Peptides as Conformational Switch: Medium‐Induced Conformational Transitions of Designed Peptides

Mutter, Manfred; Hersperger, René

doi:10.1002/anie.199001851

Cited by 77 publications

(42 citation statements)

References 23 publications

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“…These results are qualitatively in good agreement with experiments which show that polyalanine adopts an α-helical conformation in hydrophobic environments such as the solid state or in non-polar organic solutions and a β-structure conformation in polar aqueous solution 88,[106][107][108][109][110][111] . This is similarly observed in experiments on many heterogeneous peptides which can be folded into alternative stable structures by changing the solution conditions such as the pH, salt or organic cosolvent concentration, peptide concentration, and the redox state [112][113][114][115][116][117][118][119][120][121][122][123][124][125][126] . Interestingly, Knott and Chan 95 recently investigated the impact of the relative strengths of the hydrophobic and hydrogen bonding interaction on folding of polypeptide chains using a similar intermediate-resolution protein model 94 but with a continuous potential.…”

Section: Resultsmentioning

confidence: 80%

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Nguyen

Hall

2006

J. Am. Chem. Soc.

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Fibrillary protein aggregates rich in β-sheet structure have been implicated in the pathology of several neurodegenerative diseases. In this work, we investigate the formation of fibrils by performing discontinuous molecular dynamics simulations on systems containing 12 to 96 model Ac-KA 14 K-NH 2 peptides using our newly-developed off-lattice, implicit-solvent, intermediateresolution model, PRIME. We find that at a low concentration, random-coil peptides assemble into α-helices at low temperatures. At intermediate concentrations, random-coil peptides assemble into α-helices at low temperatures and large β-sheet structures at high temperatures. At high concentrations, the system forms β-sheets over a wide range of temperatures. These assemble into fibrils above a critical temperature which decreases with concentration and exceeds the isolated peptide's folding temperature. At very high temperatures and all concentrations, the system is in a random-coil state. All of these results are in good qualitative agreement with those by Blondelle and coworkers on Ac-KA 14 K-NH 2 peptides. The fibrils observed in our simulations mimic the structural characteristics observed in experiments in terms of the number of sheets formed, the values of the intra-and inter-sheet separations, and the parallel peptide arrangement within each β-sheet. Finally, we find that when the strength of the hydrophobic interaction between non-polar sidechains is high compared to the strength of hydrogen bonding, amorphous aggregates, rather than fibrillar aggregates, are formed.

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Section: Resultsmentioning

confidence: 80%

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Nguyen

Hall

2006

J. Am. Chem. Soc.

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“…No such information is available as far as we know, probably because of the difficulties in finding an appropriate peptide model. Peptides with alternate hydrophobic and hydrophilic residues have a tendency to form intermolecular P-sheet aggregates instead of a helices [42,431, and soluble homopolymers formed by hydrophilic helix-forming residues are difficult to assign by NMR in the random form. We are, at present, trying to find such a model.…”

Section: Discussionmentioning

confidence: 99%

Periodic properties of proton conformational shifts in isolated protein helices

Jiménez

Blanco

Rico

et al. 1992

European Journal of Biochemistry

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In this work, the helix-forming residues in fragments of several proteins (ribonuclease, thermolysin, tendamistat and angiogenin) were identified by NOE and the helix proton shifts were measured as 6 changes associated with helix-population increments driven by trifluoroethanol addition. When estimated in this way, a regular pattern of helix conformational shifts was clearly seen in the A6 versus sequence profiles of all the peptides studied. The helix periodicity of the Ha and Hfl resonances was especially clear, an observation that earlier statistical studies of protein 6 values failed to predict. Amide protons showed the largest helix shifts, but with a less-sharply defined periodic character. Aromatic residues considerably distorted the periodicity of the helix amide shifts in some peptides, as evidenced by the 6 shifts of a RNase A fragment 1 -15 analog in which the two aromatic residues were replaced by Ala. The relationship between helix periodicity and peptide amphiphatic character is discussed.Chemical shifts are NMR parameters readily measurable which, in addition, are very sensitive to the molecular conformation and the electronic environment. Accordingly, many attempts have been made to correlate them with protein structure [I -121. Statistical studies of protein 6 values using either limited [5] or more complete sets of data [6 -8, 101 led to the finding that the conformational shifts of backbone protons have opposite signs, depending on whether the amino acid residues are located in fl-sheet or in helical regions of a protein.Correlations have also been found between backbone I3C and 15N chemical shifts and protein secondary structure [lo, 131.The observation that alternating maxima and minima appear in regions showing secondary structure when protein conformational shifts were plotted against the peptide sequence was initially noted in [14], regularity that was more evident in helical stretches. When the 6 shifts of Ha protons, originated by helix-population changes, were measured in a few isolated short peptides, a helix period was detected in the A6 versus sequence profiles [5, 14, 151. A recent statistical analysis [16] of the periodic components present in available chemical-shift data, mainly referring to protein helices, also found a helix periodicity, this time of the 6 values of the amide but not of the Ha signals.A basic idea of this paper is that good estimates of helix shifts, more reliable than those obtained from protein 6 values, may be obtained by measuring the 6 shifts associated with helix-population changes in isolated peptides. The changes in the experimental conditions, necessary to modify the helix Correspondence fo J. L. Nieto, Instituto de Estructura de la Materia, Consejo Superior de Investigaciones Cientificas, Serrano 119, S-28006, Madrid, SpainAbbreviations. COSY, two-dimensional correlated spectroscopy; TOCSY, total correlated spectroscopy; NOESY, nuclear Overhauser effect spectroscopy. content, may be chosen so as to produce only small and known changes in 6. This ki...

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“…For other sequences, the behavior can be more complex. Experimentally, peptides have been designed that can act as conformational switches, changing conformation in response to changes in external conditions (Mutter & Hersperger, 1990). The polypeptide gramicidin A has been shown to undergo a conformational change from double-helical dimer to helical monomer upon insertion into a cell membrane (Killian, 1992).…”

Section: Pd Thomas and Ka Dillmentioning

confidence: 99%

Local and nonlocal interactions in globular proteins and mechanisms of alcohol denaturation

1993

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How important are helical propensities in determining the conformations of globular proteins? Using the twodimensional lattice model and two monomer types, H (hydrophobic) and P (polar), we explore both nonlocal interactions, through an HH contact energy, E, as developed in earlier work, and local interactions, through a helix energy, u. By computer enumeration, the partition functions for short chains are obtained without approximation for the full range of both types of energy. When nonlocal interactions dominate, some sequences undergo coil-globule collapse to a unique native structure. When local interactions dominate, all sequences undergo helix-coil transitions. For two different conformational properties, the closest correspondence between the lattice model and proteins in the Protein Data Bank is obtained if the model local interactions are made small compared to the HH contact interaction, suggesting that helical propensities may be only weak determinants of globular protein structures in water. For some HP sequences, varying U/E leads to additional sharp transitions (sometimes several) and to "conformational switching" between unique conformations. This behavior resembles the transitions of globular proteins in water to helical states in alcohols. In particular, comparison with experiments shows that whereas urea as a denaturant is best modeled as weakening both local and nonlocal interactions, trifluoroethanol is best modeled as mainly weakening HH interactions and slightly enhancing local helical interactions.Keywords: alcohol denaturation; compact conformations; helical propensities; HP lattice model; hydrophobic interaction What is the relative importance of local interactions (helical propensities) compared to nonlocal interactions (mainly solvent-mediated and hydrophobic interactions) in determining the native structures of globular proteins? One view has held that the local interactions are the main determinants of structure, while the nonlocal interactions just provide nonspecific stability to the compact state (Anfinsen & Scheraga, 1975). That is, interactions among adjacent and near-neighbor peptide units tend to drive proteins to configure into helices at certain points in the sequence, which ultimately end up as helices in the native structure. In this view, helices should be identifiable by factors that are local within the sequence, and this should strongly specify how they can pack to form the native structure. Recently, an alternative view has developed that nonlocal interactions may be a major determinant not only of the stabilities but also of the structures of globular Reprint requests to: Ken A. Dill, Department of Pharmaceutical Chemistry, Box 1204, University of California, San Francisco, California 94143-1204. proteins Chan & Dill, 1991b). In this view, a major factor in determining where helices form in native structures is the sequence positions of hydrophobic monomers. That is, predicting helices (and also sheets) in native structures is more a matter of finding the...

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Peptides as Conformational Switch: Medium‐Induced Conformational Transitions of Designed Peptides

Cited by 77 publications

References 23 publications

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Periodic properties of proton conformational shifts in isolated protein helices

Local and nonlocal interactions in globular proteins and mechanisms of alcohol denaturation

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