Interplay between hydrophobic cluster and loop propensity in beta-hairpin formation

Area of Science:

• Biochemistry
• Molecular Biology
• Protein Folding

Background:

• Antiparallel beta-sheets are crucial protein structures.
• Understanding beta-sheet stability is vital for protein folding research.
• Autonomously folding beta-hairpins serve as model systems.

Purpose of the Study:

• To investigate the primary drivers of antiparallel beta-sheet stability.
• To determine if previously identified factors are sufficient to explain beta-sheet stability.
• To analyze the influence of loop-side chain interactions on hairpin formation.

Main Methods:

• Design and synthesis of isomeric 20-residue peptides.
• Systematic variation of loop segments and side-chain interactions.
• Analysis of beta-hairpin formation and stability.

Main Results:

• Identical conformational propensities, side-chain contacts, hydrogen bonds, and intrinsic propensities did not fully explain stability.
• Beta-hairpin formation and stability were significantly influenced by the separation between the loop and hydrophobic side-chain clusters.
• A smaller separation distance correlated with increased beta-hairpin stability.

Conclusions:

• The four commonly cited factors are insufficient on their own to account for beta-sheet stability.
• The spatial arrangement of hydrophobic side-chains relative to the loop is a critical determinant of beta-hairpin stability.
• Statistical mechanical models accurately predict the impact of loop-hydrophobic cluster separation on hairpin formation.