Toward a rational design of β-peptide structures

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Abstract

Intrinsic conformational characteristics of β-peptides built up from simple achiral and chiral β-amino acid residues (i.e., HCO-β-Ala-NH2, HCO-β-Abu-NH2) were studied using quantum chemical calculations and 1H-NMR spectroscopy. A conformer-based systematic and uniform nomenclature was introduced to differentiate conformers. Geometry optimizations were performed on all homoconformers of both HCO-(β-Ala)k-NH2 and HCO-(β-Abu)k-NH2 (1 ≤ k ≤ 6) model systems at the RHF/3-21G and RHF/6-311 + +G(d, p) levels of theory. To test for accuracy and precision, additional computations were carried out at several levels of theory [e.g., RHF/6-31G(d), and B3LYP/6-311 + +G(d, p)]. To display the folding preference, the relative stability of selected conformers as function of the length of the polypeptide chain was determined. Ab initio population distribution of hexapeptides and the conformational ensemble of synthetic models composed of β-Ala and β-Abu studied using 1H-NMR in different solvents were compared at a range of temperatures. Helical preference induced by various steric effects of nonpolar side chains was tested using higher level ab initio methods for well-known model systems such as: HCO-(β-HVal-β-HAla-β-HLeu)2-NH2, HCO-(ACHC)6-NH2, HCO-(trans-ACPC)6-NH 2, and HCO-(cis-ACPC)6-NH2. The relative stabilities determined by theoretical methods agreed well with most experimental data, supporting the theory that the local conformational preference influenced by steric effects is a key determining factor of the global fold both in solution and in the gas phase.

Original languageEnglish
Pages (from-to)20-38
Number of pages19
JournalJournal of Computational Chemistry
Volume27
Issue number1
DOIs
Publication statusPublished - Jan 15 2006

Keywords

  • Ab initio
  • DFT
  • Geometry optimization
  • NMR
  • Secondary structure
  • β-peptide

ASJC Scopus subject areas

  • Chemistry(all)
  • Computational Mathematics

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