The conformational properties of α,β‐dehydroamino acids with a C‐terminal ester group

α,β‐Dehydroamino acid esters occur in nature. To investigate their conformational properties, a systematic theoretical analysis was performed on the model molecules Ac‐ΔXaa‐OMe [ΔXaa = ΔAla, (E)‐ΔAbu, (Z)‐ΔAbu, ΔVal] at the B3LYP/6‐311+ + G(d,p) level in the gas phase as well as in chloroform and water solutions with the self‐consistent reaction field‐polarisable continuum model method. The Fourier transform IR spectra in CCl₄ and CHCl₃ have been analysed as well as the analogous solid state conformations drawn from The Cambridge Structural Database. The ΔAla residue has a considerable tendency to adopt planar conformations C5 (?, ψ ≈ ? 180°, 180°) and β2 (?, ψ ≈ ? 180°, 0°), regardless of the environment. The ΔVal residue prefers the conformation β2 (?, ψ ≈ ? 120°, 0°) in a low polar environment, but the conformations α (?, ψ ≈ ? 55°, 35°) and β (?, ψ ≈ ? 55°, 145°) when the polarity increases. The ΔAbu residues reveal intermediate properties, but their conformational dispositions depend on configuration of the side chain of residue: (E)‐ΔAbu is similar to ΔAla, whereas (Z)‐ΔAbu to ΔVal. Results indicate that the low‐energy conformation β2 is the characteristic feature of dehydroamino acid esters. The studied molecules constitute conformational patterns for dehydroamino acid esters with various side chain substituents in either or both Z and E positions. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.     

Ab Initio Based conformational study of the crystalline α‐chitin

The equilibrium structure including the network of hydrogen bonds of an α‐chitin crystal is determined combining density‐functional theory (DFT), self‐consistent DFT‐based tight‐binding (SCC‐DFTB), and empirical forcefield molecular dynamics (MD) simulations. Based on the equilibrium geometry several possible crystal conformations (local energy minima) have been identified and related to hydrogen bond patterns. Our results provide new insight and allow to resolve the contradicting α‐chitin structural models proposed by various experiments. © 2012 Wiley Periodicals, Inc.     

Syntheses and anti‐tubercular activity of β‐substituted and α,β‐disubstituted peptidyl β‐aminoboronates and boronic acids

Tuberculosis is still affecting millions of people worldwide, and new resistant strains of Mycobacterium tuberculosis are being found. It is therefore necessary to find new compounds for treatment. In this paper, we report the synthesis and in vitro testing of peptidyl β‐aminoboronic acids and β‐aminoboronates with anti‐tubercular activity. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.     

Absolute configuration determination and conformational analysis of (−)‐(3S,6S)‐3α,6β‐diacetoxytropane using vibrational circular dichroism and DFT techniques

The absolute configuration of semisynthetic (?)‐3α,6β‐acetoxytropane 1 , prepared from (?)‐6β‐hydroxyhyoscyamine 2 , has been determined using vibrational circular dichroism (VCD) spectroscopy. The vibrational spectra (IR and VCD) were calculated using DFT at the B3LYP/DGDZVP level of theory for the eight more stable conformers which account for 99.97% of the total relative abundance in the first 10 kcal/mol range. The calculated VCD spectra of all considered conformations showed two distinctive spectral ranges, one between 1300 and 1200 cm^?1, and the other one in the 1150–950 cm^?1 region. When compared with the experimental VCD spectrum, the first spectral region confirmed the calculated conformational preferences, whereas the second region showed little change with conformation, thus allowing the determination of the absolute configuration of 1 as (3S,6S)‐3α,6β‐diacetoxytropane. Also, the bands in the second region showed similarities between 1 and 2 in both the experimental and calculated VCD spectra, suggesting that these bands are mainly related to the absolute configuration of the rigid tropane ring system, since they show conformational independency, no variations with the nature of the substituent, and are composed by closely related vibrational modes. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Role of two consecutive α,β-dehydrophenylalanines in peptide structure: Crystal and molecular structure of Boc-Leu-ΔPhe-ΔPhe-Ala-Phe-NHMe

An N^α-protected model pentapeptide containing two consecutive ΔPhe residues, Boc-Leu-ΔPhe-ΔPhe-Ala-Phe-NHMe, has been synthesized by solution methods and fully characterized. ¹H-nmr studies provided evidence for the occurrence of a significant population of a conformer having three consecutive, intramolecularly H-bonded β-bends in solution. The solid state structure has been determined by x-ray diffraction methods. The crystals grown from aqueous methanol are orthorhombic, space group P2₁2₁2₁, a = 11.503(2), b = 16.554(2), c = 22.107(3) Å, V = 4209(1) Å,³ and Z = 4. The x-ray data were collected on a CAD4 diffractometer using CuK_a radiation (λ = 1.5418 Å). The structure was determined using direct methods and refined by full-matrix least-squares procedure. The R factor is 5.3%. The molecule is characterized by a right handed 3₁₀-helical conformation (〈ϕ〉 = −68.2°, 〈ψ〉 = −26.3°), which is made up of two consecutive type III β-bends and one type I β-bend. In the solid state the helical molecules are aligned head-to-tail, thus forming long rod like structures. A comparison with other peptide structures containing consecutive ΔPhe residues is also provided. The present study confirms that the -ΔPhe-ΔPhe-sequence can be accommodated in helical structures. © 1997 John Wiley & Sons, Inc. Biopoly 42: 373–382, 1997     

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.     

The spatial configuration of taxonomic biodiversity along a tropical elevational gradient: α‐, β‐, and γ‐partitions

Biodiversity at larger spatial scales (γ) can be driven by within‐site partitions (α), with little variation in composition among locations, or can be driven by among‐site partitions (β) that signal the importance of spatial heterogeneity. For tropical elevational gradients, we determined the (a) extent to which variation in γ is driven by α‐ or β‐partitions; (b) elevational form of the relationship for each partition; and (c) extent to which elevational gradients are molded by zonation in vegetation or by gradual variation in climatic or abiotic characteristics. We sampled terrestrial gastropods along two transects in the Luquillo Mountains. One passed through multiple vegetation zones (tabonuco, palo colorado, and elfin forests), and one passed through only palm forest. We quantified variation in hierarchical partitions (α, β, and γ) of species richness, evenness, diversity, and dominance, as well as in the content and quality of litter. Total gastropod abundance linearly decreased with increasing elevation along both transects, but was consistently higher in palm than in other forest types. The gradual linear decline in γ‐richness was a consequence of opposing patterns with regard to α‐richness (monotonic decrease) and β‐richness (monotonic increase). For evenness, diversity, and dominance, α‐partitions and γ‐partitions evinced mid‐elevational peaks. The spatial organization of gastropod biodiversity did not mirror the zonation of vegetation. Rather, it was molded by: (a) elevational variation in productivity or nutrient characteristics, (b) the interspersion of palm forest within other forest types, and (c) the cloud condensation point acting as a transition between low and high elevation faunas. Abstract in Spanish is available with online material.     

Chiroptical properties of 2,2’‐bioxirane

The two enantiomers of 2,2′‐bioxirane were synthesized, and their chiroptical properties were thoroughly investigated in various solvents by polarimetry, vibrational circular dichroism (VCD), and Raman optical activity (ROA). Density functional theory (DFT) calculations at the B3LYP/aug‐cc‐pVTZ level revealed the presence of three conformers (G₊, G_?, and cis) with Gibbs populations of 51, 44, and 5% for the isolated molecule, respectively. The population ratios of the two main conformers were modified for solvents exhibiting higher dielectric constants (G_? form decreases whereas G₊ form increases). The behavior of the specific optical rotation values with the different solvents was correctly reproduced by time‐dependent DFT calculations using the polarizable continuum model (PCM), except for the benzene for which explicit solvent model should be necessary. Finally, VCD and ROA spectra were perfectly reproduced by the DFT/PCM calculations for the Boltzmann‐averaged G₊ and G_? conformers.     

Isocyanides Derived from α,α‐Disubstituted Amino Acids: Synthesis and Antifouling Activity Assessment

Herein, we contribute to the development of environmentally friendly antifoulants by synthesizing eighteen isocyanides derived from α,α‐disubstituted amino acids and evaluating their antifouling activity/toxicity against the cypris larvae of the Balanus amphitrite barnacle. Almost all isocyanides showed good antifouling activity without significant toxicity and exhibited EC₅₀ values of 0.07 – 7.30 μg/mL after 120‐h exposure. The lowest EC₅₀ values were observed for valine‐, methionine‐, and phenylalanine‐derived isocyanides, which achieved > 95% cypris larvae settlement inhibition at concentrations of less than 30 μg/mL without exhibiting significant toxicity. Thus, the prepared isocyanides should be useful for further research focused on the development of environmentally friendly antifouling agents.     

Interplaying factors for the formation of photoswitchable β‐hairpins: the advantage of a flexible switch

A series of peptidomimetics intended to promote the β‐hairpin motif have been studied. Structural variations include a turn region with and without a photoswitchable chromophore, and strands with amino acid side chains supporting various degrees of interstrand interactions for hairpin stabilisation. The propensity of the compounds to form β‐hairpins was evaluated experimentally by NMR spectroscopy, translational self‐diffusion studies and CD spectroscopy. In the presence of hairpin stabilising interstrand interactions, the structurally flexible stilbene chromophore appeared to be well compatible with the imposed secondary structure. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.     

Stereochemical analysis of β‐keto sulfoxides by circular dichroism

Three β‐keto sulfoxides ( 1–3 ) were synthesized in enantiopure form and investigated by means of circular dichroism (CD) spectroscopy, both in electronic and vibrational range (ECD, VCD), in combination with quantum chemical calculations. For compound 2 , the X‐ray structure was available; thus, the ECD in the solid state was also considered to reveal the differences between the molecular species in both states. Despite the simplicity of all β‐keto sulfoxides under investigation (29 atoms), reproducing even the major spectral VCD features failed for two compounds, making the use of VCD not ideal to assign their absolute configuration in a reliable way. We demonstrated, however, that the use of ECD spectroscopy, both in solution and solid state, can easily, unambiguously, and without any complication simulate all bands by applying the standard protocol for calculations. This study may stimulate the debate on the need of the use of two chiroptical methods simultaneously in the determination of absolute configurations.     

Studies on the 5α-androstane-3β, 17β-diol-6α-hydroxylase and on the 5α-androstane-3β, 17β-diol-7α-hydroxylase in anterior hypophysis of male rats.

In anterior pituitaries from male rats, it appeared that 5α-androstane-3β, 17β-diol was quickly metabolized into 5α-androstane-3β,6α-17β-triol and 5α-androstane-3β,7α, 17β-triol by action of 6α- and 7α-hydroxylases. Hydroxysteroid hydroxylases were located in endoplasmic reticulum and were dependent on NADPH⁺. Their optimum pH was 8.0, optima temperature, 37°C, and their apparent Km was 2.7 μM. Hydroxylative reactions were not reversible and not modified by gonadectomy. Hydroxylation seemed an efficient control of the pituitary level of 5α-andros-tane-3β, 17β-diol.     

A DFT study of structure and stability of pleated and rippled cross‐β sheets with hydrophobic sidechains

The rippled cross‐β sheet, a topography, in which mirror‐image peptides are arranged with alternating chirality into a periodic two‐dimensional network, is burgeoning as a new design principle for materials and biomedical applications. Experiments by the Schneider, Nilsson, and Raskatov labs have independently shown diverse racemic mixtures of aggregation‐prone peptide of different sizes to favor the rippled over the pleated topography. Yet, systematic ab initio studies are lacking, and the field is yet to develop rules that would enable the design of new rippled cross‐β frameworks from first principles. Here, DFT calculations were performed on a set of model systems, designed to begin understanding the impact that bulky, hydrophobic sidechains have upon the formation of pleated and rippled cross‐β frameworks. It is hoped that this study will help stimulate the development of a predictive, general framework to enable rational design of rippled cross‐β sheets in the future.     

The impact of β‐azido(or 1‐piperidinyl)methylamino acids in position 2 or 3 on biological activity and conformation of dermorphin analogues

The synthesis of new dermorphin analogues is described. The (R)‐alanine or phenylalanine residues of natural dermorphin were substituted by the corresponding α‐methyl‐β‐azidoalanine or α‐benzyl‐β‐azido(1‐piperidinyl)alanine residues. The potency and selectivity of the new analogues were evaluated by a competitive receptor binding assay in rat brain using [³H]DAMGO (a μ ligand) and [³H]DELT (a δ ligand). The most active analogue in this series, Tyr‐(R)‐Ala‐(R)‐α‐benzyl‐β‐azidoAla‐Gly‐Tyr‐Pro‐Ser‐NH₂ and its epimer were analysed by ¹H and ¹³C NMR spectroscopy and restrained molecular dynamics simulations. The dominant conformation of the investigated peptides depended on the absolute configuration around C^α in the α‐benzyl‐β‐azidoAla residue in position 3. The (R) configuration led to the formation of a type I β‐turn, whilst switching to the (S) configuration gave rise to an inverse β‐turn of type I′, followed by the formation of a very short β‐sheet. The selectivity of Tyr‐(R)‐Ala‐(R) and (S)‐α‐benzyl‐β‐azidoAla‐Gly‐Tyr‐Pro‐Ser‐NH₂ was shown to be very similar; nevertheless, the two analogues exhibited different conformational preferences. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.     

Synthesis and conformational studies of peptides containing TOAC,a spin-labelled Cα,α-disubstituted glycine

A variety of host L -alanine homo-peptides (to the pentamer) containing one or two spin-labelled TOAC (2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid) residues were synthesized by solution methods and fully characterized. The conformational features of the terminally blocked, doubly spin-labelled–TOAC–(Ala)₂–TOAC–Ala– pentapeptide were examined in the crystal state by X-ray diffraction and in solution using a combination of techniques (Fourier transform infrared, circular dichroism, cyclic voltammetry and electron spin resonance) in comparison with singly labelled shorter peptides. The 3₁₀-helical structure of the pentapeptide, promoted by the two C^α,α-disubstituted glycines under favourable experimental conditions, allows an interaction to take place between the two nitroxide TOAC side chains spaced by one turn of the helix. Taken together, these results suggest that TOAC is an excellent probe for exploring bends and helices in doubly labelled peptides.     

β-Turn conformations in crystal structures of model peptides containing α,α-Di-n-propylglycine and α,α-Di-n-butylglycine

The crystal state conformations of three peptides containing the α,α-dialkylated residues. α,α-di-n-propylglycine (Dpg) and α,α-di-n-butylglycine (Dbg), have been established by x-ray diffraction. Boc-Ala-Dpg-Alu-OMe (I) and Boc-Ala-Dbg-Ala-OMe (III) adopt distorted type II β-turn conformations with Ala (1) and Dpg/Dbg (2) as the corner residues. In both peptides the conformational angles at the Dxg residue (I: ? = 66.2°, ψ = 19.3°; III: ? = 66.5°. ψ = 21.1°) deviate appreciably from ideal values for the i + 2 residue in a type II β-turn. In both peptides the observed (N…O) distances between the Boc CO and Ala (3) NH groups are far too long (1: 3.44 Å: III: 3.63 Å) for an intramolecular 4 → 1 hydrogen bond. Boc-Ala-Dpg-Ata-NHMe (II) crystallizes with two independent molecules in the asymmetric unit. Both molecules HA and HB adopt consecutive β-turn (type III-III in HA and type III-I in IIB) or incipient 3₁₀-helical structures, stabilized by two intramolecular 4 → 1 hydrogen bonds. In all four molecules the bond angle N-C^α-C′ (τ) at the Dxg residues are ≥ 110°. The observation of conformational angles in the helical region of ?,ψ space at these residues is consistent with theoretical predictions. © 1995 John Wiley & Sons, Inc.     

VCD study of α‐methylbenzyl amine derivatives: Detection of the unchanged chiral motif

Chiral α‐methylbenzyl amine is a well known and often used chiral auxiliary, e.g., in the resolution of racemates or asymmetric catalysis. In this work, α‐methylbenzyl amine and its derivatives N,α‐dimethylbenzyl amine, N,N,α‐trimethylbenzyl amine, and bis[α‐methylbenzyl] amine were investigated by vibrational circular dichroism (VCD) spectroscopy and density functional theory (DFT). For all compounds, stable low energy conformers were obtained by the DFT calculations and based on those, the theoretical vibrational absorption (VA) and VCD spectra were calculated and compared with experimental spectra. Hence, the absolute configurations and conformational preferences were determined. A qualitative comparison of all the experimental VCD spectra of the investigated chiral molecules supported by the calculated ones is given which clearly shows similarities between the spectra of the different chiral amines. These can be assigned to vibrations of the unchanged chiral center. Chirality 2010. © 2010 Wiley‐Liss, Inc.     

Synthesis,conformational study,and spectroscopic characterization of the cyclic Cα,α‐disubstituted glycine 9‐amino‐9‐fluorenecarboxylic acid

A series of terminally blocked peptides (to the pentamer level) from l ‐Ala and the cyclic C^α,α‐disubstituted Gly residue Afc and one Gly/Afc dipeptide have been synthesized by solution method and fully characterized. The molecular structure of the amino acid derivative Boc‐Afc‐OMe and the dipeptide Boc‐Afc‐Gly‐OMe were determined in the crystal state by X‐ray diffraction. In addition, the preferred conformation of all of the model peptides was assessed in deuterochloroform solution by FT‐IR absorption and ¹H‐NMR. The experimental data favour the conclusion that the Afc residue tends to adopt either the fully‐extended (C₅) or a folded/helical structure. In particular, the former conformation is highly populated in solution and is also that found in the crystal state in the two compounds investigated. A comparison with the structural propensities of the strictly related C^α,α‐disubstituted Gly residues Ac₅c and Dϕg is made and the implications for the use of the Afc residue in conformationally constrained analogues of bioactive peptides are briefly examined. A spectroscopic (UV absorption, fluorescence, CD) characterization of this novel aromatic C^α,α‐disubstituted Gly residue is also reported. Copyright © 1999 European Peptide Society and John Wiley & Sons, Ltd.     

Ecosystem stability in space: α, β and γ variability

The past two decades have seen great progress in understanding the mechanisms of ecosystem stability in local ecological systems. There is, however, an urgent need to extend existing knowledge to larger spatial scales to match the scale of management and conservation. Here, we develop a general theoretical framework to study the stability and variability of ecosystems at multiple scales. Analogously to the partitioning of biodiversity, we propose the concepts of alpha, beta and gamma variability. Gamma variability at regional (metacommunity) scale can be partitioned into local alpha variability and spatial beta variability, either multiplicatively or additively. On average, variability decreases from local to regional scales, which creates a negative variability–area relationship. Our partitioning framework suggests that mechanisms of regional ecosystem stability can be understood by investigating the influence of ecological factors on alpha and beta variability. Diversity can provide insurance effects at the various levels of variability, thus generating alpha, beta and gamma diversity–stability relationships. As a consequence, the loss of biodiversity and habitat impairs ecosystem stability at the regional scale. Overall, our framework enables a synthetic understanding of ecosystem stability at multiple scales and has practical implications for landscape management.     

Polyglutamine repeats and β‐helix structure: Molecular dynamics study

Neurodegenerative diseases are often associated with the formation of highly insoluble aggregates. Despite the efforts devoted to the characterization of these aggregates, their structure remains elusive. Several neurodegenerative diseases are characterized by the expansion of CAG repeats, which code for Gln. Among the structural models proposed for the aggregates observed in polyQ-linked diseases, the nanotube beta-helix model proposed by Perutz and colleagues Proc Natl Acad Sci U S A 2002;99:5591-5595 has been influential. In the present study, the stability of this beta-helix model has been investigated by performing molecular dynamics simulations on polyQ fragments of different lengths. The results indicate that models shorter than two full beta-helix turns are unstable and collapse toward irregular structures. On the other hand, longer beta-helix models, containing more than 40 residues, achieve a dynamic regular structure. This finding is in line with the observed threshold of Gln repeats (approximately 40) correlated with the insurgence of the disease. Notably, the structure of the final state of the models longer than 40 residues strictly depends on their size. A compact stable ellipsoidal structure is formed by the model made of two full helical turns (41 residues), whereas water filled tubular structures emerge from simulation on longer polypeptides. These results have been interpreted taking into account the experimental data on polyQ aggregates. A structural interpretation of the literature data has been proposed by assuming that different beta-helical models are involved in the different stages of the aggregation process.