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

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

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

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

Crystal structure of dehydromonopetide, (Z)-N-acetyl-α,β-dehydrophenylalanine methylamide

The crystal structure of (Z)-acetyl-α,β-dehydrophenylalanine methylamide (monoclinic Cc, a = 10.241(1), b = 15.252(1), c = 8.643(1) Å, β = 120.98(1)°, Z = 4) has been solved by x-ray diffraction to an R-factor = 0.148, and compared to that of the homologous L -phenylalanine dervative. Molecules are intermolecularly hydrogen-bonded to four neighboring molecules in a three-dimensional network with alternating layers of interacting amide bonds and orthogonally arranged phenyl rings. The existence of the C^α = C^β double bond results in a phenyl orientation that is forbidden for phenylananine (χ¹ = ?7,8°), and in shorter C^α ? C^β and C^β ? C^γ distances. The geometrical paramenters of the peptide backbone are not drastically modified by α,β-unsaturation. However, the N-C^α-C′ angle is increased by nearly 5°, and the dimensions, and therefore probably the electronic conjugation, of the N-terminal amide group to be affected by the occurrence of the vicinal C^α = C^β double bond.     

Ribbon structure stabilized by C10 and C12 turns in αγ hybrid peptide

The present study describes the synthesis and crystallographic analysis of αγ hybrid peptides, Boc‐Gpn‐L‐Pro‐NHMe ( 1 ), Boc‐Aib‐Gpn‐L‐Pro‐NHMe ( 2 ), and Boc‐L‐Pro‐Aib‐Gpn‐L‐Pro‐NHMe ( 3 ). Peptides 1 and 2 adopt expanded 12‐membered (C₁₂) helical turn over γα segment. Peptide 3 promotes the ribbon structure stabilized by type II β‐turn (C₁₀) followed by the expanded C₁₂ helical γα turn. Both right‐handed and left‐handed helical conformations for Aib residue are observed in peptides 2 and 3 , respectively Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.     

Conformations of peptides containing a chiral cyclic α, α‐disubstituted α‐amino acid within the sequence of Aib residues

A single chiral cyclic α,α‐disubstituted amino acid, (3S,4S)‐1‐amino‐(3,4‐dimethoxy)cyclopentanecarboxylic acid [(S,S)‐Ac₅c^dOM], was placed at the N‐terminal or C‐terminal positions of achiral α‐aminoisobutyric acid (Aib) peptide segments. The IR and ¹H NMR spectra indicated that the dominant conformations of two peptides Cbz‐[(S,S)‐Ac₅c^dOM]‐(Aib)₄‐OEt ( 1) and Cbz‐(Aib)₄‐[(S,S)‐Ac₅c^dOM]‐OMe (2) in solution were helical structures. X‐ray crystallographic analysis of 1 and 2 revealed that a left‐handed (M) 3₁₀‐helical structure was present in 1 and that a right‐handed (P) 3₁₀‐helical structure was present in 2 in their crystalline states. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.     

Crystal structures of diketopiperazines containing α-aminoisobutyric acid: Cyclo(Aib-Aib) and cyclo(Aib-L-Ile)

The crystal and molecular structures of two α-aminoisobutyric acid (Aib)-containing diketopiperazines, cyclo(Aib-Aib) 1 and cyclo(Aib-L -Ile) 2 , are reported. Cyclo(Aib-Aib) crystallizes in the space group P1 with a = 5.649(3), b = 5.865(2), c = 8.363(1), α = 69.89(6), β = 113.04(8), γ = 116.0(3), and Z = 1, while 2 occurs in the space group P2₁2₁2₁ with a = 6.177(1), b = 10.791(1), c = 16.676(1), and Z = 4. The structures of 1 and 2 have been refined to final R factors of 0.085 and 0.086, respectively. In both structures the diketopiperazine ring shows small but significant deviation from planarity. A very flat chair conformation is adopted by 1, in which the C^α atoms are displaced by 0.07 Å on each side of the mean plane, passing through the other four atoms of the ring. Cyclo(Aib-Ile) favors a slight boat conformation, with Aib C^α and Ile C^α atoms displaced by 0.11 and 0.05 Å on the same side of the mean plane formed by the other ring atoms. Structural features in these two molecules are compared with other related diketopiperazines.     

Experimental conformational study of two peptides containing α-aminoisobutyric acid. Crystal structure of N-acetyl-α-aminoisobutyric acid methylamide

Some theoretical studies have predicted that the conformational freedom of the α-aminoisobutyric acid (H-Aib-OH) residue is restricted to the α-helical region of the Ramachandran map. In order to obtain conformational experimental data, two model peptide derivatives, MeCO-Aib-NHMe 1 and Bu^tCO-LPro-Aib-NHMe 2 , have been investigated. The Aib dipeptide 1 crystallizes in the monoclinic system (a = 12.71 Å, b = 10.19 Å, c = 7.29 Å, β = 110.02°, Cc space group) and its crystal structure was elucidated by x-ray diffraction analysis. The azimuthal angles depicting the molecular conformation (? = ?55.5°, ψ = ?39.3°) fall in the α-helical region of the Ramachandran map and molecules are hydrogen-bonded in a three-dimensional network. In CCl₄ solution, ir spectroscopy provides evidence for the occurrence of the so-called ₅ and C₇ conformers stabilized by the intramolecular i → i and i + 2 → i hydrogen bonds, respectively. The tripeptide 2 was studied in various solvents [CCl₄, CD₂Cl₂, CDCl₃, (CD₃)₂SO, and D₂O] by ir and pmr spectroscopies. It was shown to accommodate predominantly the βII folded state stabilized by the i + 3 → i hydrogen bond. All these experimental findings indicate that the Aib residue displays the same conformational behavior as the other natural chiral amino acid residues.     

Epitope analysis of the multiphosphorylated peptide αs1‐casein(59–79)

The multiphosphorylated tryptic peptide α_s1‐casein(59–79) has been shown to be antigenic with anti‐casein antibodies. In an approach to determine the amino acyl residues critical for antibody binding we undertook an epitope analysis of the peptide using overlapping synthetic peptides. With α_s1‐casein(59–79) as the adsorbed antigen in a competitive ELISA only two of five overlapping synthetic peptides at 1 mM significantly inhibited binding of the anti‐casein antibodies. Peptides Glu‐Ser(P)‐Ile‐Ser(P)‐Ser(P)‐Ser(P)‐Glu‐Glu and Ile‐Val‐Pro‐Asn‐Ser(P)‐Val‐Glu‐Glu inhibited antibody binding by 20.0±3.6% and 60.3±7.9%, respectively. The epitope of Glu⁶³‐Ser(P)‐Ile‐Ser(P)‐Ser(P)‐Ser(P)‐Glu‐Glu⁷⁰ was further localised to the phosphoseryl cluster as the peptide Ser(P)‐Ser(P)‐Ser(P) significantly inhibited binding of the anti‐casein antibodies to α_s1‐casein(59–79) by 29.5±7.4%. Substitution of Ser(P)⁷⁵ with Ser⁷⁵ in the second inhibitory peptide Ile‐Val‐Pro‐Asn‐Ser(P)⁷⁵‐Val‐Glu‐Glu also abolished inhibition of antibody binding to α_s1‐casein (59–79) demonstrating that Ser(P)⁷⁵ is also a critical residue for recognition by the antibodies. These data show that the phosphorylated residues in the cluster sequence ‐Ser(P)⁶⁶‐Ser(P)‐Ser(P)⁶⁸ and in the sequence ‐Pro⁷³‐Asn‐Ser(P)‐Val‐Glu⁷⁷‐ are critical for antibody binding to α_s1‐casein(59–79) and further demonstrate that a highly phosphorylated segment of a protein can be antigenic. Copyright © 1999 European Peptide Society and John Wiley & Sons, Ltd.     

Synthesis,and crystal and molecular structure of the 310-helical α,β-dehydro pentapeptide Boc-Leu-Phe-Ala-ΔPhe-Leu-Ome

α,β-Dehydro amino acid residues are known to constrain the peptide backbone to the β-bend conformation. A pentapeptide containing only one α,β dehydrophenylalanine (ΔPhe) residue has been synthesized and crystallized, and its solid state conformation has been determined. The pentapeptide Boc-Leu-Phe-Ala-ΔPhe-Leu-OMe (C₃₉H₅₅N₅O₈, M_w = 721.9) was crystallized from aqueous methanol. Monoclinic space group was P2₁, a = 10.290(2)°, b = 17.149(2)°, c = 12.179(2) Å, β = 96.64(1)° with two molecules in the unit cell. The x-ray (Mo K_α, λ = 0.7107A) intensity data were collected using a CAD4 diffractometer. The crystal structure was determined by direct methods and refined using least-squares technique. R = 4.4% and R_w = 5.4% for 4403 reflections having |F₀| ≥ 3σ(|F₀|). All the peptide links are trans and the pentapeptide molecule assumes 3₁₀-helical conformation. The mean ?,ψ values, averaged over the first four residues, are ?64.4°, ?22.4° respectively. There are three 4 → 1 intramolecular hydrogen bonds, characteristic of 3₁₀,-helix. In the crystal, the peptide helices interact through two head-to-tail. N? H? O intermolecular hydrogen bonds. The peptide molecules related by 2₁, screw symmetry form a skewed assembly of helices. © 1995 John Wiley & Sons, Inc.     

Characterization of a type of β‐bend ribbon spiral generated by the repeating (Xaa–Yaa–Aib–Pro) motif: The solution structure of harzianin HC IX,a 14‐residue peptaibol forming voltage‐dependent ion channels

The three‐dimensional solution structure of harzianin HC IX, a peptaibol antibiotic isolated from the fungus Trichoderma harzianum, was determined using CD, homonuclear, and heteronuclear two‐dimensional nmr spectroscopy combined with molecular modeling. This 14‐residue peptide, Ac Aib¹ Asn² Leu³ Aib⁴ Pro⁵ Ala⁶ Ile⁷ Aib⁸ Pro⁹ Iva¹⁰ Leu¹¹ Aib¹² Pro¹³ Leuol¹⁴ (Aib, α‐aminoisobutyric acid; Iva, isovaline; Leuol, leucinol), is a main representative of a short‐sequence peptaibol class characterized by an acetylated N‐terminus, a C‐terminal amino alcohol, and the presence of three Aib‐L ‐Pro motifs at positions 4–5, 8–9, and 12–13, separated by two dipeptide units. In spite of a lower number of residues, compared to the 18/20‐residue peptaibols such as alamethicin, harzianin HC IX exhibits remarkable membrane‐perturbing properties. It interacts with phospholipid bilayers, increasing their permeability and forming voltage‐gated ion channels through a mechanism slightly differing from that proposed for alamethicin. Sequence‐specific ¹H‐ and ¹³C‐nmr assignments and conformational nmr parameters (³J_NHCαH coupling constants, quantitative nuclear Overhauser enhancement data, temperature coefficients of amide and carbonyl groups, NH–ND exchange rates) were obtained in methanol solution. Sixty structures were calculated based on 98 interproton distance restraints and 6 Φ dihedral angle restraints, using high temperature restrained molecular dynamics and energy minimization. Thirty‐seven out of the sixty generated structures were consistent with the nmr data and were convergent. The peptide backbone consists in a ribbon of overlapping β‐turns twisted into a continuous spiral from Asn² to Leuol¹⁴ and forming a 26 Å long helix‐like structure. This structure is slightly amphipathic, with the three Aib–Pro motifs aligned on the less hydrophobic face of the spiral where the Asn² side chain is also present, while the more hydrophobic bulky side chains of leucines, isoleucine, isovaline, and leucinol are located on the concave side. The repetitive (Xaa–Yaa–Aib–Pro) tetrapeptide subunit, making up the peptide sequence, is characterized by four sets of (Φ,Ψ) torsional angles, with the following mean values: Φ_i = −90°, Ψ_i = −27°; Φ_i+1 = −98°, Ψ_i+1 = −17°; Φ_i+2 = −49°, Ψ_i+2 = −50°; Φ_i+3 = −78°, Ψ_i+3 = +3°. We term this particular structure, specifically occurring in the case of (Xaa–Yaa–Aib–Pro)_n sequences, the (Xaa–Yaa–Aib–Pro)‐β‐bend ribbon spiral. It is stabilized by 4 → 1 intramolecular hydrogen bonds and differs from both the canonical 3₁₀‐helix made of a succession of type III β‐turns and from the β‐bend ribbon spiral that has been described in the case of (Aib–Pro)n peptide segments. © 1999 John Wiley & Sons, Inc. Biopoly 50: 71–85, 1999     

Basic conformers in β‐peptides

The conformation of oligomers of β‐amino acids of the general type Ac‐[β‐Xaa]_n‐NHMe (β‐Xaa = β‐Ala, β‐Aib, and β‐Abu; n = 1–4) was systematically examined at different levels of ab initio molecular orbital theory (HF/6‐31G*, HF/3‐21G). The solvent influence was considered employing two quantum‐mechanical self‐consistent reaction field models. The results show a wide variety of possibilities for the formation of characteristic elements of secondary structure in β‐peptides. Most of them can be derived from the monomer units of blocked β‐peptides with n = 1. The stability and geometries of the β‐peptide structures are considerably influenced by the side‐chain positions, by the configurations at the C^α‐ and C^β‐atoms of the β‐amino acid constituents, and especially by environmental effects. Structure peculiarities of β‐peptides, in particular those of various helix alternatives, are discussed in relation to typical elements of secondary structure in α‐peptides. © 1999 John Wiley & Sons, Inc. Biopoly 50: 167–184, 1999     

The crystal structure of Z‐Gly‐Aib‐Gly‐Aib‐OtBu

The synthetic peptide Z‐Gly‐Aib‐Gly‐Aib‐OtBu was dissolved in methanol and crystallized in a mixture of ethyl acetate and petroleum ether. The crystals belong to the centrosymmetric space group P4/n that is observed less than 0.3% in the Cambridge Structural Database. The first Gly residue assumes a semi‐extended conformation (φ ±62°, ψ ?131°). The right‐handed peptide folds in two consecutive β‐turns of type II' and type I or an incipient 3₁₀‐helix, and the left‐handed counterpart folds accordingly in the opposite configuration. In the crystal lattice, one molecule is linked to four neighbors in the ab‐plane via hydrogen bonds. These bonds form a continuous network of left‐ and right‐handed molecules. The successive ab‐planes stack via apolar contacts in the c‐direction. An ethyl acetate molecule is situated on and close to the fourfold axis. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.     

Design of Peptides Using α,β-Dehydro-residues: Synthesis,Crystal Structure and Molecular Conformation of N-Boc-L-Val-ΔPhe–ΔPhe-L-Ala-OCH3

To obtain general rules of peptide design using α,β-dehydro-residues, a sequence with two consecutive ΔPhe-residues, Boc-L -Val-ΔPhe–ΔPhe- L -Ala-OCH₃, was synthesized by azlactone method in solution phase. The peptide was crystallized from its solution in an acetone/water mixture (70:30) in space group P6₁ with a=b=14.912(3) Å, c= 25.548(5) Å, V=4912.0(6) ų. The structure was determined by direct methods and refined by a full matrix least-squares procedure to an R value of 0.079 for 2891 observed [I?3σ(I)] reflections. The backbone torsion angles ?₁=?54(1)°, ψ₁= 129(1)°, ω₁=?177(1)°, ?₂ =57(1)°, ψ₂=15(1)°, ω₂ =?170(1)°, ?₃=80(1)°, ψ₃ =7(2)°, ω₃=?177(1)°, ?₄ =?108(1)° and ψ^T₄=?34 (1)° suggest that the peptide adopts a folded conformation with two overlapping β-turns of types II and III′. These turns are stabilized by two intramolecular hydrogen bonds between the CO of the Boc group and the NH of ΔPhe³ and the CO of Val¹ and the NH of Ala⁴. The torsion angles of ΔPhe² and ΔPhe³ side chains are similar and indicate that the two ΔPhe residues are essentially planar. The folded molecules form head-to- tail intermolecular hydrogen bonds giving rise to continuous helical columns which run parallel to the c-axis. This structure established the formation of two β-turns of types II and III′ respectively for sequences containing two consecutive ΔPhe residues at (i+2) and (i+3) positions with a branched β-carbon residue at one end of the tetrapeptide.     

Mixed conformation in Cα,α-disubstituted tripeptides: X-ray crystal structures of Z-Aib-Dph-Gly-Ome and Bz-Dph-Dph-Gly-Ome

We report here the synthesis and molecular structure in the solid state of fully protected tripeptides containing C^α,α-diphenylglycine (Dph), namely Z-Aib-Dph-Gly-OMe (Aib: C^α,α-dimethylgrycine) and Bz-Dph-Dph-Gly-OMe. The molecular conformation around the Dph residue, containing two bulky substituents, is fully extended, while the Aib residue, containing two smaller groups on the C^α atom, adopts the typical 3₁₀/α-helical conformation. Gly residues, without substituents on the C^α atom, show different conformational preferences. Each residue seems to behave, from a conformational point of view, independently from the presence of the other residues, and thus mixed local conformations (folded and extended) are present in the crystals. The nonconventional peptide synthesis, using the Ugi reaction, is also reported. © 1994 John Wiley & Sons, Inc.     

Technical note: A linear model for predicting δ13Cprotein

Objective : Development of a model for the prediction of δ¹³C_protein from δ¹³C_collagen and Δ¹³C_ap‐co. Model‐generated values could, in turn, serve as “consumer” inputs for multisource mixture modeling of paleodiet. Methods : Linear regression analysis of previously published controlled diet data facilitated the development of a mathematical model for predicting δ¹³C_protein (and an experimentally generated error term) from isotopic data routinely generated during the analysis of osseous remains (δ¹³C_co and Δ¹³C_ap‐co). Results : Regression analysis resulted in a two‐term linear model (δ¹³C_protein (%) = (0.78 × δ¹³C_co) ? (0.58× Δ¹³C_ap‐co) ? 4.7), possessing a high R‐value of 0.93 (r² = 0.86, P < 0.01), and experimentally generated error terms of ±1.9% for any predicted individual value of δ¹³C_protein. This model was tested using isotopic data from Formative Period individuals from northern Chile's Atacama Desert. Conclusions : The model presented here appears to hold significant potential for the prediction of the carbon isotope signature of dietary protein using only such data as is routinely generated in the course of stable isotope analysis of human osseous remains. These predicted values are ideal for use in multisource mixture modeling of dietary protein source contribution. Am J Phys Anthropol 157:694–703, 2015. © 2015 Wiley Periodicals, Inc.     

Studies of Amyloid‐Like Fibrillogenesis through β‐Sheet‐Mediated Self‐Assembly of Short Synthetic Peptides

Three structurally different types of small peptides, namely, i) Boc‐Ile‐Aib‐Ile‐OMe (Aib=α‐aminoisobutyric acid), ii) Boc‐Xx‐m‐aminobenzoic acid (Xx=β‐Ala and γ‐aminobutyric acid), and iii) Boc‐Xx‐m‐nitroaniline, were found to exhibit β‐sheet‐mediated fibrillogenesis in the solid state, revealed by FT‐IR, single‐crystal X‐ray diffraction, and FE‐SEM studies. Interestingly, the fibrils grown from peptides 2 and 3 were found to bind with the physiological dye Congo red, a characteristic feature of amyloid fibrils.     

Synthesis and Biological Evaluation of Gramicidin S‐Inspired Cyclic Mixed α/β‐Peptides

Via a Mannich reaction involving a dibenzyliminium species and the titanium enolates of Evans' chiral acylated oxazolidinones the β²‐amino acids (R)‐ and (S)‐Fmoc‐β²homovaline and (R)‐Fmoc‐β²homoleucine are synthesized. These building blocks were used, in combination with commercially available α‐ and β³‐amino acids, for the synthesis of the cyclo‐(αβ³αβ²α)₂ peptide 2 and the cyclo‐(αβ²αβ³α)₂ peptides 3 – 5 . The peptides 2 – 5 were screened for their ability to inhibit a small panel of Gram‐negative and Gram‐positive bacterial strains.     

Structural versatility of peptides from Cα,α-dialkylated glycines. I. A conformational energy computation and x-ray diffraction study of homo-peptides from Cα,α-diethylglycine

Conformational energy computations on a derivative and a homo-dipeptide of C^α,α-diethylglycine were performed. In both cases the N- and C-terminal groups are blocked as acetamido and methylamido moieties, respectively. It was found that the C^α,α-diethylglycine residues are conformationally restricted and that the minimum energy conformation corresponds to the fully extended C₅ structure when the N? C^α? C′ bond angle is smaller than 108° (as experimentally observed). The results of the theoretical analysis are in agreement with the crystal-state structural propensity of the complete series of N-trifluoroacetylated homo-peptides of this C^α,α-dialkylated residue from monomer to pentamer, determined by x-ray diffraction and also described in this work. Interestingly, for the first time, a crystallographically planar peptide backbone was observed (in the protected tripeptide). A comparison with peptides of C^α,α-dimethylglycine, C^α-methyl, C^α-ethylglycine, and C^α,α-di-n-propylglycine indicates that the fully extended conformation becomes more stable than the helical structures when both amino acid side-chain C^β atoms are substituted.     

A quantum mechanical study of the intrinsic helix-forming tendency of α-aminoisobutyric acid and dehydroalanine residues

A quantum mechanical study to compare the ability of α-aminoisobutyric acid (Aib), de-hydroalanine (ΔAla), and alanine (Ala) residues to stabilize helical conformations has been performed. To address the study, the oligopeptides X_n (X = Aib, ΔAla and Ala), where n varies from 1 to 6, were computed with the AM1 semiempirical method. The results show that the residues modified at the C^α carbon atom, Aib and ΔAla, are better helical formers than Ala. Thus, a cooperative energy effect was found for both residues, and especially for ΔAla. These terms permit the understanding the different conformational behaviors between Ala and its C^α-modified residues Aib and ΔAla. This trend is important for de novo protein design, where Aib and ΔAla must be considered useful residues in the design of synthetic helical motifs. © 1994 John Wiley & Sons, Inc.     

Type II β-turn conformation of pivaloyl-L-prolyl-α-aminoisobutyryl-N-methylamide: Theoretical,spectroscopic, and X-ray studies

Pivaloyl-L -Pro-Aib-N-methylamide has been shown to possess one intramolecular hydrogen bond in (CD₃)₂SO solution, by ¹H-nmr methods, suggesting the existence of β-turns, with Pro-Aib as the corner residues. Theoretical conformational analysis suggests that Type II β-turn conformations are about 2 kcal mol^?1 more stable than Type III structures. A crystallographic study has established the Type II β-turn in the solid state. The molecule crystallizes in the space group P2₁ with a = 5.865 Å, b = 11.421 Å, c = 12.966 Å, β = 97.55°, and Z = 2. The structure has been refined to a final R value of 0.061. The Type II β-turn conformation is stabilized by an intramolecular 4 → 1 hydrogen bond between the methylamide NH and the pivaloyl CO group. The conformational angles are ?_Pro = ?57.8°, ψ_Pro = 139.3°, ?_Aib = 61.4°, and ψ_Aib = 25.1°. The Type II β-turn conformation for Pro-Aib in this peptide is compared with the Type III structures observed for the same segment in larger peptides.