Neighbor effect on PPII conformation in alanine peptides

Area of Science:

• Structural Biology
• Biophysics
• Computational Chemistry

Background:

• The polyproline II (PPII) conformation is prevalent in short alanine oligomers.
• Previous studies suggest PPII structure in water is locally determined, consistent with Flory's isolated pair hypothesis for alanine peptides.
• Beta-branched or bulky aromatic residues are known to influence adjacent residue Phi angles.

Purpose of the Study:

• To directly investigate the neighbor effect on PPII conformation in short alanine model peptides.
• To quantify the impact of specific residues (norleucine, isoleucine) on the PPII content of a probe alanine residue.

Main Methods:

• Synthesis and analysis of model peptides: GGAAAGG, GGLnALnGG (Ln=norleucine), GGIAAGG, and GGIAIGG.
• Far-UV circular dichroism (CD) spectroscopy to assess secondary structure content.
• Nuclear magnetic resonance (NMR) 3JαN coupling constants and H-D hydrogen exchange measurements to probe local conformation and dynamics.

Main Results:

• Isoleucine significantly reduced the PPII content of the probe alanine side chain compared to alanine or norleucine.
• Observed free energy differences align with predictions from electrostatic solvation free energy (ESF) calculations.
• Data directly demonstrate the influence of neighboring residues on PPII propensity.

Conclusions:

• Neighboring residue effects are critical and must be incorporated into models predicting PPII propensities.
• The isolated pair hypothesis is insufficient for peptides with bulky or beta-branched side chains.
• Understanding these neighbor effects is essential for accurate peptide structure prediction.