Helix-Coil Stability Constants for the Naturally Occurring Amino Acids in Water. IV. Alanine Parameters from Random Poly(hydroxypropylglutamine-co-L-alanine)

Platzer, K. E. B.; Ananthanarayanan, Vettai S.; Andreatta, R. H.; Scheraga, Harold A.

doi:10.1021/ma60026a016

Cited by 101 publications

(84 citation statements)

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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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“…In spite of the large number of experimental studies conducted in peptides, there is still much debate concerning the propensity of Ala residues to stabilize ␣-helices. Ingwall et al (2) studied runs of Ala n , with n ϭ 10-1,000, flanked by Lys runs, and concluded that short (n ϳ 10) sequences of Ala peptides do not form helices in water (2,3). Similar conclusions were drawn from studies of Ala-rich random sequences.…”

supporting

confidence: 59%

α-Helical stabilization by side chain shielding of backbone hydrogen bonds

Garcı́a

Sanbonmatsu

2002

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

442

470

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We study atomic models of the thermodynamics of the structural transition of peptides that form ␣-helices. The effect of sequence variation on ␣-helix formation for alanine-rich peptides, Ac-Ala21-methyl amide (A21) and Ac-A5 (AAARA)3A-methyl amide (Fs peptide), is investigated by atomic simulation studies of the thermodynamics of the helix-coil transition in explicit water. The simulations show that the guanidinium group in the Arg side chains in the Fs peptide interacts with the carbonyl group four amino acids upstream in the chain and desolvates backbone hydrogen bonds. This desolvation can be directly correlated with a higher probability of hydrogen bond formation. We find that Fs has higher helical content than A21 at all temperatures. A small modification in the AMBER force field reproduces the experimental helical content and helix-coil transition temperatures for the Fs peptide.D etailed all-atom molecular simulation of protein folding has been limited by the inadequacy of sampling and possible inaccuracies of the semiempirical force fields used in classical simulations. The development of techniques for efficient sampling and the refinement of semiempirical force fields are crucial for modeling protein folding, structure prediction, and complex formation. Small peptides have many of the complexities associated with the energy landscape of proteins (1) and are ideal systems to understand the role of competing interactions in determining protein structures. In this work, we study the thermodynamics of the helix-coil transition of short peptides for which ample experimental data exist. We use highly parallel algorithms that enable the efficient sampling of configurational space. We validate our results through comparison with experimental data and test the sensitivity of our results to small changes in the semiempirical force field.The elucidation of ␣-helical formation energetics is relevant for understanding protein folding mechanisms. In spite of the large number of experimental studies conducted in peptides, there is still much debate concerning the propensity of Ala residues to stabilize ␣-helices. Ingwall et al. (2) studied runs of Ala n , with n ϭ 10-1,000, flanked by Lys runs, and concluded that short (n ϳ 10) sequences of Ala peptides do not form helices in water (2, 3). Similar conclusions were drawn from studies of Ala-rich random sequences. However, short (13-21) Ala-rich peptides containing interior charged amino acid side chains are found to form helices with 70-90% helical content (4-7), and short runs of Ala n (n ϭ 13) flanked by two ornithine charged amino acid are found to be about 40% helical in water (8, 9). These data have been interpreted in terms of a large intrinsic propensity of Ala residues to form helices in water. Within the Lifson-Roig (10, 11) and Zimm-Bragg (12) models for the helix-coil transition, the intrinsic propensity of an amino acid to form a helix is a measure of the interactions of the amino acid with its own and nearest-neighbor amino acid backbone (11, 13). Theore...

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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: 99%

“…However, experimental (12)(13)(14) and computational (4)(5)(6)(15)(16)(17)(18)(19)(20)(21)(22)(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 indicate that these helical propensity scales do not reflect the intrinsic properties of individual residues irrespective of the environment, and that solvent effects have to be taken into account.…”

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confidence: 99%

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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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Helix-Coil Stability Constants for the Naturally Occurring Amino Acids in Water. IV. Alanine Parameters from Random Poly(hydroxypropylglutamine-co-L-alanine)

Cited by 101 publications

References 0 publications

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

α-Helical stabilization by side chain shielding of backbone hydrogen bonds

Solvent effects on the energy landscapes and folding kinetics of polyalanine

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