Thermodynamic and Structural Impact of α,α-Dialkylated Residue Incorporation in a β-Hairpin Peptide

Abstract

Peptides containing α,α-dialkylated α-amino acids, owing to their ability to disrupt aggregation of β-amyloid proteins, have therapeutic potential in the treatment of neurodegenerative diseases. Thermodynamic and structural analyses are reported for a series of β-hairpin peptides containing α,α-dialkylated α-amino acids with varying side-chain lengths. Results of these experiments show that α,α-dialkylated α-amino acids with side-chain lengths longer than one carbon unit are tolerated in a β-hairpin, although at a moderate cost to folded stability.

Assessing the Ability of Spectroscopic Methods to Determine the Difference in the Folding Propensities of Highly Similar β-Hairpins

“…Peptides, − β-hairpins in particular, − are common model systems for the investigation of weak interactions that direct protein folding. Peptide conformational equilibria in solution is typically evaluated using nuclear magnetic resonance (NMR), circular dichroism (CD), infrared (IR) spectroscopy, differential scanning calorimetry, or by computational analysis. , Many experimental studies apply one of the above techniques, ,− whereas the ability of the methods to describe peptide folding has scarcely been compared; nor has their ability to detect a slight difference in folding upon a minor structural change of a peptide been assessed. Such a comparative evaluation is expected to help the method of selection for future studies and to provide a basis for comparison of data for systems whose folding was described using different techniques.…”

Effects of chirality and side chain length in Cα,α-dialkylated residues on β-hairpin peptide folded structure and stability

“…2). 16-Residue peptide 1 is derived from the C-terminal hairpin of protein GB1, 24,25 includes a tryptophan zipper motif, 26 and adopts a highly stable β-hairpin fold that is fully populated at 298 K. 23 Variant peptides 2-4 each include a single substitution at the A13 position. This position was chosen so as not to disrupt the packing of hydrophobic core residues W3, Y5, F12, and W14.…”

Foldamer Tertiary Structure through Sequence-Guided Protein Backbone Alteration

“…30–32 C α ,C α -dialkylated residues of increased steric bulk relative to Aib can also promote extended backbone conformations and cap β-sheets. 33,34…”

“…30−32 C α ,C αdialkylated residues of increased steric bulk relative to Aib can also promote extended backbone conformations and cap βsheets. 33,34 A drawback to backbone modifications that disrupt hydrogen bonding in a β-strand is incompatibility with incorporation at an internal position of a larger β-sheet. Given the prevalence of such motifs in proteins, we were motivated to evaluate alternative substitution strategies.…”

“…The resulting monomer can display hydrogen bond donor and acceptor moieties such that one face of the strand is complementary to a native α-peptide, while the other is blocked. Such selective backbone alteration has proved instrumental in revealing structure and assembly mechanisms of amyloidogenic sequences and developing inhibitors of amyloid formation. − C α ,C α -dialkylated residues of increased steric bulk relative to Aib can also promote extended backbone conformations and cap β-sheets. , …”