Solvent-Induced Stabilization and Folding Pathways of α-Helical Peptides: A Computational Investigation Using Steered...

Area of Science:

• Biophysics and Computational Chemistry
• Protein Science and Engineering

Background:

• Fluorinated polar solvents like hexafluoro-2-propanol (HFIP) are known to induce α-helix structures in proteins.
• This phenomenon is significant for protein engineering and the development of novel fiber materials.
• Molecular dynamics (MD) simulations are crucial for understanding protein folding dynamics.

Purpose of the Study:

• To investigate the role of HFIP in protein structural transitions using steered molecular dynamics (SMD).
• To analyze the potential of mean force (PMF) during polypeptide stretching in different solvents.
• To explore the impact of HFIP on the folding mechanisms of a mini-protein (Trp-cage).

Main Methods:

• Steered molecular dynamics (SMD) simulations were employed to stretch polypeptide models.
• Simulations were performed in hexafluoro-2-propanol (HFIP) and water to compare solvent effects.
• The potential of mean force (PMF) was calculated to quantify stretching resistance.

Main Results:

• Polypeptide stretching yielded a higher PMF in HFIP compared to water, indicating increased resistance.
• HFIP molecules were observed to accumulate in the grooves of α-helical polypeptides.
• Stretching in HFIP induced the formation of 3₁₀-helix structures, suggesting enhanced local solvation.
• Simulations of Trp-cage showed partial unfolding of α-helices and global extension, with PMF profiles supporting early α-helix formation during folding.

Conclusions:

• Hexafluoro-2-propanol (HFIP) plays a key role in promoting and stabilizing α-helical structures in polypeptides.
• Local solvation by HFIP enhances the stability of helical conformations, including 3₁₀-helices.
• The study provides an analytical framework for investigating protein folding and structural transitions in various solvents.