Hydrogen-bond energetics drive helix formation in membrane interfaces

Area of Science:

• Biochemistry
• Biophysics
• Membrane Biology

Background:

• Unfolded peptides partitioning into membrane interfaces incur a free energy cost (ΔG) due to backbone peptide bonds.
• This partitioning cost is significantly reduced when peptide bonds form hydrogen bonds.
• This reduction facilitates secondary structure formation via partitioning-folding coupling in amphiphilic peptides.

Purpose of the Study:

• To accurately compute the free energy reduction per residue (∆G(res)) driving peptide folding.
• To resolve the debate regarding the dependence of ∆G(res) on the hydrophobic moment (µH) of amphiphilic α-helical peptides.

Main Methods:

• Analysis of published data for two peptide families with varying hydrophobic moments and charges.
• Development of a correct computational method for ∆G(res).

Main Results:

• The free energy reduction per residue (∆G(res)) does not depend on the hydrophobic moment (µH).
• The best estimate for ∆G(res) is -0.37 ± 0.02 kcal mol⁻¹.
• Established a reliable method for calculating ∆G(res) in membrane-associated peptide folding.

Conclusions:

• Partitioning-folding coupling is a key mechanism for secondary structure formation at membrane interfaces.
• The free energy contribution per residue to folding is constant and not influenced by peptide amphipathicity.
• Provides a precise value for ∆G(res), crucial for understanding peptide-membrane interactions and protein folding dynamics.