Stereochemical Control of Hairpin Formation in β-Peptides Containing Dinipecotic Acid Reverse Turn Segments

Chung, Yoon Jang; Huck, Bayard R.; Christianson, Laurie A.; Stanger, Heather E.; Krauthäuser, Susanne; Powell, and Douglas R.; Gellman, Samuel H.

doi:10.1021/ja993416p

Cited by 132 publications

(115 citation statements)

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“…1) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). For the purpose of this paper, ␤-turn mimics are defined as molecules that replace the i ϩ 1 and i ϩ 2 amino acid residues of a ␤-turn.…”

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confidence: 99%

Evaluating β-turn mimics as β-sheet folding nucleators

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Liu

et al. 2009

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

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␤-Turns are common conformations that enable proteins to adopt globular structures, and their formation is often rate limiting for folding. ␤-Turn mimics, molecules that replace the i ؉ 1 and i ؉ 2 amino acid residues of a ␤-turn, are envisioned to act as folding nucleators by preorganizing the pendant polypeptide chains, thereby lowering the activation barrier for ␤-sheet formation. However, the crucial kinetic experiments to demonstrate that ␤-turn mimics can act as strong nucleators in the context of a cooperatively folding protein have not been reported. We have incorporated 6 ␤-turn mimics simulating varied ␤-turn types in place of 2 residues in an engineered ␤-turn 1 or ␤-bulge turn 1 of the Pin 1 WW domain, a three-stranded ␤-sheet protein. We present 2 lines of kinetic evidence that the inclusion of ␤-turn mimics alters ␤-sheet folding rates, enabling us to classify ␤-turn mimics into 3 categories: those that are weak nucleators but permit Pin WW folding, native-like nucleators, and strong nucleators. Strong nucleators accelerate folding relative to WW domains incorporating all ␣-amino acid sequences. A solution NMR structure reveals that the native Pin WW ␤-sheet structure is retained upon incorporating a strong E-olefin nucleator. These ␤-turn mimics can now be used to interrogate protein folding transition state structures and the 2 kinetic analyses presented can be used to assess the nucleation capacity of other ␤-turn mimics.beta-sheet nucleator ͉ kinetic assessment of turn mimics ͉ Pin WW domain ͉ protein folding

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confidence: 99%

Evaluating β-turn mimics as β-sheet folding nucleators

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Liu

et al. 2009

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

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“…The protected b-dipepetide Fmoc-b 2 -hAla-b 3 -hAlaOH was synthesized as described previously. 8,9 Peptide synthesis…”

Section: Methodsmentioning

confidence: 99%

“…1). 8,9 An analogous hydrogen-bonding pattern exists within the most common type of reverse turns in proteins, so-called b-turns, but the hydrogen-bonded ring in a b-turn has 10 atoms rather than 12, because each a-amino acid residue has three backbone atoms, whereas each b-amino acid residue has four backbone atoms. 10 Because nipecotic acid is a secondary amine and, therefore, forms tertiary amides, an R-Nip-S-Nip segment cannot access other hydrogen-bonding patterns.…”

Section: Introductionmentioning

confidence: 99%

Protein prosthesis: β‐peptides as reverse‐turn surrogates

et al. 2013

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The introduction of non-natural modules could provide unprecedented control over folding/unfolding behavior, conformational stability, and biological function of proteins. Success requires the interrogation of candidate modules in natural contexts. Here, expressed protein ligation is used to replace a reverse turn in bovine pancreatic ribonuclease (RNase A) with a synthetic b-dipeptide: b 2 -homoalanine-b 3 -homoalanine. This segment is known to adopt an unnatural reverse-turn conformation that contains a 10-membered ring hydrogen bond, but one with a donor-acceptor pattern opposite to that in the 10-membered rings of natural reverse turns. The RNase A variant has intact enzymatic activity, but unfolds more quickly and has diminished conformational stability relative to native RNase A. These data indicate that hydrogen-bonding pattern merits careful consideration in the selection of beneficial reverse-turn surrogates.

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“…The question of any selective advantage of preserving this dipeptide reverse turn during the evolution of these different species is intriguing. Residues Asn113-Pro114 located at the end of a b-hairpin were replaced with a reverse-turn peptidomimetic (Figure 13), the dipeptide (R)-nipecotic acid-(S)-nipecotic acid, shown by Chung et al, 108 to nucleate reverse-turn segments. The substitution of two exocyclic six-membered rings in the peptide backbone for the single five-membered proline ring and Asn residue was anticipated to enhance the preorganization of…”

Section: Figure 10mentioning

confidence: 99%

Back to the future: Ribonuclease A

2008

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Pancreatic ribonuclease A (EC 3.1.27.5, RNase) is, perhaps, the best‐studied enzyme of the 20th century. It was isolated by René Dubos, crystallized by Moses Kunitz, sequenced by Stanford Moore and William Stein, and synthesized in the laboratory of Bruce Merrifield, all at the Rockefeller Institute/University. It has proven to be an excellent model system for many different types of experiments, both as an enzyme and as a well‐characterized protein for biophysical studies. Of major significance was the demonstration by Chris Anfinsen at NIH that the primary sequence of RNase encoded the three‐dimensional structure of the enzyme. Many other prominent protein chemists/enzymologists have utilized RNase as a dominant theme in their research. In this review, the history of RNase and its offspring, RNase S (S‐protein/S‐peptide), will be considered, especially the work in the Merrifield group, as a preface to preliminary data and proposed experiments addressing topics of current interest. These include entropy–enthalpy compensation, entropy of ligand binding, the impact of protein modification on thermal stability, and the role of protein dynamics in enzyme action. In continuing to use RNase as a prototypical enzyme, we stand on the shoulders of the giants of protein chemistry to survey the future. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 259–277, 2008.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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Stereochemical Control of Hairpin Formation in β-Peptides Containing Dinipecotic Acid Reverse Turn Segments

Cited by 132 publications

References 58 publications

Evaluating β-turn mimics as β-sheet folding nucleators

Evaluating β-turn mimics as β-sheet folding nucleators

Protein prosthesis: β‐peptides as reverse‐turn surrogates

Back to the future: Ribonuclease A

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