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Stereochemistry of peptides containing 1-aminocycloheptane-1-carboxylic acid (Ac7c): Crystal structures of model peptides
Abstract
The crystal structures of four peptides incorporating l-aminocycloheptane-l-carboxylic acid (Ac7c) are described. Boc-Aib-Ac7c-NHMe and Boc-Pro-Ac7c-Ala-OMe adopt β-turn conformations stabilized by an intramolecular 4 × 1 hydrogen bond, the former folding into a type-I/III β-turn and the latter into a type-II β-turn. In the dipeptide esters, Boc-Aib-Ac7c-OMe and Boc-Pro-Ac7c-OMe, the Ac7c and Aib residues adopt helical conformations, while the Pro residue remains semi-extended in both the molecules of Boc-Pro-Ac7c-OMe found in the asymmetric unit. The cycloheptane ring of Ac7c residues adopts a twist-chair conformation in all the peptides studied. 1H-NMR studies in CDCl3 and (CD3)2SO and IR studies in CDCl3, suggest that Boc-Aib-Ac7c-NHMe and Boc-Pro-Ac7c-Ala-OMe maintain the β-turn conformations in solution.
... Apart from the drug molecules mentioned above, amino acid 1 a was implemented into the design of vasopressin receptor 2 agonists, [9] antimicrobial peptides, [10] and arginase inhibitors, [11] or protein nanostructures. [13] Higher cycloheptane-derived homolog 1 b (Ac7c) was used to develop β-turn mimics [14] or histone deacetylase inhibitors. [15] Further development of the ideas of three-dimensionality and sp 3 -enrichement results in enhanced interest to spirocyclic scaffolds, as representative examples of highly saturated compounds with acceptable for drug design physicochemical profile. ...
An efficient synthesis of spiro[2.3]hexane‐ and spiro[3.3]heptane‐derived α‐amino acids is reported. The used methods are divided on two different approaches. First of them involves modification of commercially available spirocyclic diesters via monohydrolysis, Curtius rearrangement and functional groups deprotection sequence. Alternative approach was based on Bucherer ‐ Bergs hydantoine synthesis with its subsequent cleavage to the target amino acid fragment. The proposed synthetic schemes offer the desired product in 31–52 % overall yield on up to 22.5 g scale. Acid‐base titration of the obtained spirocyclic amino acids revealed lowered pI values compared to the parent 1‐amino‐cyclohexane‐ and ‐cycloheptanecarboxylic acids.
... Pip was also reported to increase the water solubility of peptides [159,163]. The non-canonical residue Ind (aminoindane carboxylic acid) has a stabilizing effect on the formation of α/3 10 -helices [159,164,165]. ...
This review provides a fresh overview of non-canonical amino acids and their applications in the design of peptidomimetics. Non-canonical amino acids appear widely distributed in nature and are known to enhance the stability of specific secondary structures and/or biological function. Contrary to the ubiquitous DNA-encoded amino acids, the structure and function of these residues are not fully understood. Here, results from experimental and molecular modelling approaches are gathered to classify several classes of non-canonical amino acids according to their ability to induce specific secondary structures yielding different biological functions and improved stability. Regarding side-chain modifications, symmetrical and asymmetrical α,α-dialkyl glycines, Cα to Cα cyclized amino acids, proline analogues, β-substituted amino acids, and α,β-dehydro amino acids are some of the non-canonical representatives addressed. Backbone modifications were also examined, especially those that result in retro-inverso peptidomimetics and depsipeptides. All this knowledge has an important application in the field of peptidomimetics, which is in continuous progress and promises to deliver new biologically active molecules and new materials in the near future.
The preferred helical screw senses of chiral α-amino acids with a Cα-tetrasubstituted α-carbon atom, as determined in the crystal state by X-ray diffraction analyses on derivatives and peptides, are reviewed. This survey covers Cα-methylated and Cα-ethylated α-amino acids, as well as α-amino acids cyclized on the α-carbon, including those characterized by the combination of lack of chirality at the α-carbon with either side-chain or axial chirality. Although, in general, chiral Cα-tetrasubstituted α-amino acids show a less pronounced bias toward a single helical screw sense than their proteinogenic (Cα-trisubstituted) counterparts, our analysis highlights significant differences in terms of magnitude and direction of such a bias among the various sub-families of residues, and between individual amino acids within each sub-family as well. The experimental findings can be rationalized, at least in part, on the basis of steric considerations.
As a part of the development of conformational guidelines for the design of metabolically altered peptidomimetics, we present conformational energy calculations on model dipeptide compounds with glycine (Gly), L-alanine (Ala), α-aminoisobutyric acid (Aib), L-tert-butylglycine (Tle), L-phenylglycine (Phg), (α,α)-diphenylglycine (Dφg), L-2-aminobutyric acid (Abu), 2-amino-2-ethylbutync acid (Deg), L-2-amino-2-vinylacetic acid (Ava) and (α,α)-divinylglycine (Dvg). The energy calculations have been made using molecular mechanics methods with a force field derived from MM2. The salient features are expressed in terms of conformational energy plots, drawn as a function of the backbone torsion angles φ(Ci-1′-Ni-Ciα-Ci′) and ψ(Ni- Ciα-Ni + 1). The low-energy structures of these compounds are qualitatively consistent with the X-ray crystal structure analyses of peptides and peptidomimetics. They are also in agreement with the results of the solution-phase studies carried out by NMR and IR techniques. The results obtained have important implications in the design of conformationally restricted peptidomimetics.
The solution conformation of a designed tetradecapeptide Boc-Val-Ala-Leu-Dpg-Val-Ala-Leu-Val-Ala-Leu-Dpg-Val-Ala-Leu-OMe (Dpg-14) containing two di-n-propyl glycine (Dpg) residues has been investigated by (1)H NMR and circular dichroism in organic solvents. The peptide aggregates formed at a concentration of 3 mM in the apolar solvent CDCl(3) were broken by the addition of 12% v/v of the more polar solvent DMSO-d(6). Successive N(i)H <--> N(i+1)H NOEs observed over the entire length of the sequence in this solvent mixture together with the observation of several characteristic medium-range NOEs support a major population of continuous helical conformations for Dpg-14. Majority of the observed coupling constants (3)JNHC(alpha)H) also support phi values in the helical conformation. Circular dichroism spectra recorded in methanol and propan-2-ol give further support in favor of helical conformation for Dpg-14 and the stability of the helix at higher temperature.
A pentapeptide, Boc-Leu-Ac8c-Ala-Leu-Ac8c-OMe 1, an octapeptide, acid residue (Ac8c) were synthesized and conformationally characterized by x-ray diffraction studies in the crystal state. Peptides 1 and 2 were also studied by NMR in CDCl3 solution. Peptide 1 adopts a purely 310-helical conformation in crystals, stabilized by three intramolecular 1 ← 4 hydrogen bonds. Peptide 2 in crystals is largely 310-helical with distortion in the backbone at the N-terminus by the insertion of a water molecule between Ac8c (2) CO and Ala (6) NH groups. Peptide 3 forms a C10-ring structure, i.e. a type III (III′) β- turn conformation stabilized by an intramolecular 1 ← 4 hydrogen bond. Five cyclooctane rings assume boat-chair conformations, whereas the sixth [Ac8c(8) in 2] is appreciably distorted, resembling a chiral intermediate in the pseudorotational pathway from the boat-chair to the twisted boat-chair conformation. Internal bond angles of the cyclooctane rings are appreciably distorted from the tetrahedral value, a characteristic feature of the cyclooctane ring. Peptide 1 crystallized in the space group P212121 with a = 11.900(4) Å, b = 18.728(6) Å, c = 20.471(3) Å and Z = 4. The final R1 and wR2 values are 0.0753 and 0.2107, respectively, for 3901 observed reflections [Fo ≥ 3σ(Fo)]. Peptide 2 crystallized in space group P21 with a = 12.961(5) Å, b = 17.710(10) Å, c = 15.101(7) Å, β = 108.45(4)° and Z = 2. The final R1 and wR2 values are 0.0906 and 0.1832, respectively, for 2743 observed reflections [Fo ≥ 3σ (Fo)]. 1H-NMR studies on both the peptides strongly suggest the persistence of 310-helical conformations in solution. Peptide 3 crystallized in the space group P21/n, with a= 10.018(1) Å, b = 20.725(1) Å, c = 12.915(1) Å and Z = 4. The final R1 and wR2 values are 0.0411 and 0. 1105, respectively, for 3634 observed reflections [Fo ≥ 4σ(Fo)]. Copyright
Four residues making almost a complete 180 degrees turn in the direction of the peptide chain define a reverse turn, a common motif and recognition site in proteins. Cyclization between residues i and i + 3 and incorporation of heterochiral dipeptides (such as d-Pro-l-Pro) in the i + 1 and i + 2 positions are used to constrain a peptide to a reverse-turn conformation. A combined approach, cyclic tetrapeptides (CTPs) based on heterochiral dipeptides of chimeric amino acids, is evaluated as minimalist scaffolds for reverse-turn conformations. Cyclo-(d-Pro-l-Pro-d-Pro-l-Pro) has been studied with density functional theory (DFT) calculations and molecular dynamics simulations. The all-trans amide conformer was the most stable in vacuo, while the cis-trans-cis-trans (ctct) or trans-cis-trans-cis (tctc) amide conformer was more favored in water due to its large dipole moment. Different conformations could be selectively stabilized by different substitutions on the proline rings. Due to the small 12-membered ring and exocyclic constraints, conformational interconversions could only occur at high temperature. The presence of seven hydrogens on each ring that could be functionalized offers an overwhelming diversity to design molecules to probe receptors. The spatial relationships of C(alpha)-C(beta) vectors of reverse turns in proteins were subjected to principal component analysis for determination of the relative orientation of the C(alpha)-C(beta) vectors. Most reverse-turn structures could be mimicked effectively with a subset of CTP scaffolds with an root-mean-square displacement (RMSD) of approximately 0.5 A. Structural diversity of CTP scaffolds could be enhanced by the incorporation of proline analogues, such as azaproline (azPro) or pipecolic (Pip), azapipecolic (azPip), nipecotic (Nip), and isonipecotic (Inp) acids.
Conformational energy computations of the monopeptides from three achiral α,α-dialkylated glycyl residues with acyclic side
chains (namely α,α-dimethyl-; α,α-diethyl-; and α, α-di-n-propylglycines) are reported as a function of the relevant N-Cα-C′ bond angle. In parallel, experimental studies were performed in the solid state (infrared absorption and X-ray diffraction)
and in solution (infrared absorption and proton magnetic resonance) on the corresponding protected homo-peptide series (the
former series to the dodecamer, the other two series to the pentamers). The results obtained unequivocally indicate that the
preference from a helical to a fully extended conformation increases as side-chain bulkiness increases. The longest homo-peptides
from α,α-dimethylglycine form stable 310-helices. A picture of the mode of self-association of the helical structures has also been determined. The results of the
theoretical analyses fit well with the experimentally observed conformational properties in the solid state and in chloroform
solution.
The molecular and crystal structures of the C alpha,alpha-dialkylated alpha-amino acid residue 1-aminocyclopropane-1-carboxylic acid hemihydrate (H2+-Ac3c-O-.1/2 H2O) and nine derivatives and dipeptides have been determined by X-ray diffraction. The derivatives are pBrBz-Ac3c-OH, Piv-Ac3c-OH, Z-Ac3c-OH, the alpha-and beta-forms of t-Boc-Ac3c-OH, Z-Ac3c-OMe, and the 5(4H)-oxazolone from pBrBz-Ac3c-OH; the dipeptides are H-(Ac3c)-OMe and c(Ac3c)2. The values determined for the torsion angles about the N-C alpha (phi) and C alpha-C' (psi) bonds for the single Ac3c residue of Piv-Ac3c-OH, the alpha- and beta-forms of t-Boc-Ac3-OH and Z-Ac3c-OMe, and the C-terminal Ac3c residue of H-(Ac3c)2-OMe correspond to folded conformations in the "bridge" region of the Ramachandran map. The structures of pBrBz-Ac3c-OH and Z-Ac3c-OH, however, are unusual in having a semi-extended conformation for the phi, psi angles. The N-terminal Ac3c residue of H-(Ac3c)2-OMe adopts a novel type of C5 conformation, characterized inter alia by an (amino) N. . .H-N (peptide) intramolecular hydrogen bond. While the acyl N alpha-blocking groups form trans amides (pBrBz-Ac3c-OH and Piv-Ac3c-OH), the urethane groups may adopt either the trans [Z-Ac3c-OH and t-Boc-Ac3c-OH (alpha-form)] or the cis amide conformations [t-Boc-Ac3c-OH(beta-form) and Z-Ac3c-OMe]. The five- and six-membered rings of the 5(4H)-oxazolone and the 2,5-dioxopiperazine, respectively, are planar. The four independent molecules in the asymmetric unit of the free alpha-amino acid are zwitterionic.
The x-ray structure of Boc-L-Ala-Aib-Ala-Aib-Ala-Glu(OBzl)-Ala-Aib-Ala-Aib-Ala-OMe(I) represents the first α-helix determined by direct methods. This undecapeptide is a model of the N-terminus of alamethicin, and it exhibits voltage-dependent pores in bilayer membranes at a higher voltage and concentration than alamethicin. The molecule crystallizes in the monoclinic space group P21 with a = 10.602(1), b = 23.884(3), c = 13.622(1) Å, β = 95.61(6)°, and Z = 2. It adopts a right-handed α-helical conformation in the solid state with intramolecular 5 → 1 hydrogen bonds. An additional intramolecular hydrogen bond is bifurcated, forming a stronger 4 → 1 interaction (i.e., a β-turn III) and a weaker 5 → 1 interaction, thus prolonging the α-helical part up to 9 residues. The α-helix radius of 2.1 Å, the height per residue (distance Ni … Ni + 4) of 1.53 Å, the resulting length of the α-helical part of 13.8 Å (9 residues) resp. 15.3 Å (10 residues), the van der Waals radius (4.7 Å), and the minimal diameter of pores formed by aggregation of 3–10 α-helices were calculated omitting the Glu(OBzl) side chain. In the crystal, the α-helices are linked head to tail via two hydrogen bridges forming continuous chains. Adjacent helices are oriented in antiparallel with their helix axes and have only van der Waals contacts.
A method is described for calculating sets of dihedral angles in a seven- membered ring with equal tetrahedral bond angles and equal bond lengths. Representative values are given for the separate chair and boat manifolds of solutions.
The crystal structures of two peptides containing 1-aminocyclohexanecarboxylic acid (Acc6) are described. Boc-Aib-Acc6-NHMe · H2O adopts a β-turn conformation in the solid state, stabilized by an intramolecular 4 1 hydrogen bond between the Boc CO and methylamide NH groups. The backbone conformational angles (φAib = – 50.3°, ψAib = – 45.8°; φAcc6 = – 68.4°, ψAcc6 = – 15°) lie in between the values expected for ideal Type I or III β-turns. In Boc-Aib-Acc6-OMe, the Aib residue adopts a partially extended conformation (φAib = – 62.2°, ψAib = 143°) while the Acc6residue maintains a helical conformation (φAcc6 = 48°, ψAcc6= 42.6°). 1H n.m.r. studies in CDCl3 and (CD3)2SO suggest that Boc-Aib-Acc6-NHMe maintains the β-turn conformation in solution.
The conformational preferences of terminally-blocked homopeptides of 1-aminocyclopentane-1-carboxylic acid from monomer to hexamer in chloroform solution were assessed by infrared absorption and 1H nuclear magnetic resonance as a function of concentration, temperature, and addition of perturbing agents. The results obtained strongly support the view that an incipient 310-helix is first formed at the tripeptide level. A comparison is made with the preferred conformation of homopeptides from the higher homologue 1-aminocyclohexane-1-carboxylic acid and the open chain analogue Cα,α-diethylglycine.
Coformational energy calculations on the 1-aminocyclopentane-1-carboxylic acid monopeptide Ac-Acc5-NHMe indicate that this Cα,α-dialkylated, cyclic α-amino acid residue is conformationally restricted and that its minimum energy conformation falls in the α/310-helical region. The results of the theoretical analysis are in agreement with the crystal-state structural tendency of pBrBz(Acc5)4OtBu·2MeOH, pBrBz(Acc5)5OtBu·MeOH, and Z(Acc5)6OtBu, determined by X-ray diffraction and also described in this work (formation of 310-helices). The implications for the use of Acc5 residues in designing conformationally constrained analogues of bioactive peptides are briefly discussed.
The structures of the prolyl residues as found in the crystals of various oligopeptides were studied, and a few interesting structural features were found, (i) The Cα–C′–N angle of the peptide group formed by the N atom of the pyrrolidine ring and the Cα and C′ atoms of the preceding residue is widened to about 118° from the usual value of 114° due to the steric repulsion between the Cα and the two hydrogen atoms bonded to the Cδ atom of the pyrrolidine ring, (ii) The Cγ atoms of some pyrrolidine rings have some sort of disorder, and the Cβ–Cγ and Cγ–Cδ bonds seem to be shortened and the Cβ–Cγ–Cδ angles seem to be widened than usual, (iii) Almost half of the pyrrolidine rings have an approximate C2 (half-chair) symmetry, the twofold axis passing through the N atom and the midpoint of the Cβ–Cγ bond. The others have an approximate Cs (envelope) symmetry, the mirror plane passing through either the Cβ or Cγ atom with equal probabilities. In this case the NCαCαCγCδ or NCαCβCδgroups are almost planar, respectively, (iv) The conformation of Cγ-exo against the C′ atom bonded to the Cα atom is mainly found in the residues having the α-helix type torsion angles, while the Cγ-endo is in those having the collagen type torsion angles.
The crystal structures of 1-aminocyclohexane-1-carboxylic acid (H-Acc6-OH) and six derivatives (including dipeptides) have been determined. The derivatives are Boc-Acc6-OH, Boc-(Acc6)2-OH, Boc-L-Met-Acc6-OMe, ClCH2CO-Acc6-OH, p-BrC6H4CO-Acc6-OH oxazolone, and the symmetrical anhydride from Z-Acc6-OH, [(Z-Acc6)2O]. The cyclohexane rings in all the structures adopt an almost perfect chair conformation. The amino group occupies the axial position in six structures; the free amino acid is the only example where the carbonyl group occupies an axial position. The values determined for the torsion angles about the N–Cα(φ) and Cα–CO (ψ) bonds correspond to folded, potentially helical conformations for the Acc6 residue.
Average bond distances and bond angles as well as conformational preferences in the φ and ψ torsion angles of carboxylic amides with different substitution patterns have been derived by analyzing data from many crystal structures retrieved from the Cambridge Structural Database (CSD).
The average lengths of bonds involving the elements H, B, C, N, O, F, Si, P, S, Cl, As, Se, Br, Te, and l in organic compounds are reported.
Energy functions of bending of the C—C—C angle and of twisting of the CH2—CH2 torsional angle have been examined through their effect on calculations of stable conformations and excess enthalpies of all the cycloalkane molecules from C6H12 to C12H24.The total strain energy was expressed as a function of the internal coordinates—bond lengths, bond angles and torsional angles. H—H distances were derived by matrix algebra, and the method of steepest descent was applied. Energy parameters like the bending force constant, the zero-strain value of bond angles, torsional potential barrier, were varied one at a time, and their effect on conformation and strain energy examined. Results have been compared with calorimetric measurements and with Xray and electron diffractions. Enthalpy of translation-rotation-vibration was also considered and found to be significant. Best agreement between calculations and experiment was obtained when the energy parameters were derived from n-alkanes. Thus, the n-alkane bond angle value of 112·7° is preferable to the tetrahedral angle as the zero-strain value; the torsional potential barrier of propane, 3·4 kcal/mole, is preferable to the corresponding value for ethane, 2·8 kcal/mole.
The conformational analysis of a protected homodipeptide of 1-aminocyclopentanecarboxylic acid (Acc5) has been carried out. 1H-nmr studies establish a β-turn conformation for Boc-Acc5-Acc5-NHMe in chloroform and dimethylsulfoxide solutions involving the methylamide NH in an intramolecular hydrogen bond. Supportive evidence for the formation of an intramolecular hydrogen bond is obtained from ir studies. X-ray diffraction studies reveal a type III β-turn conformation in the solid state stabilized by a 4 → 1 hydrogen bond between the Boc CO and methylamide NH groups. The ϕ,ψ values for both Acc5 residues are close to those expected for an ideal 310-helical conformation (ϕ≃ ± 60°, ψ∼ ±30°).
The preferred conformation of N- and C-protected homopeptide series of 1-aminocyclohexane-1-carboxylic acid from monomer to pentamer in chloroform solution was determined by using infrared absorption and 1H nuclear magnetic resonance as a function of concentration, temperature, and addition of perturbing agents. The results obtained are strongly in favor of the onset of an incipient 310 helix at the tripeptide level, as found in the crystal state. A comparison is also made with the conformational propensities of homopeptides of 1-aminocyclopentane-1-carboxylic acid and the Cα,α-dialkylated glycyl residues with linear side chains.
Conformational energy computations on the 1-aminocyclohexane-1-carboxylic acid monopeptide, Ac-Acc6-NHMe, indicate that this Cα,α-dialkylated, cyclic α-amino acid residue is conformationally restricted and that its minimum energy conformation falls in the α/310 helical region, irrespective of the position (either axial or equatorial) of the α-amino group. The results of the theoretical analysis are in agreement with the crystal-state structural tendency of Z(Acc6)4O-t-Bu (monoclinic and triclinic forms) and p-BrBz(Acc6)4O-t-Bu, determined by X-ray diffraction and also described in this paper (formation of 310 helices). The implications for the use of Acc6 residues in designing conformationally constrained analogues of bioactive peptides are briefly discussed.
The IR absorption and XH NMR analysis of the preferred conformation of monodisperse Z-(Aib)n-OtBu (Z = (benzyloxy)carbonyl, OtBu = tert-butoxy, Aib = α-aminoisobutyric acid; n = 1-12) strongly indicates the formation of fully developed stable 310-helices for the higher (n = 8-12) homooligomers (pleionomers). This experimental study was performed in the solid state as well as in deuteriochloroform solution, in the latter case as a function of concentration, temperature, and addition of dimethyl sulfoxide and the free radical Tempo. A picture of the mode of self-association of the helical structures has also been obtained. A detailed theoretical study of Aib N-acetyl-N′-methyl amide by conformational energy computations indicates that the fully extended structure is less stable than the helical structures, irrespective of the actual value of the N-Cα-C′ valence angle.
Computation of the energies of hydrocarbon molecule conformations as a function of various geometric parameters is discussed and machine computation advanced as a means of coping with the enormous calculations necessary for their solution. New functions for non-bonded interactions are developed and compared with several previous ones. The cyclo-alkanes, C5-7, are taken as examples, their conformations of minimum energy computed, and these energies compared with experimental values. The conformations and pseudorotations of the flexible forms of these rings are discussed in the light of the calculations, and special attention is paid to a discussion of the more complex conformational analysis of cycloheptanes.
The basic method of Westheimer (which utilizes classical mechanics to calculate the exact structures and conformational energies of molecules) has been further refined so that for a series of hydrocarbons, calculated energies may be used as a basis for the calculation of heats of formation without loss of correlation with the other experimental results. Previous predictions regarding the structures and energies of certain systems are revised, and additional systems are considered. The calculations predicted that trans-1,3-di-t-butylcyclohexane would exist as a conformational mixture of chair and boat forms, and variable-temperature infrared spectra showed two conformations differing in enthalpy by 0.4 kcal/mol.
Constants in the functions used for the calculation of minimum-energy conformations for n-butane and cycloalkanes were varied so as to find the set which best reproduced a dozen items of experimental data (geometry and energies). The resultant best functions were then applied to obtain the geometry and energies of the symmetrical cycloalkane rings.
A unique mean plane is defined for a general monocyclic puckered ring. The geometry of the puckering relative to this plane is described by amplitude and phase coordinates which are generalizations of those introduced for cyclopentane by Kilpatrick, Pitzer, and Spitzer. Unlike earlier treatments based on torsion angles, no mathematical approximations are involved. A short treatment of the four-, five-, and six-membered ring demonstrates the usefulness of this concept. Finally, an example is given of the analysis of crystallographic structural data in terms of these coordinates.
A relatively complete calculation of the low-energy conformations of cycloheptane is presented. The various paths for pseudorotation and the various transition states are rigorously characterized. It is shown that the pseudorotation paths of cycloheptane can be visualized as occurring on a helical track wound around a torus. Our results for the equilibrium conformations of cycloheptane are compared to the results of other calculations and found to agree qualitatively. Our calculated results give the best agreement with the available rotational constants, but final determination of the details of the potential functions and of the detailed properties of the conformations of cycloheptane will have to await the results of future experiments.
Empirical observations by other workers have suggested that peptides containing α-aminoisobutyric acid obligatorily adopt 310-helical forms in the crystal state. The reasons for this conformational preference have not been understood heretofore, and this question is addressed in the present study. The preferred conformations of N-acetyl-Ń-methyl(α-aminoisobutyryl)namide (with n = 1, 2, 3) have been determined by empirical conformational energy calculations; minimum energy conformations were located by minimizing the energy with respect to all the dihedral angles of the molecule. The conformational space of the α-aminoisobutyric acid residue is sterically severely restricted and therefore sensitive to the covalent geometry assigned to this residue, in particular to the bond angles between the substituents on the Cα atom. Tetrahedral symmetrical geometry for these substituents favors the α-helical conformation for the α-aminoisobutyric acid residue (and di- and tripeptides thereof) whereas asymmetric geometry, derived from well-refined X-ray structures, gives the 310 conformation as the preferred structure. Analysis of pairwise atomic interactions indicates that favorable backbone-backbone interactions lower the overall energy of the molecule in the 310 conformation when the substitution on the Cα atom is asymmetric.
The conformational preferences of the N- and C-protected homopeptides from α,α-di-n-propylglycine (to the pentapeptide) in the solid state and in chloroform solution have been assessed by using infrared absorption and H nuclear magnetic resonance. A comparison is made with the conformations adopted by the corresponding series from α-aminoisobutyric acid, also dialkylated at the α-carbon, and from L-norvaline, in which the single alkyl side chain is the same as those in α,α-di-n-propylglycine. The highest L-norvaline homopeptides exhibit a significant tendency for adopting an intermolecularly H-bonded β-structure, in contrast to the α,α-di-n-propylglycine and α-aminoisobutyric acid peptides where intramolecular H-bonding is the dominating factor. The likely absence of a conformational transition with increasing main-chain length and the exceptional structural stability upon heating of all the α,α-di-n-propylglycine homopeptides represent an additional relevant finding of the present work.
Conformational energy computations on a derivative and a homodipeptide of α,α-di-n-propylglycine were performed. In both cases the N- and C-terminal groups are blocked as acetamido and methylamido moieties, respectively. To analyze the effect of side-chain length, we carried out computations also on N-acetyl-α-methyl-α-ethyl-D-glycine methylamide. Literature data on N-acetyl-α,α-dimethylglycine methylamide were compared with our results. It was found that the minimum energy conformations for the α,α-di-n-propylglycine derivative and homodipeptide correspond to the fully extended conformation. A comparison with the derivatives of α-methyl-α-ethyl-D-glycine and α,α-dimethylglycine indicates that the preference from a folded to a fully extended conformation increases with increasing bulkiness of the Cα-substituents. The results of the theoretical analysis of the conformation of the derivative and homodipeptide of α,α-di-n-propylglycine are in agreement with their conformational properties in the solid state, determined by X-ray diffraction and also described in this work. In this latter study the N- and C-terminal groups are blocked as trifluoroacetamido and N′,N′-dibenzylacylhydrazido moieties, respectively.
Conformational energy calculations on the model system N-acetyl-1-aminocyclohexanecarboxylic acid N′-methylamide (Ac-Acc6-NHMe), using an average geometry derived from 13 crystallographic observations, establish that the Acc6 residue is constrained to adopt conformations in the 310/α-helical regions of φ, ψ space (φ = ± 50 ± 20°, ψ = ± 50 ± 20°). In contrast, the α,α-dialkylated residue with linear hydrocarbon side chains, α,α-di-n-propylglycine favors fully extended backbone structures (φ ≈ ψ ≈ 180°). The crystal structures of two model peptides, Boc-(Acc6)3-OMe (type III β-turn at -Acc6(1)-Acc6(2)-) and Boc-Pro-Acc6-Ala-OMe (type II β-turn at -Pro-Acc6-), establish that Acc6 residues can occupy either position of type III β-turns and the i + 2 position of type II β-turns. The stereochemical rigidity of these peptides is demonstrated in solution by NMR studies, which establish the presence of one intramolecular hydrogen bond in each peptide in CDCl3 and (CD3)2SO. Nuclear Overhauser effects permit characterization of the β-turn conformations in solution and establish their similarity to the solid-state structures. The implications for the use of Acc6 residues in conformational design are considered.
Die Alkoholyse von -Aminosuremethylestern ist zur Gewinnung von Aminosureestern schwerflüchtiger Alkohole brauchbar. Bei Verwendung von Natriumalkoxyd als Umesterungskatalysator erfolgt am -Kohlenstoffatom der Aminosure ganz oder teilweise Racemisierung; die optische Aktivitt bleibt dagegen erhalten, wenn als Katalysator ein Aluminiumalkoxyd verwendet wird. Die benötigten Aminosure-methylester können, namentlich wenn sie in grösseren Mengen gebraucht werden, auf einfachste Weise mit Hilfe von Thionylchlorid hergestellt werden.
Conformational energy computations on a derivative and a homo-dipeptide of Cα,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 Cα,α-diethylglycine residues are conformationally restricted and that the minimum energy conformation corresponds to the fully extended C5 structure when the NCαC′ 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 Cα,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 Cα,α-dimethylglycine, Cα-methyl, Cα-ethylglycine, and Cα,α-di-n-propylglycine indicates that the fully extended conformation becomes more stable than the helical structures when both amino acid side-chain Cβ atoms are substituted.
The conformational preferences of linear peptides containing α,α-disubstituted α-amino acids, derived from the crystal structures of 28 compounds, are reviewed. In particular, the sensitivity of peptide conformation to the geometry of these unusual amino acids is underlined. We also consider possible future directions of research, which, we hope, will result in a complete understanding of the structures adopted by peptaibol antibiotics.
Boc-L-Leu-Aib-Pro-Val-Aib-Aib-Glu(OBzl)-Gln-Phl (Boc = t-butyloxycarbonyl, Aib = α-aminoisobutyric acid, Bzl = benzyl, Phl = phenylalaninol), C59H90N10O14, the protected C-terminal nonapeptide with the sequence 12–20 of alamethicin, crystallizes in the orthorhombic space group P212121 with a = 15.666, b = 16.192, c = 26.876 Å, and Z = 4. The molecular conformation is right-handed helical with three α-(5 → 1 hydrogen bonds) and three β-turns (4 → 1 hydrogen bonds). All but two of the hydrogen bonds are significantly longer than the usual value and show bifurcation to some extent. The α/3-helical nonapeptide molecules are arranged head-to-tail along the a direction. The resulting linear antiparallel chains are linked by a weak intermolecular hydrogen bridge, thus forming a two-dimensional layer structure in the ab plane. The conformation of this nonapeptide is almost identical with that of the corresponding C-terminal part found by x-ray crystallography of the eicosapeptide alamethicin.
The results of X‐ray diffraction analyses on two α‐aminoisobutyric acid (Aib) derivatives, methyl α‐(acetylamino)isobutanoate (Ac‐Aib‐OMe, 1) and benzyl α‐[(benzyloxycarbonyl)amino]isobutanoate (Z‐Aib‐OBzl, 2), and two terminally blocked, Aib‐containing dipeptides, methyl α‐[(acetyl‐L‐alanyl)amino]isobutanoate (Ac‐L‐Ala‐Aib‐OMe, 3) and tert‐butyl α‐{[(benzyloxycarbonyl)amino]isobutanoyl}‐L‐alaninate (Z‐Aib‐L‐Ala‐OtBu, 4) are described. In the asymmetric unit of all four compounds two independent molecules were found. In all cases but one (molecule A of 3) the Aib residue is folded, the sets of Φ, ψ (or Φ, ψT) torsion angles falling in the region of the conformational energy map where both α‐ and 310‐helices are found. A correlating statistical analysis of bond lengths, bond angles, and torsion angles from available crystal structures of 20 Aib derivatives and 11 Aib‐containing linear dipeptides was also performed to obtain precise information on the geometry and conformation of the Aib residue without the influence of the constraints imposed by the intramolecular hydrogen bonds characterizing higher‐order folded and helical peptides.
Structural parameters, derived from X-ray crystallographic data, have been compiled for amino acid and linear peptide derivatives which contain the N-terminal tert-butoxycarbonyl (Boc) group or its next higher homolog, the tert-amyloxycarbonyl group. The comparison of the geometry of the urethane group in Boc-derivatives with that of the peptide group shows small differences in bond angles about the trigonal carbon, because of altered interactions when a CαH group of a peptide unit is replaced by an ester oxygen. In contrast to the strong preference of the peptide bond for the trans form (except when it precedes proline), the urethane amide bond adopts both the cis and trans conformations in crystals. The cis urethane conformation is preferred in crystals of compounds with a tertiary nitrogen (such as Boc-Pro) or in structures stabilized by strong intermolecular interactions. Conformational energy computations on Boc-amino acid N'-methylamides indicate that the trans and cis conformations of the urethane amide bond have nearly equal energies (even for amino acids other than proline), in contrast to the peptide bond, for which the trans conformation has a much lower energy. The computed increase of the cis content in Boc-amino acid derivatives (as compared with the corresponding N-acetyl derivatives) is consistent with the observed distributions of conformations in crystal structures and with n.m.r. studies in solution. Usually, the substitution of a Boc for an N-acetyl end group does not alter the conformational preferences (as indicated by φ, Ψ values and relative energies) of the amino acid residue which follows the end group when the amide bond is trans. Particular conformations, however, can be stabilized by strong attractive interactions between some side chains (e.g. that of phenylalanine) and the bulky Boc end group.
The crystal-state molecular structures of five linear Ac3c homo-oligopeptides to the tetramer were determined by x-ray diffraction. The oligomers are H-(Ac3c)2-OMe, Fmoc-(Ac3c)2-OMe MeOH, Ac-(Ac3c)2-OMe, pBrBz-(Ac3c)3-OMe · H2O, and t-Boc-(Ac3c)4-OMe · 2H2O. The results indicate the propensity of the tri- and tetrapeptides to fold into type I β-bends and distorted 310-helices, respectively, in partial contrast to Aib, Ac5c, and Ac6c homo-peptides of comparable main-chain length, where regular type III β-bends and 310-helical structures were found. When the influence of the constraints produced by the intramolecular H bonds of the C10-type is absent, other less common structural features may be observed. The average geometry of the cyclopropyl group of the Ac3c residue is found to be asymmetric and the NCαC′ bond angle significantly expanded from the regular tetrahedral value.
We have carried out a systematic analysis of the solid-state conformational preferences of a number of linear homo-oligoprolines (to the tetramer) by ir absorption and x-ray diffraction. The peptides present different chiral sequences (tacticities), various types (urethane and amide) of N-protecting groups, and free and blocked C-termini (which imply different capabilities of forming H-bonds). The following conclusions can be drawn: (i) values for the geometry of the prolyl residue and the peptide bond in the cis and in the trans conformations are proposed; (ii) in general the conformational angles φ and ψ in the linear homo-oligoprolines have values appropriate for the polyproline II structure (conformation F); (iii) the pyrrolidine ring shows various types of puckering with no apparent relation to the backbone conformation; (iv) Pro-Pro peptide bonds generally take the trans conformation, the few cases of cis conformation being formed by Pro residues of different chirality; (v) the single H-bond donor — OH, when present, is always bonded to H-acceptors, which can be either the urethane or the amide or the peptide carbonyl but never the carbonyl group of the — COOH moiety.
Average bond distances and bond angles in carboxylic esters with different substitution patterns have been derived by analyzing data from many crystal structures retrieved from the Cambridge Structural Database (CSD). Conformation-al preferences in the attachment of substituents are found.
The preferred conformations of model cyclopropylglycine peptides have been investigated by means of ab initio and empirical methods. Empirical computations performed with fixed bond lengths and valence angles using two well-known force fields show that only values of ϕ in the ranges ±70° ± 20° are sterically allowed, and that the C7-conformation corresponds to the absolute energy minimum irrespective of the terminal groups used. Also, ab initio computations give similar results, but suggest greater stabilities for bridge and, especially, extended structures. These discrepancies can be removed, adding to the empirical force field a twofold torsional potential on ψ and using softer steric repulsive potentials. Complete geometry optimization using both ab initio and empirical methods does not affect the relative stabilities of folded conformations, but leads to a further significant stabilization of the fully extended structure via large modifications of some valence angles.
1-Aminocycloheptanecarboxylic acid hydrobromide monohydrate crystallizes in space group P 2 1 2 1 2 1 with cell dimensions a = 25??69, b = 6??85 and c = 6??61 ??. The structure was solved in the hk 0 and h 0 l projections, and refined with the three-dimensional data to an R factor of 9??86%. The cycloheptane ring is disordered, which leads to ???predominant??? and ???alternative??? conformations. Both of these conformations correspond to a skew-chair form. The structure is stabilized by a three-dimensional network of hydrogen bonds.
The present study concerns the energies of the conformations of proline. We present results of an improved molecular mechanics calculation for ring conformations of Ac-Pro-OCHâ and for the s-cis and s-trans conformations. Internal coordinates including all torsions have been calculated from crystal coordinates for more than 40 x-ray determinations to give a consistent set of data which define proline ring geometries. Results from the present work and from the many previous studies on proline derivatives by other workers permit the following definitive statements: (1) Although four parameters are theoretically necessary to define the conformational state of a five-membered ring having fixed bond lengths, in practice two parameters ordinarily suffice for the proline ring. (2) There are two broad energy minima with a barrier high enough to rule out pseudorotation, but affording such flexibility of structure as to preclude the meaningful designation as envelope and chair or exo and endo. The most common conformational state approximates a range of C/super ..beta../ - C/sup ..gamma../ half chairs. (3) There is as yet no really good method to get experimental measures of the conformational state of the proline ring in solution, although useful limits can often be established by treating NMR coupling constants by the Karplus relationships. (4) ¹³CNMR is especially useful for studying s-cis-s-trans equilibria of N-acylproline derivatives. Ratios range from about 15 to 40 percent s-cis for open chain derivatives. (5) The difference of the torsions chiâ - phi is not a constant but ranges from 54 to 80°. This lack of constancy must be taken into account if proper conclusions are to be drawn from energy maps of proline-containing peptides.
The use of backbone conformational constraints has acquired increasing importance in the design and synthesis of structurally restricted agonists and antagonists of bioactive peptides. Here I discuss the preferred conformations of four among the most popular types of such peptide surrogates: (a) Peptides from C alpha, alpha-dialkylated residues, (b) tetrazolyl peptides, (c) (gamma- and delta-) lactam-containing peptides, and (d) thiated peptides. Emphasis is given to conformational energy computations and x-ray diffraction analyses of selected model compounds and analogues of small bioactive peptides such as the formylmethionyl tripeptide chemoattractant and MIF.
We have carried out an analysis of crystal structure data on prolyl and hydroxyprolyl moieties in small molecules. The flexibility of the pyrrolidine ring due to the pyramidal character of nitrogen has been defined in terms of two projection angles delta 1 and delta 2. The distribution of these parameters in the crystal structures is found to be consistent with results of the energy calculations carried out on prolyl moieties in our laboratory.
A general approach to study peptide structure is presented using three areas of ongoing research in our laboratories. The first involves the molecular basis for taste of peptide derivatives. We synthesized dipeptides based on L-aspartyl-α-aminocycloalkane carboxylic acid methyl ester. A homologous series of cycloalkane derivatives was studied. The cyclopropane, cyclobutane, and cyclopentane derivatives are sweet, the cyclohexane and cycloheptane peptides are bitter, and the cyclooctane homolog is tasteless. The related acyclic analog L-aspartyl-aminoisobutyric acid methyl ester is sweet, while the L-aspartyl diethyl glycine carboxylic acid methyl ester is tasteless. A model is presented to explain these experimental observations. The second area involves depsipeptides as isosteric replacements of α-hydroxy acids for amino acid residues in peptide chains. We have synthesized sequentially defined polydepsipeptides as model systems for polypeptides. A detailed analysis of the conformational order for these polydepsipeptides is presented. The third area involves partial retro–inverso peptide modifications of isomeric cyclic enkephalin analogs, which illustrate the relationship between the modification and biological activity. We are probing the intramolecular hydrogen-bonding features for these biologically active molecules. From such findings we are relating the structural and conformational preferences deduced from spectroscopy and molecular mechanics to biological activity.
Analogs of chemotactic peptides (Formyl-Met-X-Phe-OMe) containing the stereochemically constrained residues alpha-aminoisobutyric acid (Aib), 1-aminocyclopentanecarboxylic acid (Acc5) and 1-aminocyclohexanecarboxylic acid (Acc6) at position 2 are compared with the parent sequence (X = Leu) for their ability to induce lysozyme release in rabbit neutrophils. The Acc6 analog is about 78 times more active than the parent peptide, For-Met-Leu-Phe-OH, whereas Aib and Acc5 analogs are approximately 3 and 2 times, respectively, less active than the parent peptide. NMR and model building studies clearly favour a Met-Acc6 beta-turn solution conformation in the Acc6 analog, suggesting that the neutrophil receptor is capable of recognizing a folded peptide structure. The significant differences in the activities of the Acc5 and Acc6 analogs suggest an important role for the residue 2 sidechain in receptor interactions.
Several L-aspartyl-D-alanyl tripeptides have been synthesized to investigate the structural requirements of the C-terminal amino acid needed to elicit a taste response. Following our suggestion that a rigid, hydrophobic residue is required, both alpha, alpha-dialkane and cycloalkane alpha-amino acid methyl esters were incorporated into the tripeptide. The L-aspartyl-D-alanine-based tripeptide derivatives of alpha-aminoisobutyric acid methyl ester, alpha, alpha-diethylglycine methyl ester, and alpha-aminocycloalkanecarboxylic acid methyl esters from three- to six-membered rings are sweet. The higher analogues of the cycloalkane series containing alpha-aminocycloheptanecarboxylic acid methyl ester and alpha-aminocyclooctanecarboxylic acid methyl ester are bitter. It is important to note that this series of tripeptides (analogous to the previously reported dipeptides) goes from sweet to bitter to tasteless as the ring size of the C-terminal amino acid increases. The relationships between effective volume of the C-terminal residue, size requirements of the sweet receptor, and taste are discussed.