Synthesis and NMR Analysis in Solution of Oligo(3-hydroxyalkanoic acid) Derivatives with the Side Chains of Alanine, Valine, and Leucine (β-Depsides): Coming Full Circle from PHB toβ-Peptides to PHB

Albert, Matthias; Seebàch, Dieter; Duchardt, Elke; Schwalbe, Harald

doi:10.1002/1522-2675(200202)85:2<633::aid-hlca633>3.0.co;2-1

Cited by 18 publications

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“…The local and global conformational characteristics of molecule 2 have been investigated by NMR techniques [11]. In particular, the population of rotameric states about dihedral angles f 2 have been deduced from measurements of vicinal J values, according to a three-state model Pachler analysis and on the assumption of fast rotameric interconversion.…”

Section: Results ± Comparison Of Calculated and Experimentally Determentioning

confidence: 99%

“…Dihedral angles f 2 were chosen for two reasons: they are the ones most amenable for the application of NMR techniques, and a (À)-sc conformation is a characteristic feature of both helices proposed as model structures for PHB 6 ). In Table 7, vicinal J-coupling constants calculated as time averages over the simulation trajectories are compared with measured values [11]. With the two Karplus Table 6.…”

Section: Results ± Comparison Of Calculated and Experimentally Determentioning

confidence: 99%

“…Vicinal 3 J-Coupling Constants (in Hz) in molecule 2. Trajectory averages calculated with the two different Karplus equations and measured values[11]. Hz larger than the uncertainty in the simulated values due to the use of a particular Karplus relationship.…”

mentioning

confidence: 91%

“…For detailed discussions on investigations of OHA derivatives 1 and 2 by NMR, see our previous papers[7] [8] and the accompanying publication[11].…”

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confidence: 99%

“…) See our recent papers[7] [8], the accompanying publication in this issue[11], a review article[1], and leading references cited therein.…”

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confidence: 99%

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A Molecular-Dynamics Simulation Study of the Conformational Preferences of Oligo(3-hydroxyalkanoic acids) in Chloroform Solution

Gee

Hamprecht

Schuler

et al. 2002

HCA

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The GROMOS96 molecular-dynamics (MD) program and force field was used to calculate the conformations at 298 K in CHCl 3 solution of two hexakis(3-hydroxyalkanoic acids). One consists of (R)-3-hydroxybutanoate (HB) residues only: HÀ(OCH(Me)ÀCH 2 ÀCO) 6 ÀOH (1). The other one carries the side chains of valine, alanine, and leucine: HÀ(OCH(CHMe 2 )CH 2 ÀCOÀOÀCH(Me)ÀCH 2 ÀCOÀOÀCH(CH 2 CHMe 2 )ÀCH 2 ÀCO) 2 ÀOH (2), with homochiral 3-hydroxyalkanoate (HA) moieties. In both cases, the conformational equilibria were sampled 2500 times for 25 ns. Other than clusters of arrangements with interresidual hydrogen bonding (between the O-and C-terminal OH and COOH groups, and with chain-bound ester carbonyl O-atoms; Fig. 6), there are no preferred backbone conformations in which the molecules 1 and 2 spend more than 5% of the time. Specifically, neither the 2 1 -nor the 3 1 -helical conformation of the oligoester backbone (found in stretched fibers, in lamellar crystallites, and in single crystals of polymers PHB and of oligomers OHB) is sampled to any significant extent ( Fig. 8 and 9), in spite of the high population, in both oligomers, of the (À)-synclinal conformation around the C(2)ÀC (3) bond (angle f 2 in Fig. 2). In contrast to b-oligopeptides, for which strongly preferred secondary structures are found after a few ns, and for which the number of conformations levels off with time, the number of conformational clusters of the corresponding oligoesters found by our force-field MD calculations increases steadily over the observation time of 25 ns (Fig. 5). Thus, the conclusion from biological and physical-chemical studies, according to which the PHB chain is extremely flexible, is confirmed by our computational investigation: in CHCl 3 solution, the hexakis(3-hydroxyalkanoate) chain samples its conformational space randomly! 1. Introduction. ± Associated with the biological role of the short-chain poly[(R)-3-hydroxybutanoate] (PHB) [1], which has been shown to allow the passage of ions across phospholipid bilayer membranes under voltage-driven and concentration-driven conditions [2], or to function as a transmembrane ion-channel when associated with Ca polyphosphate [1 ± 3], is the question of its secondary structure. From the investigation of PHB or PHB derivatives in the solid state, two different folding patterns were recognized: a 2 1 helix in stretched fibers [4] and in lamellar crystallites of the polymer

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Section: Results ± Comparison Of Calculated and Experimentally Determentioning

confidence: 99%

Section: Results ± Comparison Of Calculated and Experimentally Determentioning

confidence: 99%

mentioning

confidence: 91%

“…For detailed discussions on investigations of OHA derivatives 1 and 2 by NMR, see our previous papers[7] [8] and the accompanying publication[11].…”

mentioning

confidence: 99%

“…) See our recent papers[7] [8], the accompanying publication in this issue[11], a review article[1], and leading references cited therein.…”

mentioning

confidence: 99%

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A Molecular-Dynamics Simulation Study of the Conformational Preferences of Oligo(3-hydroxyalkanoic acids) in Chloroform Solution

Gee

Hamprecht

Schuler

et al. 2002

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The World of β‐ and γ‐Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components

Seebàch

Beck

Bierbaum

2004

Chemistry & Biodiversity

926

562

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The origins of our nearly ten-year research program of chemical and biological investigations into peptides based on homologated proteinogenic amino acids are described. The road from the biopolymer poly[ethyl (R)-3-hydroxybutanoate] to the beta-peptides was primarily a step from organic synthesis methodology (the preparation of enantiomerically pure compounds (EPCs)) to supramolecular chemistry (higher-order structures maintained through non-covalent interactions). The performing of biochemical and biological tests on the beta- and gamma-peptides, which differ from natural peptides/proteins by a single or two additional CH(2) groups per amino acid, then led into bioorganic chemistry and medicinal chemistry. The individual chapters of this review article begin with descriptions of work on beta-amino acids, beta-peptides, and polymers (Nylon-3) that dates back to the 1960s, even to the times of Emil Fischer, but did not yield insights into structures or biological properties. The numerous, often highly physiologically active, or even toxic, natural products containing beta- and gamma-amino acid moieties are then presented. Chapters on the preparation of homologated amino acids with proteinogenic side chains, their coupling to provide the corresponding peptides, both in solution (including thioligation) and on the solid phase, their isolation by preparative HPLC, and their characterization by mass spectrometry (HR-MS and MS sequencing) follow. After that, their structures, predominantly determined by NMR spectroscopy in methanolic solution, are described: helices, pleated sheets, and turns, together with stack-, crankshaft-, paddlewheel-, and staircase-like patterns. The presence of the additional C--C bonds in the backbones of the new peptides did not give rise to a chaotic increase in their secondary structures as many protein specialists might have expected: while there are indeed more structure types than are observed in the alpha-peptide realm - three different helices (10/12-, 12-, and 14-helix) if we include oligomers of trans-2-aminocyclopentanecarboxylic acid, for example - the structures are already observable with chains made up of only four components, and, having now undergone a learning process, we are able to construct them by design. The structures of the shorter beta-peptides can also be reliably determined by molecular-dynamics calculations (in solution; GROMOS program package). Unlike in the case of the natural helices, these compounds' folding into secondary structures is not cooperative. In beta- and gamma-peptides, it is possible to introduce heteroatom substituents (such as halogen or OH) onto the backbones or to incorporate heteroatoms (NH, O) directly into the chain, and, thanks to this, it has been possible to study effects unobservable in the world of the alpha-peptides. Tests with proteolytic enzymes of all types (from mammals, microorganisms, yeasts) and in vivo examination (mice, rats, insects, plants) showed beta- and gamma-peptides to be completely stable towards proteolysis and, as ...

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Physiological Importance of Poly‐(R)‐3‐hydroxybutyrates

Reusch

2012

Chemistry & Biodiversity

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Poly-(R)-3-hydroxybutyrates (PHB), linear polymers of (R)-3-hydroxybutyrate, are components of all biological cells in which short polymers (<200 monomer residues) are covalently attached to certain proteins and/or noncovalently associated with polyphosphates - inorganic polyphosphate (polyP), RNA, and DNA. The low concentrations, lack of unusual atoms or functional groups, and flexible backbones of this complexed PHB, referred to as cPHB, make them invisible to many analytical procedures; whereas other physical properties - water-insolubility, high intrinsic viscosity, temperature sensitivity, multiple bonding interactions with other molecules - make them requisite participants in vital physiological processes as well as contributors to the development of certain diseases.

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Synthesis and NMR Analysis in Solution of Oligo(3-hydroxyalkanoic acid) Derivatives with the Side Chains of Alanine, Valine, and Leucine (β-Depsides): Coming Full Circle from PHB toβ-Peptides to PHB

Cited by 18 publications

References 50 publications

A Molecular-Dynamics Simulation Study of the Conformational Preferences of Oligo(3-hydroxyalkanoic acids) in Chloroform Solution

A Molecular-Dynamics Simulation Study of the Conformational Preferences of Oligo(3-hydroxyalkanoic acids) in Chloroform Solution

The World of β‐ and γ‐Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components

Physiological Importance of Poly‐(R)‐3‐hydroxybutyrates

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