α-Helices propagating from stable nucleators exhibit unconventional thermal folding

Area of Science:

• Protein structure and dynamics
• Biophysical chemistry
• Molecular biology

Background:

• Thermal perturbations significantly impact protein structure, particularly in helical peptides.
• The relationship between thermal stabilities of nucleating and propagating helical segments remains incompletely understood.
• Previous work characterized the helix-nucleating propensities of constrained α-turns.

Purpose of the Study:

• To investigate the thermal stabilities of helices propagating from specific α-helix nucleators.
• To elucidate the interdependence between nucleating and propagating segments in resisting thermal denaturation.
• To correlate helicity and rigidity with protein folding cooperativity.

Main Methods:

• Analysis of Nuclear Magnetic Resonance (NMR) spectra.
• Far-ultraviolet Circular Dichroism (far-UV CD) spectroscopy.
• Modeling of thermal folding and denaturation in peptide models.

Main Results:

• Helical folds in propagating backbones exhibit resistance to thermal perturbations when the nucleating template remains intact.
• The threshold temperature for this resistance is influenced by the similarity between nucleating and propagating helical segment characteristics.
• Observed correlations between helicity and rigidity in both segments indicate a subtle interdependence.

Conclusions:

• The nucleating template plays a critical role in maintaining the thermal stability of propagating helical structures.
• Interdependence between nucleating and propagating segments explains phenomena like cooperativity and residual helix formation during protein folding.
• These findings offer insights into the fundamental mechanisms governing protein structural integrity under thermal stress.