Backbone N-Amination Promotes the Folding of β-Hairpin Peptides via a Network of Hydrogen Bonds
OPEN ACCESS
Loading...
Author / Producer
Date
2022-12-26
Publication Type
Journal Article
ETH Bibliography
yes
Citations
Altmetric
OPEN ACCESS
Data
Rights / License
Abstract
Molecular dynamics (MD) simulations have been used to characterize the effects of backbone N-amination of residues in a model beta-hairpin peptide. This modification is of considerable interest as N-aminated peptides have been shown to inhibit amyloid-type aggregation. Six derivatives of the beta-hairpin peptide, which contain one, two, or four N-aminated residues, have been studied. For each peptide 100 ns MD simulations starting from the folded beta-hairpin structure were performed. The effects of the N-amination prove to be very sequence dependent. N-Amination of a residue involved in interstrand hydrogen bonding (Val3) leads to unfolding of the beta-hairpin, whereas N-amination of a residue toward the C-terminus (Leu11) gives fraying at the termini of the peptide. In the other derivatives the peptide remains folded, with increasing levels of N-amination reducing the right-handed twist of the beta-hairpin and favoring population of a type II' rather than a type I' beta-turn. MD simulations (100 ns) have also been run for each peptide starting from an unfolded extended chain. Here, the peptide with four N-aminated residues shows the most folding into the beta-hairpin (34%). Analysis of the simulations shows that N-amination favors the population of beta (phi, psi) conformations by the preceding residue due to, at least in part, a network of weak NH2(i)-CO(i) and NH2(i)-CO(i-2) hydrogen bonds. It also leads to a reduction of misfolding because of changes in the hydrogen-bonding potential. Both of these features help funnel the peptide to the folded beta-hairpin structure. The conformational insights provided through this work give a firm foundation for the design of N-aminated peptide inhibitors for modulating protein-protein interactions and aggregation.
Permanent link
Publication status
published
External links
Editor
Book title
Journal / series
Volume
62 (24)
Pages / Article No.
6704 - 6714
Publisher
American Chemical Society