Effect of Charged Amino Acid Side Chain Length at
Non-Hydrogen Bonded Strand Positions on β‑Hairpin Stability
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Abstract
β-Sheets
have been implicated in various neurological disorders,
and ∼20% of protein residues adopt a sheet conformation. Therefore,
studies on the structural origin of sheet stability can provide fundamental
knowledge with potential biomedical applications. Oppositely charged
amino acids are frequently observed across one another in antiparallel
β-sheets. Interestingly, the side chains of natural charged
amino acids Asp, Glu, Arg, Lys have different numbers of hydrophobic
methylenes linking the backbone to the hydrophilic charged functionalities.
To explore the inherent effect of charged amino acid side chain length
on antiparallel sheets, the stability of a designed hairpin motif
containing charged amino acids with varying side chain lengths at
non-hydrogen bonded positions was studied. Peptides with the guest
position on the N-terminal strand and the C-terminal strand were investigated
by NMR methods. The charged amino acids (Xaa) included negatively
charged residues with a carboxylate group (Asp, Glu, Aad in increasing
length), positively charged residues with an ammonium group (Dap,
Dab, Orn, Lys in increasing length), and positively charged residues
with a guanidinium group (Agp, Agb, Arg, Agh in increasing length).
The fraction folded and folding free energy for each peptide were
derived from the chemical shift deviation data. The stability of the
peptides with the charged residues at the N-terminal guest position
followed the trends: Asp > Glu > Aad, Dap < Dab < Orn
∼
Lys, and Agb < Arg < Agh < Agp. The stability of the peptides
with the charged residues at the C-terminal guest position followed
the trends: Asp < Glu < Aad, Dap ∼ Dab < Orn ∼
Lys, and Agb < Arg ∼ Agp < Agh. These trends were rationalized
by thermodynamic sheet propensity and cross-strand interactions