Backbone N‑Amination Promotes the Folding of β‑Hairpin Peptides via a Network of Hydrogen Bonds

Molecular dynamics (MD) simulations have been used to
characterize
the effects of backbone N-amination of residues in a model β-hairpin
peptide. This modification is of considerable interest as N-aminated
peptides have been shown to inhibit amyloid-type aggregation. Six
derivatives of the β-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 β-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 β-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 β-hairpin and favoring population
of a type II′ rather than a type I′ β-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 β-hairpin (34%). Analysis
of the simulations shows that N-amination favors the population of
β (φ, ψ) 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 β-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.