Pseudo-prolines: Induction ofcis/trans-conformational interconversion by decreased transition state barriers

Mutter, Manfred; Wöhr, Torsten; Gioria, Séverine; Keller, Michael

doi:10.1002/(sici)1097-0282(1999)51:2<121::aid-bip2>3.0.co;2-o

Cited by 72 publications

(72 citation statements)

References 31 publications

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“…The probability distribution for cis-trans prolyl bonds is affected by neighboring amino acids (2, 3), pH and ionic strength (4), solvent (5-11) and chain length (12). It has been noted experimentally that the PPII structure is favored in water, benzyl alcohol, and most of the other solvents, while the PPI structure is favored in the presence of aliphatic alcohols like propanol (12)(13)(14)(15). The two forms can reversibly interconvert by means of changes in solvent composition (5,7,10,16,17), as analyzed via circular dichronism (CD) spectroscopy experiments (12,(18)(19)(20).…”

Section: Cis-trans Isomerization | Left-handed Helix | Molecular Dynamentioning

confidence: 99%

Conformations and free energy landscapes of polyproline peptides

Moradi

Babin

Roland

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

100

146

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The structure of the proline amino acid allows folded polyproline peptides to exist as both left-(PPII) and right-handed (PPI) helices. We have characterized the free energy landscapes of hexamer, nanomer, and tridecamer polyproline peptides in gas phase and implicit water as well as explicit hexane and 1-propanol for the nanomer. To enhance the sampling provided by regular molecular dynamics, we used the recently developed adaptively biased molecular dynamics method, which describes Landau free energy maps in terms of relevant collective variables. These maps, as a function of the collective variables of handedness, radius of gyration, and three others based on the peptide torsion angle ω, were used to determine the relative stability of the different structures, along with an estimate of the transition pathways connecting the different minima. Results show the existence of several metastable isomers and therefore provide a complementary view to experimental conclusions based on photo-induced electron transfer experiments with regard to the existence of stable heterogeneous subpopulations in PPII polyproline.cis-trans isomerization | left-handed helix | molecular dynamics | PPI | PPII T he concept of molecular chirality is used to describe molecular structures that are not superposable on their mirror images. Chiral molecules are quite prevalent in biological systems, which are primarily homochiral systems. For example, most proteins contain only L-amino acids, while DNA is made up primarily of D-deoxyribose. The relationship between chirality and helical polypeptide structure was first mentioned by Pauling (1) in reference to the α-helix. The naturally occurring L-amino acids predominantly form right-handed helices, whereas their stereoisomers D-amino acids favor left-handed helices. Indeed, right-handed helices are prevalent in biology, not only in peptides (with structural motifs such as α-helix , 3 10 helix, and π helix) but also in the double-helical structure of B-and A-DNA. Although much less common, left-handed helices with the same chiral units as right-handed helices also exist, such as those found in PPII and in Z-DNA.In this paper, we investigate the free energy landscape of several short polyproline peptides. Proline is unique among the natural amino acids in that its side chain is cyclized to the backbone, restricting its backbone dihedral angle to φ = −75• , giving proline an exceptional rigidity and a considerably restricted conformational space. Polyproline is known to form helical structures with two well-characterized conformations: a left-handed polyproline helix (PPII) is formed when the sequential residues all adopt backbone dihedral angles (φ, ψ) of (−75• , 146• ), with all prolyl bonds in the trans-isomer conformation (i.e. backbone dihedral angle ω = 180• ) with 3 residues per turn; and a more compact right-handed polyproline helix (PPI) is formed with all sequential residues adopting dihedral angles of roughly (−75• , 160• ) and all prolyl bonds assume a cis-isomer conformation (i.e. b...

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Section: Cis-trans Isomerization | Left-handed Helix | Molecular Dynamentioning

confidence: 99%

Conformations and free energy landscapes of polyproline peptides

Moradi

Babin

Roland

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

100

146

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“…A unique characteristic of Pro is its ability to interconvert between cis-and trans-configurations (36,37). To evaluate the influence of cis/trans-switching on the activity of ␤-sheet breaker peptides, we synthesized derivatives containing pseudoprolines in place of Pro.…”

Section: Intravenous Injectionmentioning

confidence: 99%

Pharmacological Profiles of Peptide Drug Candidates for the Treatment of Alzheimer's Disease

Adessi¹,

Frossard²,

Boissard³

et al. 2003

Journal of Biological Chemistry

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186

142

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Amyloid plaques in brain, composed of aggregates of amyloid-␤ peptide, play a central role in the pathogenesis of Alzheimer's disease and represent a good target for treatment. We have shown previously that a 5-amino acid ␤-sheet breaker peptide (iA␤5p), end-protected, has the ability to induce a dramatic reduction in amyloid deposition in two different transgenic Alzheimer's models (Permanne, B., Adessi, C., Saborio, G. P., Fraga, S., Frossard, M.-J., Dewachter, I., Van Dorpe, J., Banks, W. A., Van Leuven, F., and Soto, C. (2002) FASEB J. 16, 860 -862). The aim of this study was to evaluate the effect of chemical modifications of the peptide bonds at the metabolite cleavage sites on the pharmacological properties of iA␤5p derivatives. Using a rational approach, peptide analogs were designed and tested for in vitro activity and enzymatic stability. One peptide analog containing a methyl group introduced at the nitrogen atom of one amide bond showed increased stability in vitro, a 10-fold higher in vivo half-life, and good brain uptake compared with iA␤5p while maintaining a similar activity in vitro. Our results suggest that the pharmacological profile of ␤-sheet breaker peptides can be improved to produce compounds with drug-like properties that might offer a new promise in the treatment of Alzheimer's disease.Alzheimer's disease is a degenerative disorder of the brain for which there is no cure or effective treatment. Recent studies suggest that cerebral amyloid plaques play a central role in the pathogenesis of the disease (1-3). An attractive therapeutic strategy for Alzheimer's disease is to block the early steps of misfolding and aggregation of the soluble amyloid-␤ peptide (A␤) 1 (3). We proposed that short synthetic peptides capable of binding A␤ but unable to become part of a ␤-sheet structure (␤-sheet breaker peptides) may destabilize the amyloidogenic A␤ conformer and hence preclude amyloid formation (3-5). A major drawback with the use of peptides as drugs in neurological diseases is their rapid metabolism by proteolytic enzymes and their poor blood-brain barrier (BBB) permeability (6 -9). We reported previously that a 5-residue synthetic peptide (iA␤5, LPFFD) was able to inhibit and disassemble amyloid fibrils in vitro, to prevent A␤ neurotoxicity in cell culture, to arrest deposition of amyloid lesions, and to induce dissolution of preformed plaques in a rat brain model of amyloidosis (4,5,10). More recently, we showed that iA␤5 with N-and C-terminal protections to minimize exopeptidase cleavage (iA␤5p, Ac-LPFFD-NH 2 ) was rapidly taken up by the brain and reduced in vivo amyloid deposition and cerebral damage in a double transgenic animal model of Alzheimer's disease (11). In addition, this compound showed low toxicity, low immunogenicity, and high solubility. The weakest aspect of this compound is its relatively short in vivo half-life.The goal of this work was to introduce a series of chemical modifications into iA␤5p aiming to increase stability and simultaneously maintaining (or enhancing) pot...

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“…The righthanded polyproline I helical conformation has similar backbone dihedral angles but has all peptide bonds in the cis conformer. This conformation is observed for homopolymers of proline in organic solvents and is disfavored in aqueous solution (Mutter et al 1999).…”

mentioning

confidence: 91%

Polyproline II helical structure in protein unfolded states: Lysine peptides revisited

2002

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The left-handed polyproline II (PPII) helix gives rise to a circular dichroism spectrum that is remarkably similar to that of unfolded proteins. This similarity has been used as the basis for the hypothesis that unfolded proteins possess considerable PPII helical content. It has long been known that homopolymers of lysine adopt the PPII helical conformation at neutral pH, presumably a result of electrostatic repulsion between side chains. It is shown here that a seven-residue lysine peptide also adopts the PPII conformation. In contrast with homopolymers of lysine, this short peptide is shown to retain PPII helical character under conditions in which side-chain charges are heavily screened or even neutralized. The most plausible explanation for these observations is that the peptide backbone favors the PPII conformation to maximize favorable interactions with solvent. These data are evidence that unfolded proteins do indeed possess PPII content, indicating that the ensemble of unfolded states is significantly smaller than is commonly assumed.

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Pseudo-prolines: Induction ofcis/trans-conformational interconversion by decreased transition state barriers

Cited by 72 publications

References 31 publications

Conformations and free energy landscapes of polyproline peptides

Conformations and free energy landscapes of polyproline peptides

Pharmacological Profiles of Peptide Drug Candidates for the Treatment of Alzheimer's Disease

Polyproline II helical structure in protein unfolded states: Lysine peptides revisited

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