BetaCore, a designed water soluble four-stranded antiparallel b-sheet protein

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2-AMINO-6-[2-(2-AMINOOXY-ACETYLAMINO)-ACETYLAMINO]-HEXANOIC ACID

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2-AMINO-6-[2-(2-OXO-ACETYLAMINO)-ACETYLAMINO]-HEXANOIC ACID

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(2S)-2-amino-6-[2-(2-aminooxyethanoylamino)ethanoylamino]hexanoic acid

(2S)-2-amino-6-[2-(oxaldehydoylamino)ethanoylamino]hexanoic acid

Protein science : a publication of the Protein Society
BetaCore, a designed water soluble four-stranded antiparallel beta-sheet protein.

A new strategy for the design and construction of peptide fragments that can achieve defined, nativelike secondary structure is presented. The strategy is based upon the hypothesis that 'core elements' of a protein, synthesized in a single polypeptide molecule, will favor nativelike structure, and that by incorporating a cross-link, nativelike core structure will dominate the ensemble as the more extended conformations are excluded. 'Core elements' are the elements of packed secondary structure that contain the slowest exchanging backbone amide protons in the native protein. The 'core elements' in bovine pancreatic trypsin inhibitor (BPTI) are the two long strands of antiparallel beta-sheet (residues 18-24 and 29-35) and the small beta-bridge (residues 43-44). To test the design strategy, we synthesized an 'oxidized core module', which contains the antiparallel strands connected by a modified reverse turn (A27 replaced by D), a natural disulfide cross-link at the open end of the hairpin, and N- and C-termini blocking groups. A peptide with identical sequence but lacking the disulfide cross-link at the open end was used as the 'reduced core module' control. The conformational behavior of both peptides was examined using (1)H NMR spectroscopy. Chemical shift dispersion, chemical shift deviation from random coil values, sequential and long-range NOEs, and H/D amide exchange rates were compared for the two peptides. We conclude that the ensemble of oxidized and reduced core module conformations samples both nativelike 4:4 and non-native 3:5 beta-hairpin structure, and that the oxidized module samples nativelike structure for a greater fraction of the time than the reduced module.

Carulla, N.; Woodward, C.; Barany, G.
Synthesis and Characterization of a b-Hairpin Peptide That
Represents a 'Core Module' of Bovine Pancreatic Trypsin
Inhibitor (BPTI).
Biochemistry, 39, 7927-7937 (2000).

Synthesis and characterization of a beta-hairpin peptide that represents a 'core module' of bovine pancreatic trypsin inhibitor (BPTI).

A 25-residue disulfide-cross-linked peptide, termed 'oxidized core module' (OxCM), that includes essentially all of the secondary structural elements of bovine pancreatic trypsin inhibitor (BPTI) most refractory to hydrogen exchange, was shown previously to favor nativelike beta-sheet structure [Carulla, N., Woodward, C., and Barany, G. (2000) Synthesis and Characterization of a beta-Hairpin Peptide That Represents a 'Core Module' of Bovine Pancreatic Trypsin Inhibitor (BPTI). Biochemistry 39, 7927-7937]. The present work prepares to explore the hypothesis that the energies of nativelike conformations, relative to other possible conformations, could be decreased further by covalent linkage of two OxCMs. Optimized syntheses of six approximately 50-residue OxCM dimers are reported herein, featuring appropriate monomer modifications followed by oxime-forming ligation chemistry to create covalent cross-links at various positions and with differing lengths. Several side reactions were recognized through this work, and modified procedures to lessen or mitigate their occurrence were developed. Particularly noteworthy, guanidine or urea denaturants that were included as peptide-solubilizing components for some reaction mixtures were proven to form adducts with glyoxylyl moieties, thus affecting rates and outcomes. All six synthetic OxCM dimers were characterized by 1D (1)H NMR; three of them showed considerable chemical shift dispersion suggestive of self-association and mutual stabilization between the monomer units.

Carulla, N.; Woodward, C.; Barany, G.
Toward New Designed Proteins Derived from Bovine Pancreatic
Trypsin Inhibitor (BPTI): Covalent Cross-Linking of Two
'Core Modules' by Oxime-Forming Ligation.
Bioconjugate Chemistry, 12, 726-741 (2001).

Toward new designed proteins derived from bovine pancreatic trypsin inhibitor (BPTI): covalent cross-linking of two 'core modules' by oxime-forming ligation.

A Chain A, Solution Structure Of Betacore,A Designed Water Soluble Four-Stranded AntiparallelB-Sheet Protein

B Chain B, Solution Structure Of Betacore,A Designed Water Soluble Four-Stranded AntiparallelB-Sheet Protein