High Helicities of Lys-Containing, Ala-Rich Peptides Are Primarily Attributable to a Large, Context-Dependent Lys Stabilization

Williams, Lawrence J.; Kather, Kristian; Kemp, D. S.

doi:10.1021/ja9801947

Cited by 47 publications

(60 citation statements)

References 82 publications

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“…This force field also gives values for the helix propagation and nucleation parameters for Ala measured by Yang et al (9) but in disagreement with other experimental measurements (2, 3). Our calculations show that the Arg side chain significantly stabilizes the helix state of the Fs peptide, in agreement with Williams et al (15) and Vila et al (14). However, we also find that A21 is 34% helical at 275 K, consistent with Spek et al (8) …”

supporting

confidence: 92%

“…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). Theoretical (14) and experimental studies on prenucleated synthetic peptides (15) have suggested that the high helical propensity of Ala-containing peptides is a consequence of the neighboring side chains and is an effect extrinsic to the Ala side chains. Specifically, Vila et al (14) have argued that the high helical propensity of Ala-rich peptides containing large charged side chains is stabilized by the effect of the side chains in reducing the accessibility of the peptide backbone to water.…”

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confidence: 99%

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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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supporting

confidence: 92%

mentioning

confidence: 99%

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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“…In the CD investigations reported here, there is no indication that A3 or B6 shows a similar conversion to β-sheet; their temperature-dependent conformational behavior is similar to that of other previously reported alanine-rich peptides. 23,24,57,58 The thermal stability of the protein polymers at higher concentrations of 1 mg/mL in pH 2.3, 10 mM phosphate buffer was also monitored via differential scanning calorimetry. Figure 3a shows the calorimetric data for both A3 and B6 at a scan rate of 60 °C/h.…”

Section: Resultsmentioning

confidence: 99%

Conformational Properties of Helical Protein Polymers with Varying Densities of Chemically Reactive Groups

et al. 2005

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Protein engineering strategies have proven valuable for the production of a variety of well-defined macromolecular materials with controlled properties that have enabled their use in a range of materials and biological applications. In this work, such biosynthetic strategies have been employed in the production of monodisperse alanine-rich, helical protein polymers with the sequences [AAAQEAAAAQAAAQAEAAQAAQ] 3 and [AAAQAAQAQAAAEAAAQAAQAQ] 6 . The composition of these protein polymers is similar to that of a previously reported family of alaninerich protein polymers, but the density and placement of chemically reactive residues has been varied to facilitate the future use of these macromolecules in elucidating polymeric structure-function relationships in biological recognition events. Both protein polymers are readily expressed from E. coli and purified to homogeneity; characterization of their conformational behavior via circular dichroic spectroscopy (CD) indicates that they adopt highly helical conformations under a range of solution conditions. Differential scanning calorimetry, in concert with CD, demonstrates that the conformational transition from helix to coil in these macromolecules can be well-defined, with helicity, conformational transitions, T m values, and calorimetric enthalpies that vary with the molecular weight of the protein polymers. A combination of infrared spectroscopy and CD also reveals that the macromolecules can adopt β-sheet structures at elevated temperatures and concentrations and that the existence and kinetics of this conformational transition appear to be related to the density of charged groups on the protein polymer.

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“…Recently, it was proposed that alcohol may act on the exposed CO and NH groups by diminishing their exposure to the solvent, i.e., shifting the conformational equilibrium toward more compact structures, such as ␣-helical conformation (23). An alternative proposal for shifting the helix-coil equilibrium of polyalanine toward an ␣-helical conformation is to introduce charged residues into the sequence (48,49); however, in this case, the tendency to form the ␣-helix should not be associated with the ␣-helical propensity of alanine discussed herein.…”

Section: Resultsmentioning

confidence: 99%

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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High Helicities of Lys-Containing, Ala-Rich Peptides Are Primarily Attributable to a Large, Context-Dependent Lys Stabilization

Cited by 47 publications

References 82 publications

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

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

Conformational Properties of Helical Protein Polymers with Varying Densities of Chemically Reactive Groups

Solvent effects on the energy landscapes and folding kinetics of polyalanine

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