53, 662-671] revealed that about 13% of the organic molecular crystals containing both cyano and halogen groups have cyano-halogen interactions in their packing. Three geometric parameters for the C-X...N[triple-bond]C interaction (X = F, Cl, Br or I), viz. the N...X distance and the C-X...N and C-N...X angles, were analysed. The results indicate that all the short cyano-halogen contacts in the CSD can be classified as halogen bonds, which are directional noncovalent interactions.

Involvement of an ent-copalyl diphosphate synthase in tissue-specific accumulation of specialized diterpenes in Andrographis paniculata.

Ent-labdane-related diterpene (ent-LRD) specialized (i.e. secondary) metabolites of the medicinal plant kalmegh (Andrographis paniculata) have long been known for several pharmacological activities. However, our understanding of the ent-LRD biosynthetic pathway has remained largely incomplete. Since ent-LRDs accumulate in leaves, we carried out a comparative transcriptional analysis using leaf and root tissues, and identified 389 differentially expressed transcripts, including 223 transcripts that were preferentially expressed in leaf tissue. Analysis of the transcripts revealed various specialized metabolic pathways, including transcripts of the ent-LRD biosynthetic pathway. Two class II diterpene synthases (ApCPS1 and ApCPS2) along with one (ApCPS1') and two (ApCPS2' and ApCPS2″) transcriptional variants that were the outcomes of alternative splicing of the precursor mRNA and alternative transcriptional termination, respectively, were identified. ApCPS1 and ApCPS2 encode for 832- and 817-amino acids proteins, respectively, and are phylogenetically related to the dicotyledons ent-copalyl diphosphate synthases (ent-CPSs). The spatio-temporal patterns of ent-LRD metabolites accumulation and gene expression suggested a likely role for ApCPS1 in general (i.e. primary) metabolism, perhaps by providing precursor for the biosynthesis of phytohormone gibberellin (GA). However, ApCPS2 is potentially involved in tissue-specific accumulation of ent-LRD specialized metabolites. Bacterially expressed recombinant ApCPS2 catalyzed the conversion of (E,E,E)-geranylgeranyl diphosphate (GGPP), the general precursor of diterpenes to ent-copalyl diphosphate (ent-CPP), the precursor of ent-LRDs. Taken together, these results advance our understanding of the tissue-specific accumulation of specialized ent-LRDs of medicinal importance.

Synthesis of novel anticancer agents through opening of spiroacetal ring of diosgenin.

Diosgenin has been modified to furostane derivatives after opening the F-spiroacetal ring. The aldehyde group at C26 in derivative 8 was unexpectedly transformed to the ketone 9. The structure of ketone 9 was confirmed by spectroscopy and finally by X-ray crystallography. Five of the diosgenin derivatives showed significant anticancer activity against human cancer cell lines. The most potent molecule of this series i.e. compound 7, inhibited cellular growth by arresting the population at G0/G1 phase of cell division cycle. Cells undergo apoptosis after exposure to the derivative 7 which was evident by increase in sub G0 population in cell cycle analysis. Docking experiments showed caspase-3 and caspase-9 as possible molecular targets for these compounds. This was further validated by cleavage of PARP, a caspase target in apoptotic pathway. Compound 7 was found non-toxic up to 1000mg/kg dose in acute oral toxicity in Swiss albino mice.

(1S,5R,7R,30S)-14-De-oxy-isogarcinol.

The title compound, C(38)H(50)O(5) {systematic name: 10-(3-hy-droxy-benzo-yl)-2,2,7,7-tetra-methyl-3,6,8-tris-(3-methyl-but-2-en-yl)-3,4,4a,5,6,7-hexa-hydro-4a,8-methano-2H-cyclo-octa-[b]pyran-9,11(8H)-dione}, is a polyisoprenylated benzophenone, isolated for the first time from the fruits of Garcinia indica during our investigation of bioactive compounds from this plant and their large-scale extraction. The relative configuration of the title compound was chosen based on comparison of its spectroscopic and optical rotation data with that of the isomorphous and isostructural compound isogarcinol, whose absolute configuration is known. The crystal packing features O-H⋯O hydrogen bonds. A Cambridge Structural Database analysis revealed that the crystal structure reported here is isomorphous and isostructural with that of isogarcinol.

Asparagine and glutamine differ in their propensities to form specific side chain-backbone hydrogen bonded motifs in proteins.

Short range side chain-backbone hydrogen bonded motifs involving Asn and Gln residues have been identified from a data set of 1370 protein crystal structures (resolution ≤ 1.5 Å). Hydrogen bonds involving residues i - 5 to i + 5 have been considered. Out of 12,901 Asn residues, 3403 residues (26.4%) participate in such interactions, while out of 10,934 Gln residues, 1780 Gln residues (16.3%) are involved in these motifs. Hydrogen bonded ring sizes (C(n), where n is the number of atoms involved), directionality and internal torsion angles are used to classify motifs. The occurrence of the various motifs in the contexts of protein structure is illustrated. Distinct differences are established between the nature of motifs formed by Asn and Gln residues. For Asn, the most highly populated motifs are the C(10)(CO(δ)(i) …NH(i + 2)), C(13)(CO(δ)(i) …NH(i + 3)) and C(17)(N(δ)H(i) …CO(i - 4)) structures. In contrast, Gln predominantly forms C(16)(CO(ε)(i) …NH(i - 3)), C(12)(N(ε)H(i) …CO(i - 2)), C(15)(N(ε)H(i) …CO(i - 3)) and C(18)(N(ε)H(i) …CO(i - 4)) motifs, with only the C(18) motif being analogous to the Asn C(17) structure. Specific conformational types are established for the Asn containing motifs, which mimic backbone ß-turns and α-turns. Histidine residues are shown to serve as a mimic for Asn residues in side chain-backbone hydrogen bonded ring motifs. Illustrative examples from protein structures are considered.

Gabapentin: a stereochemically constrained gamma amino acid residue in hybrid peptide design.

Nature has used the all-alpha-polypeptide backbone of proteins to create a remarkable diversity of folded structures. Sequential patterns of 20 distinct amino acids, which differ only in their side chains, determine the shape and form of proteins. Our understanding of these specific secondary structures is over half a century old and is based primarily on the fundamental elements: the Pauling alpha-helix and beta-sheet. Researchers can also generate structural diversity through the synthesis of polypeptide chains containing homologated (omega) amino acid residues, which contain a variable number of backbone atoms. However, incorporating amino acids with more atoms within the backbone introduces additional torsional freedom into the structure, which can complicate the structural analysis. Fortunately, gabapentin (Gpn), a readily available bulk drug, is an achiral beta,beta-disubstituted gamma amino acid residue that contains a cyclohexyl ring at the C(beta) carbon atom, which dramatically limits the range of torsion angles that can be obtained about the flanking C-C bonds. Limiting conformational flexibility also has the desirable effect of increasing peptide crystallinity, which permits unambiguous structural characterization by X-ray diffraction methods. This Account describes studies carried out in our laboratory that establish Gpn as a valuable residue in the design of specifically folded hybrid peptide structures. The insertion of additional atoms into polypeptide backbones facilitates the formation of intramolecular hydrogen bonds whose directionality is opposite to that observed in canonical alpha-peptide helices. If hybrid structures mimic proteins and biologically active peptides, the proteolytic stability conferred by unusual backbones can be a major advantage in the area of medicinal chemistry. We have demonstrated a variety of internally hydrogen-bonded structures in the solid state for Gpn-containing peptides, including the characterization of the C(7) and C(9) hydrogen bonds, which can lead to ribbons in homo-oligomeric sequences. In hybrid alphagamma sequences, distinct C(12) hydrogen-bonded turn structures support formation of peptide helices and hairpins in longer sequences. Some peptides that include the Gpn residue have hydrogen-bond directionality that matches alpha-peptide helices, while others have the opposite directionality. We expect that expansion of the polypeptide backbone will lead to new classes of foldamer structures, which are thus far unknown to the world of alpha-polypeptides. The diversity of internally hydrogen-bonded structures observed in hybrid sequences containing Gpn shows promise for the rational design of novel peptide structures incorporating hybrid backbones.