X-ray Studies on Crystalline Complexes Involving Amino Acids and Peptides. XIII. Effect of Chirality on Molecular Aggregation: The Crystal Structures of L-Arginine D-Aspartate and L-Arginine D-Glutamate Trihydrate

The crystal structures of (1) L-arginine D-asparate, C6HIsN40~.C4H6NO4 [triclinic, P1, a=5.239(1), b=9.544(1), c=14.064(2)A, a=85"58(1), /3=88.73 (1), ~/=84.35 (1) °, Z=2] and (2) L-arginine D-glutamate trihydrate, C6H15N40~-.CsHsNO4.3H20 [monoclinic, P2~, a=9.968(2), b=4.652(1), c=19.930 (2) A, fl = 101.20 (1) °, Z = 2] have been determined using direct methods. They have been refined to R =0.042 and 0.048 for 2829 and 2035 unique reflections respectively [I>2cr(I)]. The conformations of the two arginine molecules in the aspartate complex are different from those observed so far in the crystal structures of arginine, its salts and complexes. In both complexes, the molecules are organized into double layers stacked along the longest axis. The core of each double layer consists of two parallel sheets made up of main-chain atoms, each involving both types of molecules. The hydrogen bonds within each sheet and those that interconnect the two sheets give rise to EL-, DD- and DE-type head-to-tail sequences. Adjacent double layers in (1) are held together by side-chain-side-chain interactions whereas those in (2) are interconnected through an extensive network of water molecules which interact with sidechain guanidyl and carboxylate groups. The aggregation pattern observed in the two LD complexes is fundamentally different from that found in the corresponding EL complexes.

Conformations Of Peptides Containing 1-Aminocyclohexane-Carboxylic Acid (Acc6) - Crystal-Structures Of 2 Model Peptides

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.

Stereochemistry of Peptides Containing 1-AminocyclopentanecarboxylicA cid ( Am5): Solution and Solid-state Conformations of Boc-Acc '-Acc'-NHMe

The conformational analysis of a protected homodipeptide of 1-aminocyclopentanecarboxylic acid (Acc5) has been carried out. 1H-nmr studies establish a -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 -turn conformation in the solid state stabilized by a 4 1 hydrogen bond between the Boc CO and methylamide NH groups. The , values for both Acc5 residues are close to those expected for an ideal 310-helical conformation ( ± 60°, ±30°).

Synthetic peptides as chemoattractants for bull spermatozoa structure activity correlations

The ability of various synthetic peptide analogs of. Formyl-Met-Leu-Phe to induce chemotaxis in bull sperm is compared using an inverted capillary assay. The formyl group is essential for chemotactic activity and corresponding t-butyloxycarbonyl tripeptides are inactive. Sequence analogs, Formyl-Met-Phe-Leu, Formyl-Leu-Met-Phe and Formyl-Leu-Phe-Met are active. Replacement of Met and Leu by Pro does not diminish activity. Formyl-Met-Leu-Phe-NH2 is active suggesting that electrostatic interactions involving the carboxyl group may be unimportant in receptor interactions. The studies establish the importance of an amino terminal formyl group and a sequence of at least three hydrophobic residues, for inducing sperm chemotaxis.

Stereochemical studies on cyclic peptides. XIII. Energy minimization studies on cyclic hexapeptides having hydrogen bonds

The basic cyclic hexapeptide conformations which accommodate hydrogen bonded β and γ turns in the backbone have been worked out using stereochemical criteria and energy minimization procedures. It was found that cyclic hexapeptides can be made up of all possible combinations of 4 ± 1 hydrogen bonded types I, I', II and II' β turns, giving rise to symmetric conformations having twofold and inversion symmetries as well as nonsymmetric structures. Conformations having exclusive features of 3 ± 1 hydrogen bonded γ turns were found to be possible in threefold and S6 symmetric cyclic hexapeptides. The results show that the cyclic hexapeptides formed by the linking of two β turn tripeptide fragments differ mainly in (a) the hydrogen bonding scheme present in the β turn tripeptides and (b) the conformation at the α-carbon atoms where the two tripeptide fragments link. The different hydrogen bonding schemes found in the component β turns are: 1) a β turn with only a 4 ± 1 hydrogen bond, 2) a type I or I' β turn with 4 ± 1 and 3 ± 1 hydrogen bonds occurring in a bifurcated form and 3) a type II or II' β turn having both the 4 ± 1 and the 3 ± 1 hydrogen bonds with the same acceptor oxygen atom. The conformation at the linking α-carbon atoms was found to lie either in the extended region or in the 3 ± 1 hydrogen bonded γ turn or inverse γ turn regions. Further, the threefold and the S6 symmetric conformations have three γ turns interleaved by three extended regions or three inverse γ turns, respectively. The feasibility of accommodating alanyl residues of both isomeric forms in the CHP minima has been explored. Finally, the available experimental data are reviewed in the light of the present results.

X-ray studies on crystalline complexes involving amino acids and peptides. Part XIV: Closed conformation and head-to-tail arrangement in a new crystal form of L-histidine L-aspartate monohydrate

A new form of L-histidine L-aspartate monohydrate crystallizes in space group P22 witha = 5.131(1),b = 6.881(1),c= 18.277(2) Å,β= 97.26(1)° and Z = 2. The structure has been solved by the direct methods and refined to anR value of 0.044 for 1377 observed reflections. Both the amino acid molecules in the complex assume the energetically least favourable allowed conformation with the side chains staggered between the α-amino and α-scarboxylate groups. This results in characteristic distortions in some bond angles. The unlike molecules aggregate into alternating double layers with water molecules sandwiched between the two layers in the aspartate double layer. The molecules in each layer are arranged in a head-to-tail fashion. The aggregation pattern in the complex is fundamentally similar to that in other binary complexes involving commonly occurring L amino acids, although the molecules aggregate into single layers in them. The distribution of crystallographic (and local) symmetry elements in the old form of the complex is very different from that in the new form. So is the conformation of half the histidine molecules. Yet, the basic features of molecular aggregation, particularly the nature and the orientation of head-to-tail sequences, remain the same in both the forms. This supports the thesis that the characteristic aggregation patterns observed in crystal structures represent an intrinsic property of amino acid aggregation.

Resolution of racemic gossypol and interaction of individual enantiomers with serum albumins and model peptides

Racemic gossypol has been resolved by HPLC separation of diastereomeric (−) norepinephrine adducts on a reverse-phase column. The binding constants for the interaction of the three gossypol forms (+, − and −) with human and bovine serum albumins have been determined by fluoresence quenching studies. The KD values demonstrate that all three forms bind equally effectively to the two proteins, suggesting an absence of chiral discrimination in albumin-gossypol interactions. Circular dichroism studies of (+)-gossypol binding to the model dibasic peptides, Boc-Lys-Pro-Aib-Lys-NHMe and gramicidin S, suggesting that distortions of binaphthyl geometry may occur only for specific orientations of interacting residues at the receptor site.

Acyclic peptides as conformational models Crystal structure of Boc-Aib-Leu-Pro-NHMe± 2H2O

The tripeptide Boc-Aib-Leu-Pro-NHMe crystallizes in the orthorhombic space group P212121 with a = 9.542, b = 15.200, c = 18.256 Å and Z = 4. Each peptide is associated wth two water molecules in the asymmetric unit of the crystal. The structure has been solved by direct methods and refined to an R-value of 0.069. The peptide adopts a structure without any intramolecular hydrogen bond. The three residues occupy distinctly different regions of the Ramachandran map: Aib in the left-handed 310-helical region (± = 67°, ± = 23°), Leu in the β-sheet region (± = - 133°, ± = 142°) and Pro in the poly (Pro) II region (± = - 69°, ± = 151°). An interesting observation is that each water molecule participates in four hydrogen bonds with distorted tetrahedral coordination about the oxygen atom.

Advances in gene delivery through molecular design of cationic lipids

This feature article describes the recent developments in the design of cationic lipids and their applications in gene delivery. Various structure-activity investigations explaining the variations in gene transfection efficacies with respect to different molecular structures of the cationic lipids have been discussed. Gene transfer abilities are presented in relation to aggregation properties of different aqueous formulations such as cationic liposomes and surfactant aggregates from various amphiphiles and cationic lipids, as a function of their hydrophobic parts, linkers and head groups.

X-Pro peptides. A theoretical study of the hydrogen bonded conformations of (alpha-aminoisobutyryl-L -prolyl)n sequences

Intramolecularly hydrogen bonded conformations of (Aib-Pro)n sequences have been analysed theoretically. Both 4-1 (C10 and 3-1 (C7 hydrogen bonded regular structures are shown to be stereochemically feasible. Conformational energies for the helical structures have been estimated using classical potential energy methods. Both C10 and C7 conformations have very similar energies. Pyrrolidine ring puckering has a pronounced effect on the energies, and only Cv-endo puckered Pro residues can be accommodated. The theoretical calculations using spectroscopic data suggest that the recently proposed novel 310 helical conformation for benzyloxycarbonyl(Aib-Pro)4-methyl ester is in solution, is indeed energetically and stereochemically favourable.

Proline-containing β-turns in peptides and proteins: Analysis of structural data on globular proteins

Tetrapeptide sequences of the type Z-Pro-Y-X were obtained from the crystal structure data on 34 globular proteins, and used in an analysis of the positional preferences of the individual amino acid residues in the β-turn conformation. The effect of fixing proline as the second position residue in the tetrapeptide sequence was studied by comparing the data obtained on the positional preferences with the corresponding data obtained by Chou and Fasman using the Z-R-Y-X sequence, where no particular residue was fixed in any of the four positions. While, in general, several amino acid residues having relatively very high or very low preferences for specific positions were found to be common to both the Z-Pro-Y-X and Z-R-Y-X sequences, many significant differences were found between the two sets of data, which are to be attributed to specific interactions arising from the presence of the proline residue.

Cyclic biscystine peptides. Models for antiparallel -sheet conformations

The cyclic biscystine peptides (la) and (lb) adopt antiparallel 0-sheet conformations in solution, characterized by distinctive 1H n.m.r. spectral paramete.

X-Ray Studies On Crystalline Complexes Involving Amino-Acids And Peptides .11. Peptide Aggregation And Water-Structure In The Crystals Of A Hydrated 1-1 Complex Between L-Histidyl-L-Serine And Glycyl-L-Glutamic Acid

The hexahydrate of a 1:1 complex between L-histidyl-L-serine and glycyl-L-glutamic acid crystallizes in space group P1 with a = 4.706(1), b= 8.578(2), c= 16.521(3) ÅA; α= 85.9(1), β= 89.7(1)°, = 77.4(1). The crystal structure, solved by direct methods, has been refined to an R value of 0.046 for 2150 observed reflections. The two peptide molecules in the structure have somewhat extended conformations. The unlike molecules aggregate into separate alternating layers. Each layer is stabilized by hydrogen bonded head-to-tail sequences as well as sequences of hydrogen bonds involving peptide groups. The arrangement of molecules in each layer is similar to one of the plausible idealized arrangements of L-alanyl-L-alanine worked out from simple geometrical considerations. Adjacent layers in the structure are held together by interactions involving side chains as well as water molecules. The water structure observed in the complex provides a good model, at atomic resolution, for that in protein crystals. An interesting feature of the crystal structure is the existence of two water channels in the interfaces between adjacent peptide layers.

Infrared studies on the conformation of synthetic alamethicin fragments and model peptides containing .alpha.-aminoisobutyric acid

ABSTRACT: Infrared studies of synthetic alamethicin fragments and model peptides containing a-aminoisobutyric acid (Aib) have been carried out in solution. Tripeptides and larger fragments exhibit a strong tendency to form /3 turns, stabilized by 4 - 1 10-atom hydrogen bonds. Dipeptides show less well-defined structures, though C5 and C7 conformations are detectable. Conformational restrictions imposed by Aib residues result in these peptides populating a limited range of states. Integrated intensities of the hydrogen-bonded N-H stretching band can be used to quantitate the number of intramolecular hydrogen bonds. Predictions made from infrared data are in excellent agreement with nuclear magnetic resonance and X-ray diffraction studies. Assignments of the urethane and tertiary amide carbonyl groups in the free state have been made in model peptides. Shifts to lower frequency on hydrogen bonding are observed for the carbonyl groups. The 1-6 segment of alamethicin is shown to adopt a 310 helical structure stabilized by four intramolecular hydrogen bonds. The fragments Boc-Leu-Aib-Pro-Val-Aib-OMe (1 2-1 6) and Boc-Gly-Leu-Aib-Pro-Val-Aib-OMe (1 1-1 6) possess structures involving 4 - 1 and 5 - 1 hydrogen bonds. Supporting evidence for these structures is obtained from proton nuclear magnetic resonance studies.