Conformational Study of Solid Polypeptides by <sup>1</sup>H Combined Rotation and Multiple Pulse Spectroscopy NMR. 2. Amide Proton Chemical Shift

Kimura, Hirokazu; Ozaki, Takuo; Sugisawa, Hisashi; Deguchi, K.; Shoji, Akira

doi:10.1021/ma980020+

Cited by 22 publications

(20 citation statements)

References 32 publications

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“…R < 1/2, the transition temperatures between an α-helical state to a non-α-helical state are between T * =0.085 and T * =0.11. 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] .…”

Section: Resultssupporting

confidence: 90%

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: Resultssupporting

confidence: 90%

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Nguyen

Hall

2006

J. Am. Chem. Soc.

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“…Accordingly, polyalanine is expected to adopt an ␣-helical conformation in a nonpolar organic solvent and ␤-structures with coil conformations in a polar aqueous solution. Solid-state (i.e., hydrophobic environment) (42)(43)(44)(45) and aqueous solution (12)(13)(14) measurements of polyalanine support its conformational dependence on the chemical environments with the ubiquity of the ␣-helix and ␤-structures prevailing in hydrophobic and in polar environments, respectively. The dependence of the conformation of alanine on the solvent characteristics (i.e., the polarity and dielectric constant of the solvent) is supported by experimental evidence that the helical propensity of alanine in water shows a dramatic increase on addition of certain alcohols (e.g., trifluoroethanol) (46,47).…”

Section: Resultsmentioning

confidence: 87%

Solvent effects on the energy landscapes and folding kinetics of polyalanine

Levy

Jortner

Becker

2001

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

146

132

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The effect of a solvation on the thermodynamics and kinetics of polyalanine (Ala12) is explored on the basis of its energy landscapes in vacuum and in an aqueous solution. Both energy landscapes are characterized by two basins, one associated with ␣-helical structures and the other with coil and ␤-structures of the peptide. In both environments, the basin that corresponds to the ␣-helical structure is considerably narrower than the basin corresponding to the ␤-state, reflecting their different contributions to the entropy of the peptide. In vacuum, the ␣-helical state of Ala12 constitutes the native state, in agreement with common helical propensity scales, whereas in the aqueous medium, the ␣-helical state is destabilized, and the ␤-state becomes the native state. Thus solvation has a dramatic effect on the energy landscape of this peptide, resulting in an inverted stability of the two states. Different folding and unfolding time scales for Ala12 in hydrophilic and hydrophobic chemical environments are caused by the higher entropy of the native state in water relative to vacuum. The concept of a helical propensity has to be extended to incorporate environmental solvent effects.T he chemical environment exerts a fundamental influence on the structure, thermodynamics, and dynamics of polypeptides. Particularly, the solvent may affect the dynamics and structure of the polypeptide and consequently alter its function, as has been demonstrated in a variety of biologically important phenomena, ranging from the rate of oxygen uptake in myoglobin to the stabilization of opposite-charged side-chain pairs at the surface of proteins (1, 2). The variance of the properties of a polypeptide in different solvents depends on the nature of the solvent-polypeptide intermolecular interactions, which lead to a rich repertoire of phenomena. These interactions involve the effect of organic solvents on the destabilization of the hydrophobic core and the exposure of side chains, as well as the opposite effects of aqueous solvents on the protein structures favoring the hydrophilic protein surface and the hydrophobic core (1, 3). Theoretical and computational evidence (4-6) for medium effects on polypeptide structures has accumulated. Following the Zimm-Bragg theory of the helix-coil equilibrium (7), it has been established that short polypeptides should not form helices in water. Indeed, numerous studies report that the relative tendency for helix formation in water is low at physiological temperatures (6,8).The structure of polyalanine peptides is of considerable interest as, in general, regardless of specific chemical environments, the commonly reported secondary structure propensity scales for amino acids (9-11) rank alanine as having the highest ␣-helical propensity. However, experimental (12-14) and computational (4-6, 15-23) studies showed that polyalanines tend to adopt random-coil conformations in aqueous solution. The ambiguity of the helical propensities, even for alanine, which is known as an excellent helix former, may indic...

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“…Contour lines are labeled with a rounded-up value of the highest free energy in the enclosed region. that show that polyalanine adopts an ␣-helical conformation in hydrophobic environments such as the solid state or in nonpolar organic solutions and a ␤-structure conformation in polar aqueous solution (Ingwall et al 1968;Platzer et al 1972;Shoji et al 1990;Blondell et al 1997;Kimura et al 1998;Lee and Ramamoorthy 1999;Warrass et al 2000). This is also observed in experiments on many heterogeneous peptides that 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 (Rosenheck and Doty 1961;Kabsch and Sander 1984;Mutter and Hersperger 1990;Mutter et al 1991;Reed and Kinzel 1991;Zhong and Johnson 1992;Cohen et al 1993;Dado and Gellman 1993;Waterhous and Johnson 1994;Cerpa et al 1996;Fukushima 1996;Schenck et al 1996;Zhang and Rich 1997;Tuchscherer et al 1999;Awasthi et al 2001;Wildman et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Solvent effects on the conformational transition of a model polyalanine peptide

2004

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We have investigated the folding of polyalanine by combining discontinuous molecular dynamics simulation with our newly developed off-lattice intermediate-resolution protein model. The thermodynamics of a system containing a single Ac-KA 14 K-NH 2 molecule has been explored by using the replica exchange simulation method to map out the conformational transitions as a function of temperature. We have also explored the influence of solvent type on the folding process by varying the relative strength of the side-chain's hydrophobic interactions and backbone hydrogen bonding interactions. The peptide in our simulations tends to mimic real polyalanine in that it can exist in three distinct structural states: ␣-helix, ␤-structures (including ␤-hairpin and ␤-sheet-like structures), and random coil, depending upon the solvent conditions. At low values of the hydrophobic interaction strength between nonpolar side-chains, the polyalanine peptide undergoes a relatively sharp transition between an ␣-helical conformation at low temperatures and a random-coil conformation at high temperatures. As the hydrophobic interaction strength increases, this transition shifts to higher temperatures. Increasing the hydrophobic interaction strength even further induces a second transition to a ␤-hairpin, resulting in an ␣-helical conformation at low temperatures, a ␤-hairpin at intermediate temperatures, and a random coil at high temperatures. At very high values of the hydrophobic interaction strength, polyalanines become ␤-hairpins and ␤-sheet-like structures at low temperatures and random coils at high temperatures. This study of the folding of a single polyalanine-based peptide sets the stage for a study of polyalanine aggregation in a forthcoming paper.Keywords: polyalanine; ␣-␤ transition; secondary structures; solvent conditions; discontinuous molecular dynamics Small peptides undergo a spontaneous reversible disorderto-order transition to a unique, three-dimensional equilibrium structure such as an ␣-helix or a ␤-structure when exposed to favorable physiological conditions. The information necessary to drive this folding transition is universally accepted to be encrypted solely within the linear amino acid sequence (Anfinsen 1973;Anfinsen and Scheraga 1975). However, experiments indicate that many peptides can be folded into alternative stable structures by changing the solution conditions (Rosenheck and Doty 1961;Kabsch and Sander 1984;Mutter and Hersperger 1990;Mutter et al. 1991;Zhong and Johnson 1992;Cohen et al. 1993;Waterhous and Johnson 1994). For example, many peptides are well known to undergo a sharp helix-coil transition as the temperature is increased (Poland and Scheraga 1970;Rohl and Baldwin 1998). Furthermore, the conformational transition between the ␣-helix and ␤-structure is greatly influenced by solvent conditions, including the pH (Mutter and Hersperger 1990;Cerpa et al. 1996;Tuchscherer et al. 1999), the temperature (Cerpa et al. 1996;Fukushima 1996;Zhang and Rich 1997), the salt or organic cosolvent ...

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Conformational Study of Solid Polypeptides by ¹H Combined Rotation and Multiple Pulse Spectroscopy NMR. 2. Amide Proton Chemical Shift

Cited by 22 publications

References 32 publications

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Solvent effects on the energy landscapes and folding kinetics of polyalanine

Solvent effects on the conformational transition of a model polyalanine peptide

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Conformational Study of Solid Polypeptides by 1H Combined Rotation and Multiple Pulse Spectroscopy NMR. 2. Amide Proton Chemical Shift

Cited by 22 publications

References 32 publications

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Solvent effects on the energy landscapes and folding kinetics of polyalanine

Solvent effects on the conformational transition of a model polyalanine peptide

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Conformational Study of Solid Polypeptides by ¹H Combined Rotation and Multiple Pulse Spectroscopy NMR. 2. Amide Proton Chemical Shift