Dynamics and cooperativity of Trp-cage folding

Area of Science:

• Biophysics
• Computational Chemistry
• Protein Folding

Background:

• Understanding protein folding mechanisms is crucial for molecular biology and drug discovery.
• The Trp-cage peptide is a model system for studying fast protein folding dynamics.

Purpose of the Study:

• To investigate the molecular mechanisms governing Trp-cage folding.
• To elucidate the role of specific interactions, such as salt bridges and hydrophobic effects, in stabilizing the folded state.

Main Methods:

• Multiple independent molecular dynamics (MD) simulations were conducted.
• Simulations were performed at varying temperatures (300, 325, and 375 K).
• A generalized Born (GB) implicit solvent model was employed.

Main Results:

• Observed orientational movement of the Trp6 side-chain contributing to hydrophobic core formation with a 3(10)-helix.
• Identified the breaking and formation of a salt bridge between Asp9 and Arg16 as a prerequisite for folding/refolding.
• Demonstrated cooperation between the salt bridge and Trp6 orientation for stable tertiary structure formation.

Conclusions:

• The salt bridge and Trp6 orientation are key to Trp-cage tertiary structure stability.
• Analysis of backbone motions suggests specific residue interactions (Trp6-helix, Pro12-Pro17/18) are temperature-dependent driving forces for hydrophobic collapse.