Interplay among side chain sequence, backbone composition, and residue rigidification in polypeptide folding and...

Area of Science:

• Biochemistry and Structural Biology
• Peptide Chemistry
• Protein Mimetics

Background:

• Polypeptide conformation is known to depend on side-chain sequence, but the role of the alpha-amino acid backbone is less understood.
• The GCN4-pLI peptide, with a pure alpha-backbone, forms a stable four-helix bundle quaternary structure.

Purpose of the Study:

• To investigate the importance of the alpha-amino acid backbone in maintaining peptide structure.
• To explore how varying alpha- and beta-amino acid residue patterns affect quaternary structure formation and stability.

Main Methods:

• Synthesized and analyzed peptides with invariant side-chain sequences but varied alpha/beta-amino acid backbone compositions.
• Utilized physical characterization in solution and crystallographic structure determination.
• Incorporated cyclically constrained beta-amino acid residues to assess their stabilizing effects.

Main Results:

• Diverse alpha/beta-peptide backbones successfully adopted quaternary structures similar to the alpha-peptide prototype.
• Beta-residue incorporation reduced helix bundle stability, but stability did not correlate simply with beta-residue content.
• Cyclically constrained beta-amino acids stabilized folds and restored quaternary structure to otherwise unfolded backbones.

Conclusions:

• Peptide backbone composition exhibits significant plasticity in manifesting sequence-encoded structural information.
• Alpha/beta-peptides can form stable, sequence-defined quaternary structures.
• Findings provide a basis for designing nonnatural oligomers that mimic protein structure and function.