Water-mediated interactions destabilize proteins.

Area of Science:

• Biophysics
• Computational Chemistry
• Protein Science

Background:

• The classical view posits that protein folding is driven by the hydrophobic effect, where nonpolar groups avoid water.
• Water-mediated interactions between nonpolar groups are traditionally considered a key factor in protein thermodynamic stability.
• This perspective suggests the energetic cost of hydrating nonpolar groups drives protein folding.

Purpose of the Study:

• To critically re-evaluate the classical understanding of hydrophobic interactions in protein folding.
• To investigate the role of water-mediated interactions versus dispersion forces in protein association.
• To accurately calculate solvation free energy for protein folding using advanced computational methods.

Main Methods:

• Employed liquid-state density functional theory (LS-DFT) for accurate solvation free-energy calculations.
• Analyzed a thermodynamic cycle of protein folding, focusing on the leucine zipper formation in the GCN4-p1 coiled-coil protein.
• Examined the GCN4-p1 protein, a model system for studying hydrophobic interactions.

Main Results:

• Demonstrated that water-mediated interactions are unfavorable for the association of nonpolar groups in the native state of GCN4-p1.
• Identified dispersion forces between nonpolar groups as the primary drivers of association in coiled-coil protein formation.
• Accurately predicted the pressure-stabilized isolated helical state, consistent with experimental observations.

Conclusions:

• Challenges the classical concept that the energetic cost of hydrating nonpolar groups drives protein folding.
• Highlights the significant role of dispersion forces in stabilizing protein structures like coiled-coils.
• Suggests a revised understanding of hydrophobic interactions in protein thermodynamics and folding mechanisms.