Dataset Information

Stabilizing capping motif for beta-hairpins and sheets.

ABSTRACT: Although much has been learned about the design of models of beta-sheets during the last decade, modest fold stabilities in water and terminal fraying remain a feature of most beta-hairpin peptides. In the case of hairpin capping, nature did not provide guidance for solving the problem. Some observations from prior turn capping designs, with further optimization, have provided a generally applicable, "unnatural" beta cap motif (alkanoyl-Trp at the N terminus and Trp-Thr-Gly at the C terminus) that provides a net contribution of 6 + kJ/mol to beta-hairpin stability, surpassing all other interactions that stabilize beta-hairpins including the covalent disulfide bond. The motif, made up entirely of natural residues, is specific to the termini of antiparallel beta-strands and reduces fraying at the ends of hairpins and other beta-sheet models. Utilizing this motif, 10- to 22-residue peptide scaffolds of defined stereochemistry that are greater than 98% folded in water have been prepared. The beta-cap can also be used to staple together short antiparallel beta-strands connected by a long flexible loop.

SUBMITTER: Kier BL

PROVIDER: S-EPMC2890817 | biostudies-other | 2010 Jun

REPOSITORIES: biostudies-other

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Stabilizing capping motif for beta-hairpins and sheets.

Kier Brandon L BL Shu Irene I Eidenschink Lisa A LA Andersen Niels H NH

Proceedings of the National Academy of Sciences of the United States of America 20100519 23

Although much has been learned about the design of models of beta-sheets during the last decade, modest fold stabilities in water and terminal fraying remain a feature of most beta-hairpin peptides. In the case of hairpin capping, nature did not provide guidance for solving the problem. Some observations from prior turn capping designs, with further optimization, have provided a generally applicable, "unnatural" beta cap motif (alkanoyl-Trp at the N terminus and Trp-Thr-Gly at the C terminus) th ...[more]

PMID: 20484672

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Project description:The development of peptide beta-hairpins is problematic, because folding depends on the amino acid sequence and changes to the sequence can significantly decrease folding. Robust beta-hairpins that can tolerate such changes are attractive tools for studying interactions involving protein beta-sheets and developing inhibitors of these interactions. This paper introduces a new class of peptide models of protein beta-sheets that addresses the problem of separating folding from the sequence. These model beta-sheets are macrocyclic peptides that fold in water to present a pentapeptide beta-strand along one edge; the other edge contains the tripeptide beta-strand mimic Hao [JACS 2000, 122, 7654] and two additional amino acids. The pentapeptide and Hao-containing peptide strands are connected by two delta-linked ornithine (deltaOrn) turns [JACS 2003, 125, 876]. Each deltaOrn turn contains a free alpha-amino group that permits the linking of individual modules to form divalent beta-sheets. These "cyclic modular beta-sheets" are synthesized by standard solid-phase peptide synthesis of a linear precursor followed by solution-phase cyclization. Eight cyclic modular beta-sheets 1a-1h containing sequences based on beta-amyloid and macrophage inflammatory protein 2 were synthesized and characterized by 1H NMR. Linked cyclic modular beta-sheet 2, which contains two modules of 1b, was also synthesized and characterized. 1H NMR studies show downfield alpha-proton chemical shifts, deltaOrn delta-proton magnetic anisotropy, and NOE cross-peaks that establish all compounds but 1c and 1g to be moderately or well folded into a conformation that resembles a beta-sheet. Pulsed-field gradient NMR diffusion experiments show little or no self-association at low (</=2 mM) concentrations. Changes to the residues in the Hao-containing strands of 1c and 1g improve folding and show that folding of the structures can be enhanced without altering the sequence of the pentapeptide strand. Well-folded cyclic modular beta-sheets 1a, 1b, and 1f each have a phenylalanine directly across from Hao, suggesting that cyclic modular beta-sheets containing aromatic residues across from Hao are better folded.

Dataset Information

Stabilizing capping motif for beta-hairpins and sheets.

Publications

Stabilizing capping motif for beta-hairpins and sheets.

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