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The supramolecular chemistry of ?-sheets.

ABSTRACT: Interactions among ?-sheets occur widely in protein quaternary structure, protein-protein interaction, and protein aggregation and are central in Alzheimer's and other amyloid-related diseases. This Perspective looks at the structural biology of these important yet under-appreciated interactions from a supramolecular chemist's point of view. Common themes in the supramolecular interactions of ?-sheets are identified and richly illustrated though examples from proteins, amyloids, and chemical model systems. ?-Sheets interact through edge-to-edge hydrogen bonding to form extended layers and through face-to-face hydrophobic or van der Waals interactions to form layered sandwich-like structures. Side chains from adjacent layers can fit together through simple hydrophobic contacts or can participate in complementary interdigitation or knob-hole interactions. The layers can be aligned, offset, or rotated. The right-handed twist of ?-sheets provides additional opportunities for stabilization of edge-to-edge contacts and rotated layered structures.

SUBMITTER: Cheng PN

PROVIDER: S-EPMC3642101 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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The supramolecular chemistry of β-sheets.

Cheng Pin-Nan PN Pham Johnny D JD Nowick James S JS

Journal of the American Chemical Society 20130402 15

Interactions among β-sheets occur widely in protein quaternary structure, protein-protein interaction, and protein aggregation and are central in Alzheimer's and other amyloid-related diseases. This Perspective looks at the structural biology of these important yet under-appreciated interactions from a supramolecular chemist's point of view. Common themes in the supramolecular interactions of β-sheets are identified and richly illustrated though examples from proteins, amyloids, and chemical mod ...[more]

PMID: 23548073

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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

The supramolecular chemistry of ?-sheets.

Publications

The supramolecular chemistry of β-sheets.

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