Conformation of histidine model peptides. III. Chiroptical properties of cyclo-L-alanyl-L-histidine and cyclo-L-histidinyl-L-histidine

The chiroptical properties of the cyclic dipeptides cyclo-L -alanyl-L -histidine and cyclo-L -histidinyl-L -histidine have been investigated as a function of molecular conformation. The rotatory strengths of the n-π* transitions of the peptide chromophores and the lowest energy π-π* transitions of the imidazole chromophores have been calculated as a function of the angle of fold of the cyclic dipeptide group and the dihedral angles χ¹ and χ² of the amino acid side chains. The results of this investigation are consistent with the preferred position of the dihedral angle χ¹ occurring near 60° in the free base form of cyclo-L -alanyl-L -histidine, and near 180° when the imidazole side chain is protonated. Furthermore, in the case of the free base form of the imidazole group, it is possible that the tautomeric isomer in which N^ε is protonated may be more prevalent than the isomer in which N^δ is protonated.     

Conformation of histidine model peptides. II. Spectroscopic properties of the imidazole chromophore.

Semi-empirical molecular orbital calculations have been carried out for the free base and cationic forms of imidazole so as to obtain data which are required for the calculation of the chiroptical properties of molecules that contain this chromophoric group. The polarization, energy, and monopolar charge distribution are reported for the lowest energy electronic transitions. The absorption spectra for imidazole have been determined to 180 nm and circular dichroism spectra for L -histidinol and L -2-amino-1-butanol have been measured.     

Conformational analysis of amino acids and peptides using specific isotope substitution. I. Conformation of L-phenylalanylglycine.

L-Phenylalanyl-(R)-[²H]glycine, L-valyl-(R)-[²H]glycine, and L-phenylalanyl [¹⁵N]glycine were prepared. Assignments for pro-R and pro-S proton NMR signals of the glycine residue were done and coupling constants between proton and ¹⁵N were obtained. Based on the data an attempt to explain the origin of the nonequivalence of the glycine methylene protons was made, and a conformational model for L-phenylalanylglycine is proposed.     

Conformational energy studies of beta-sheets of model silk fibroin peptides. I. Sheets of poly(Ala-Gly) chains

A new model structure is proposed for the silk I form of the crystalline domains of Bombyx mori silk fibroin and the corresponding crystal form of poly(L-Ala-Gly). It was deduced from conformational energy computations on stacked sheet structures of poly(L-Ala-Gly). The novel sheet structure contains interstrand hydrogen bonds but is composed of anti-parallel polypeptide chains whose conformation differs from that of the antiparallel beta-sheets that constitute the silk II structure. The strands of the new sheet have a two-residue repeat, in which the Ala residues adopt a right-handed and the Gly residues a left-handed sheet-like conformation. The computed unit cell is orthorhombic, with cell dimensions a = 8.94 A, b = 6.46 A, and c = 11.26 A. The model accounts for most spacings in the observed fiber x-ray diffraction patterns of silk I and of the silk-I-like form of poly(L-Ala-Gly), and it is consistent with nmr and ir spectroscopic data. As a test of the computations, the well-established beta-sheet structure of silk II and the corresponding form of poly(L-Ala-Gly) have been reproduced. The computed energies for the two forms of poly(L-Ala-Gly) indicate that the silk-II-like form is more stable, by about 1.0 kcal/mol per residue. The main difference between the two structures is the orientation of the Ala side chains of neighboring strands in each sheet. In the Pauling-Corey beta-sheet and in the silk II form, referred to as an "in-register" structure, the Ala side chains of every strand point to the same side of a sheet. In the silk I structure, referred to as "out-of-register," the side chains of Ala residues in adjacent strands point to opposite sides of the sheet.     

Conformational energy calculations on alginic acid. II. Conformational statistics of the copolymers

Conformational energy maps have been calculated for α-D -mannuronic acid (1–4) α-L -guluronic acid and for α-L -guluronic acid (1–4) β-D -mannuronic acid. These have been used, together with maps previously calculated for the homomonomeric dimers, to estimate the characteristic ratios and Kuhn lengths of the alternating copolymer and of a stochastic copolymer similar in composition to that extracted from L. digitata.The results show that the alternating copolymer is less extended than either homopolymer. Kuhn lengths calculated for the stochastic copolymer agree well with experimental results on high ionic strength solutions of alginate isolated from L digitata.     

Conformational energy calculations on alginic acid I. Helix parameters and flexibility of the homopolymers

Conformational energy maps have been calculated for the 1-4-linked dimers of β-D -mannuronic acid and α-L -guluronic acid. Helix parameters have been calculated for poly(mannuronic acid) and for poly(guluronic acid), which are in reasonable agreement with data from x-ray fiber diffraction studies of these polysaccharides. The flexibility of the homopolymers was investigated by calculating the characteristic ratios, i.e., the ratio of the mean-square end-to-end lengths of the unperturbed chains to the product of the number of residues in the chains and the virtual bond lengths. The general conclusions are that both polymers are very stiff and extended, but that poly(mannuronic acid) is less extended than poly(guluronic acid).     

Conformational energy calculations with averaged potential functions: Application to the repeat peptides of elastin

We present a method that can reduce conformational energy calculations for an arbitrary peptide consisting of n residues (n-peptide) to the complexity of a computation for (Gly)_n. This reduction, and the concomitant savings in computer time, is accomplished by replacing all side chains, as well as the backbone C^αH^α and C^αH₂^α groups, by “interaction centers.” The backbone CONH group is left intact in order to preserve its directional character. The interaction centers “see” each other, and the atoms of the CONH group via Boltzmann and space-averaged effective center-center and center-atom potentials, respectively. This averaged-interaction method is tested on the repeat tetra-, penta-, and hexapeptides of elastin, Val-Pro-Gly-Gly (VPGG), Val-Pro-Gly-Val-Gly (VPGVP), and Ala-Pro-Gly-Val-Gly-Val (APGVGV), using the stereoalphabet strategy for the energy calculations. The excellent qualitative and quantitative agreement we obtain with both full atom-atom calculations and extensive nmr data, coupled with the order-of-magnitude reduction in computer time, augurs well for the potential usefulness of the method.     

Conformation of cyclic dipeptides from empirical energy calculations

Empirical energy calculations on cyclo-Gly-X with X- Phe, Tyr, Val, and Leu as a function of the side-chain torsion angles χ indicate that the conformation of minimum energy are characterized by χ₁ = 60°, χ² = 90° for Phe and Try, χ¹ = ?60° for Val and χ¹ = ?60°, χ² = 180° and χ¹ = 60° and χ² = 150° for Leu. The minimum energy conformation of cyclo-Gly-Phe and cyclo-Gly-Val have the side chains of Phe and Val stacked over the poperazinedione ring as suggested by NMR and found for cyclo-Gly-Tyr crystal structure. In contrast, the Leu side chain is expected to exist in an extended or a quasi-folded form.     

Conformational energy calculations on glycosylated turns in glycoproteins

Analysis of the amino acid sequence of glycoproteins has suggested the β-turn as a likely site of glycosylation in glycoproteins. According to this model, the peptide chain traverses the interior of a globular protein, reversing its direction at the protein surface, a likely point for the attachment of hydrophilic carbohydrate residues. In order to search for plausible conformations of glycosylated β-turns in asparagine-linked glycoproteins, we have adapted the conformational energy calculation method of Scheraga and coworkers for use in carbohydrates. The parameters for nonbonded and hydrogen-bonded interactions have been published, and electrostatic parameters are derived from a CNDO calculation on a model glycopeptide. Our results indicate that the orientation of the glycosyl amide bond having the amide proton nearly trans to the anomeric proton of the sugar has the lowest energy. Although CD and nmr experiments in our laboratory have consistently found this conformation, our calculations show the conformation having these two protons in a cis relationship to lie very close in energy. Calculations on the glycopeptide linkage model, α-N-acetyl, δ-N(2-acetamido-1,2-dideoxy-β-D -glucopyranosyl)-N′-methyl-L -asparaginyl amide show that several distinct geometries are allowed for glycosylated β-turns. For a type I β-turn, three conformations of the glycosylated side chain are found within 4 kcal of the minimum, while two conformations of the glycosylated side chain are allowed for a type II turn. The hydrogen-bonded C7 conformation is also allowed. Stereoviews of the low-energy conformations reveal no major hydrogen-bonding interaction between the peptide and sugar.     

Conformational transitions in model silk peptides

Protein structural transitions and beta-sheet formation are a common problem both in vivo and in vitro and are of critical relevance in disparate areas such as protein processing and beta-amyloid and prion behavior. Silks provide a "databank" of well-characterized polymorphic sequences, acting as a window onto structural transitions. Peptides with conformationally polymorphic silk-like sequences, expected to exhibit an intractable beta-sheet form, were characterized using Fourier transform infrared spectroscopy, circular dichroism, and electron diffraction. Polymorphs resembling the silk I, silk II (beta-sheet), and silk III (threefold polyglycine II-like helix) crystal structures were identified for the peptide fibroin C (GAGAGS repetitive sequence). Two peptides based on silk amorphous sequences, fibroin A (GAGAGY) and fibroin V (GDVGGAGATGGS), crystallized as silk I under most conditions. Methanol treatment of fibroin A resulted in a gradual transition from silk I to silk II, with an intermediate state involving a high proportion of beta-turns. Attenuated total reflectance Fourier transform infrared spectroscopy has been used to observe conformational changes as the peptides adsorb from solution onto a hydrophobic surface. Fibroin C has a beta-strand structure in solution but adopts a silk I-like structure upon adsorption, which when dried on the ZnSe crystal contains silk III crystallites.     

Conformational change of the triple-helical structure. I. Synthesis of model peptides of collagen by the solid-phase method

As model peptides of collagen, (Pro-Pro-Gly)_n (n = 10, 12, 14, and 15) and (Pro-Pro-Gly)_n(Ala-Pro-Gly)_m(Pro-Pro-Gly)_n (2n + m = 15; m = 1, 3, and 5) were synthesized by the solid-phase method. The final products were pure when checked by high-voltage paper electrophoresis and by amino acid analysis. Elemental composition was also examined.     

Conformational energy calculations for dinucleotide molecules. A study of the component mononucleotide adenosine 3''-monophosphate.

Semi-empirical conformational energy calculations were performed for the mononucleotides 5'-AMP, NMN+ and 3'-AMP. Only intramolecular forces are considered. Essentially all conformational states were explored to investigate the population distribution likely to be found in a non-crystalline environment. The calculations suggest that 5'-AMP and 3'-AMP are relatively flexible and a mixture of conformational states is expected. In contrast, the results for NMN+ suggest that a strong electrostatic interaction between the positively charged nicotinamide nitrogen atom and negatively charged phosphate oxygen is possible, stabilizing a few specific states. This interaction will be most significant in a solvent-free situation or an apolar environment.     

Conformational energy calculations of enzyme-substrate complexes of lysozyme. I. Energy minimization of monosaccharide and oligosaccharide inhibitors and substrates of lysozyme

Conformational energy calculations were performed on monosaccharide and oligosaccharide inhibitors and substrates of lysozyme to examine the preferred conformations of these molecules. A grid-search method was used to locate all of the low-energy conformational regions for N-acetyl-β-D -glycosamine (NAG), and energy minimization was then carried out in each of these regions. Three stable positions for the N-acetyl group have ben located, in two of which the plane of the amide unit is normal to the mean plane of the pyranosyl ring. Nine local energy minima were located for the —CH₂OH group. The positions of the two vicinal cis —OH groups are determined predominantly by interactions with either the —CH₂OH or the N-acetyl group. The most stable conformations of β-N-acetylmuramic acid (NAM) were determined from the study of the low-energy conformations of NAG. In the two stable orientations for the D -lactic acid side chain, the O—C—C′ plane (C′ being the carbon atom of the terminal carboxyl group) was found to be normal to the mean plane of the pyranosyl ring. The low-energy positions for the COOH group of NAM are determined mainly by interactions with neighboring groups. The conformational preferences of the α-anomers of NAG and NAM were also explored. The calculated conformation of the N-acetyl group for α-NAG was quite close to that determined by X-ray analysis. Two of the three lowest energy conformations of α-NAM are similar to the corresponding conformations of the β-anomer. A third low-energy structure, which has a hydrogen bond from the NH of the N-acetyl group to the C?O of the lactic acid group, corresponds very closely to the X-ray structure of this molecule. The preferred conformations of the disaccharides NAG–NAG, NAM–NAG and NAG–NAM were also investigated. Two preferred orientations of the reducing pyranosyl ring relative to the nonreducing ring were found for all of these disaccharides, both of which are close to the extended conformation. In one of these conformations, a hydrogen bond can form between the OH group attached to C₃ of the reducing sugar and the ring oxygen of the preceding residue. Each conformation can be stabilized further by a hydrogen bond between the CH₂OH (donor) of residue i + 1 and the C?O of residue i (acceptor). The interactions that determine conformations for all oligosaccharides containing both NAG and NAM are shown to be exclusively intraresidue and nearest neighbor interactions, so that it is possible to predict all stable conformations of oligosaccharides containing NAG and NAM in any sequence.