For Short Alanine-Lysine Peptides the Helical Propensities of Lysine Residues (<i>s</i> Values) Are Strongly Temperature Dependent

Renold, Peter; Tsang, Kwok Yin; Shimizu, Linda S.; Kemp, D. S.

doi:10.1021/ja961646n

Cited by 12 publications

(25 citation statements)

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“…When N-terminally linked to helically disposed polypeptides, Ac-Hel 1 initiates and strongly stabilizes α-helical conformations and allows NMR-based quantitation of their helicity . By studying Ac-Hel 1 conjugates of short alanine-rich peptides (5−15 residues), we have characterized helices that are too unstable to be detected in the corresponding nontemplated peptides, and we have used them to characterize the stabilities of alanine-rich helices containing a single lysine residue . The resulting helical propensities are inconsistent with others that have been recently reported.…”

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confidence: 86%

“…Context independence has been criticized as a general model assumption. , For the particular case of amino acid residues bearing charged side chains, w values have been predicted and shown − to be strongly site dependent (charge−helix dipole interaction). The relative importance of context- or site-dependent and context- and site-independent contributions to helicity is currently unknown, but an accurate helicity algorithm clearly must include mutually consistent coefficients that reflect all these contributions, which must be measured by site mutations in a host that is free of significant uncharacterized site or context effects.…”

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confidence: 99%

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

1998

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Peptides 1K, YKGGGAAAAAAAAKAAAAAAAAAGGGK-NH 2 ; 2K, YKGGGAAAAAKAAAAA-KAAAAAAGGGK-NH 2 ; and 3K, YKGGGAAAAKAAAAKAAAAKAAAGGGK-NH 2 have been prepared by solid-phase synthesis, purified, and characterized by amino acid analysis, MALDI mass spectrometry, and ultracentrifugation. Their circular dichroism (CD) spectra of unaggregated solutions are reported for measurements in 0.01 M NaCl at 2, 25, and 60 °C and at 2 °C in aqueous guanidinium hydrochloride (0-3 M) and aqueous trifluoroethanol (TFE, 0-15 mol %). The CD spectra exhibit a helical signature in 0.01 M NaCl or in water-TFE at 2 °C, and the intensities of the mean residue ellipticities at the minimums of 222 nm in 0.01 M NaCl are (1K) -9100, (2K) -18 100, and (3K) -19 900 deg cm -1 dmol -1 . These ellipticities are accurately modeled using a Lifson-Roig algorithm by the helical propensities previously reported by Renold et al.

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confidence: 86%

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

1998

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“…Using the Ac-Hel 1 template as both a nucleation site and a reporter of helix content, Kemp and coworkers (2,(4)(5)(6) have reported significant helix formation for a number of short alanine-based peptide sequences under a variety of conditions. Quite surprisingly, however, the authors conclude from their data that alanine is helix-indifferent with an equilibrium constant for propagation of approximately one (2,4).…”

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confidence: 99%

“…A large nucleation propensity is inconsistent, however, with the extent of fraying observed in alanine-based peptides (10)(11)(12). Furthermore, to model their Ac-Hel 1 -peptide conjugate data, Kemp and coworkers (2,(4)(5)(6) assume that the nucleation propensity of alanine is 1-2 orders of magnitude smaller than that of the template, and the measured values of the nucleation propensity determined with standard peptide helices (8,10) fall into this range. Kemp and coworkers (5,6) have also suggested that the helix content of alanine-lysine peptides results from a large helix propensity of lysine.…”

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confidence: 99%

“…Furthermore, to model their Ac-Hel 1 -peptide conjugate data, Kemp and coworkers (2,(4)(5)(6) assume that the nucleation propensity of alanine is 1-2 orders of magnitude smaller than that of the template, and the measured values of the nucleation propensity determined with standard peptide helices (8,10) fall into this range. Kemp and coworkers (5,6) have also suggested that the helix content of alanine-lysine peptides results from a large helix propensity of lysine. Substantial helix formation is observed, however, in alanine-based peptides solubilized with polar residues other than lysine (8,(13)(14)(15)(16).…”

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Alanine is helix-stabilizing in both template-nucleated and standard peptide helices

Rohl

Fiori

Baldwin

1999

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

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Alanine-based peptides of defined sequence and length show measurable helix contents, allowing them to be used as a model system both for analyzing the mechanism of helix formation and for investigating the contributions of side-chain interactions to protein stability. Extensive characterization of many peptide sequences with varying amino acid contents indicates that the favorable helicity of alanine-based peptides can be attributed to the large helix-stabilizing propensity of alanine. The resulting model provides a physically plausible resolution of the discrepancies between the two systems and allows the helix contents of both template-nucleated and standard peptide helices to be predicted by using a single set of helix propensities. Helix formation in both standard peptides and template-peptide conjugates can be attributed to the large intrinsic helix-forming tendency of alanine.The energetic cost of ␣-helix nucleation generally is considered to originate from the requirement of constraining the conformation of three consecutive amino acids before the first helical hydrogen bond can form (1). In contrast, helix propagation requires only one additional residue to be constrained for the formation of one additional hydrogen bond. The overall extent of helix formation depends on the energetics of both nucleation and propagation, as well as on chain length. To separate the effects of helix nucleation and propagation experimentally, Kemp and coworkers (2, 3) have designed a template (Ac-Hel 1 ; see Fig. 1A) that overcomes the nucleation penalty for helix formation by providing hydrogen-bond acceptors for the otherwise unsatisfied NH groups at the N terminus of the helix. Short peptides attached to this template show significant helix formation that is nucleated preferentially from the template. Because the template efficiently nucleates helical segments, the macroscopic characteristics of the template-nucleated helix depend primarily on the nucleation properties of the template and the propagation propensities of the attached amino acid residues.Using the Ac-Hel 1 template as both a nucleation site and a reporter of helix content, Kemp and coworkers (2, 4-6) have reported significant helix formation for a number of short alanine-based peptide sequences under a variety of conditions. Quite surprisingly, however, the authors conclude from their data that alanine is helix-indifferent with an equilibrium constant for propagation of approximately one (2, 4). In direct contrast, alanine is observed to be a strong helix former in a variety of standard peptide systems (7-9). To explain this paradox, Kemp and coworkers (2) have suggested that the helix content of standard alanine-based peptides might originate from an anomalously large nucleation propensity of alanine. A large nucleation propensity is inconsistent, however, with the extent of fraying observed in alanine-based peptides (10-12). Furthermore, to model their Ac-Hel 1 -peptide conjugate data, Kemp and coworkers (2, 4-6) assume that the nucleation propen...

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Dichroic statistical model for prediction and analysis of peptide helicity

Shalongo

Stellwagen

1997

Proteins

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Traditional statistical models for the prediction of peptide helicity are written in terms of the mean fractional helicity of the peptide residues. Far ultraviolet circular dichroic measurements of peptide solutions are converted to mean fractional helicity by partitioning the observed ellipticity between that of a perfect helix and a random coil. This partition does not adequately represent the ensemble of peptide molecules present in solution that populate imperfect helical conformations of quite variable lengths. A new dichroic statistical model has been written in terms of ellipticity rather than fractional helical content that recognizes (1) the source of ellipticity, peptide bond adsorption; (2) the differential ellipticity of peptide bonds in the terminal and interior helical turns; and (3) the contributions of each participant in a conformational ensemble to the observed ellipticity. Comparative analyses of host/guest peptides indicates that significant differences are obtained between residue w and n weights and ellipticity values using the traditional and dichroic statistical models.

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For Short Alanine-Lysine Peptides the Helical Propensities of Lysine Residues (s Values) Are Strongly Temperature Dependent

Cited by 12 publications

References 13 publications

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

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

Alanine is helix-stabilizing in both template-nucleated and standard peptide helices

Dichroic statistical model for prediction and analysis of peptide helicity

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