The nucleation of monomeric parallel β-sheet-like structures and their self-assembly in aqueous solution

Penchit Chitnumsub, Wayne R. Fiori, Hilal A. Lashuel, Humberto Diaz, Jeffery W. Kelly

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

The aromatic diacid residue 4,6-dibenzofuranbispropionic acid (1) was designed to nucleate a parallel β-sheet-like structure in small peptides in aqueous solution via a hydrogen-bonded hydrophobic cluster. Even though a 14-membered ring hydrogen bond necessary for parallel β-sheet formation is favored in simple amides composed of 1, this hydrogen bonding interaction does not appear to be sufficient to nucleate parallel β-sheet formation in the absence of hydrophobic clustering between the dibenzofuran portion of 1 and the hydrophobic side chains of the flanking α-amino acids. The subsequence -hydrophobic residue-1-hydrophobic residue- is required for folding in the context of a nucleated two-stranded parallel β-sheet structure. In all cases where the peptidomimetics can fold into two diastereomeric parallel β-sheet structures having different hydrogen bonding networks, these conformations appear to exchange rapidly. The majority of the parallel β-sheet structures evaluated herein undergo linked intramolecular folding and self-assembly, affording a fibrillar β-sheet quaternary structure. To unlink folding and assembly, asymmetric parallel β-sheet structures incorporating N-methylated α-amino acid residues have been synthesized using a new solid phase approach. Residue 1 facilitates the folding of several peptides described within affording a monomeric parallel β-sheet-like structure in aqueous solution, as ascertained by a variety of spectroscopic and biophysical methods, increasing our understanding of parallel β-sheet structure. Copyright (C) 1999 Elsevier Science Ltd.

Original languageEnglish
Pages (from-to)39-59
Number of pages21
JournalBioorganic and Medicinal Chemistry
Volume7
Issue number1
DOIs
Publication statusPublished - 1 Jan 1999
Externally publishedYes

Fingerprint

Hydrogen Bonding
Self assembly
Hydrogen
Hydrogen bonds
Nucleation
Peptidomimetics
Amino Acids
Peptides
Amides
Cluster Analysis
Conformations
dibenzofuran
4,6-dibenzofuranbispropionic acid
Ring Chromosome 14 Syndrome

Keywords

  • 4,6-Dibenzofuranbispropionic acid
  • Fibril
  • Parallel β-sheet

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

The nucleation of monomeric parallel β-sheet-like structures and their self-assembly in aqueous solution. / Chitnumsub, Penchit; Fiori, Wayne R.; Lashuel, Hilal A.; Diaz, Humberto; Kelly, Jeffery W.

In: Bioorganic and Medicinal Chemistry, Vol. 7, No. 1, 01.01.1999, p. 39-59.

Research output: Contribution to journalArticle

Chitnumsub, Penchit ; Fiori, Wayne R. ; Lashuel, Hilal A. ; Diaz, Humberto ; Kelly, Jeffery W. / The nucleation of monomeric parallel β-sheet-like structures and their self-assembly in aqueous solution. In: Bioorganic and Medicinal Chemistry. 1999 ; Vol. 7, No. 1. pp. 39-59.
@article{a51657ab2a0048f9b5df3019dc595e7f,
title = "The nucleation of monomeric parallel β-sheet-like structures and their self-assembly in aqueous solution",
abstract = "The aromatic diacid residue 4,6-dibenzofuranbispropionic acid (1) was designed to nucleate a parallel β-sheet-like structure in small peptides in aqueous solution via a hydrogen-bonded hydrophobic cluster. Even though a 14-membered ring hydrogen bond necessary for parallel β-sheet formation is favored in simple amides composed of 1, this hydrogen bonding interaction does not appear to be sufficient to nucleate parallel β-sheet formation in the absence of hydrophobic clustering between the dibenzofuran portion of 1 and the hydrophobic side chains of the flanking α-amino acids. The subsequence -hydrophobic residue-1-hydrophobic residue- is required for folding in the context of a nucleated two-stranded parallel β-sheet structure. In all cases where the peptidomimetics can fold into two diastereomeric parallel β-sheet structures having different hydrogen bonding networks, these conformations appear to exchange rapidly. The majority of the parallel β-sheet structures evaluated herein undergo linked intramolecular folding and self-assembly, affording a fibrillar β-sheet quaternary structure. To unlink folding and assembly, asymmetric parallel β-sheet structures incorporating N-methylated α-amino acid residues have been synthesized using a new solid phase approach. Residue 1 facilitates the folding of several peptides described within affording a monomeric parallel β-sheet-like structure in aqueous solution, as ascertained by a variety of spectroscopic and biophysical methods, increasing our understanding of parallel β-sheet structure. Copyright (C) 1999 Elsevier Science Ltd.",
keywords = "4,6-Dibenzofuranbispropionic acid, Fibril, Parallel β-sheet",
author = "Penchit Chitnumsub and Fiori, {Wayne R.} and Lashuel, {Hilal A.} and Humberto Diaz and Kelly, {Jeffery W.}",
year = "1999",
month = "1",
day = "1",
doi = "10.1016/S0968-0896(98)00222-3",
language = "English",
volume = "7",
pages = "39--59",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "1",

}

TY - JOUR

T1 - The nucleation of monomeric parallel β-sheet-like structures and their self-assembly in aqueous solution

AU - Chitnumsub, Penchit

AU - Fiori, Wayne R.

AU - Lashuel, Hilal A.

AU - Diaz, Humberto

AU - Kelly, Jeffery W.

PY - 1999/1/1

Y1 - 1999/1/1

N2 - The aromatic diacid residue 4,6-dibenzofuranbispropionic acid (1) was designed to nucleate a parallel β-sheet-like structure in small peptides in aqueous solution via a hydrogen-bonded hydrophobic cluster. Even though a 14-membered ring hydrogen bond necessary for parallel β-sheet formation is favored in simple amides composed of 1, this hydrogen bonding interaction does not appear to be sufficient to nucleate parallel β-sheet formation in the absence of hydrophobic clustering between the dibenzofuran portion of 1 and the hydrophobic side chains of the flanking α-amino acids. The subsequence -hydrophobic residue-1-hydrophobic residue- is required for folding in the context of a nucleated two-stranded parallel β-sheet structure. In all cases where the peptidomimetics can fold into two diastereomeric parallel β-sheet structures having different hydrogen bonding networks, these conformations appear to exchange rapidly. The majority of the parallel β-sheet structures evaluated herein undergo linked intramolecular folding and self-assembly, affording a fibrillar β-sheet quaternary structure. To unlink folding and assembly, asymmetric parallel β-sheet structures incorporating N-methylated α-amino acid residues have been synthesized using a new solid phase approach. Residue 1 facilitates the folding of several peptides described within affording a monomeric parallel β-sheet-like structure in aqueous solution, as ascertained by a variety of spectroscopic and biophysical methods, increasing our understanding of parallel β-sheet structure. Copyright (C) 1999 Elsevier Science Ltd.

AB - The aromatic diacid residue 4,6-dibenzofuranbispropionic acid (1) was designed to nucleate a parallel β-sheet-like structure in small peptides in aqueous solution via a hydrogen-bonded hydrophobic cluster. Even though a 14-membered ring hydrogen bond necessary for parallel β-sheet formation is favored in simple amides composed of 1, this hydrogen bonding interaction does not appear to be sufficient to nucleate parallel β-sheet formation in the absence of hydrophobic clustering between the dibenzofuran portion of 1 and the hydrophobic side chains of the flanking α-amino acids. The subsequence -hydrophobic residue-1-hydrophobic residue- is required for folding in the context of a nucleated two-stranded parallel β-sheet structure. In all cases where the peptidomimetics can fold into two diastereomeric parallel β-sheet structures having different hydrogen bonding networks, these conformations appear to exchange rapidly. The majority of the parallel β-sheet structures evaluated herein undergo linked intramolecular folding and self-assembly, affording a fibrillar β-sheet quaternary structure. To unlink folding and assembly, asymmetric parallel β-sheet structures incorporating N-methylated α-amino acid residues have been synthesized using a new solid phase approach. Residue 1 facilitates the folding of several peptides described within affording a monomeric parallel β-sheet-like structure in aqueous solution, as ascertained by a variety of spectroscopic and biophysical methods, increasing our understanding of parallel β-sheet structure. Copyright (C) 1999 Elsevier Science Ltd.

KW - 4,6-Dibenzofuranbispropionic acid

KW - Fibril

KW - Parallel β-sheet

UR - http://www.scopus.com/inward/record.url?scp=0032978519&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032978519&partnerID=8YFLogxK

U2 - 10.1016/S0968-0896(98)00222-3

DO - 10.1016/S0968-0896(98)00222-3

M3 - Article

VL - 7

SP - 39

EP - 59

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 1

ER -