How robust are protein folding simulations with respect to force field parameterization?

Area of Science:

• Computational chemistry
• Biophysics
• Protein dynamics

Background:

• Molecular dynamics (MD) simulations offer atomic-level insights into protein folding.
• Experimental data on protein folding pathways can be challenging to obtain.
• The accuracy of MD simulations depends on the chosen force field parameters.

Purpose of the Study:

• To investigate the influence of different molecular mechanics force fields on protein folding pathways.
• To assess the reliability of MD simulations in capturing the complete protein folding process.

Main Methods:

• Equilibrium molecular dynamics simulations were performed.
• A fast-folding variant of the villin headpiece was simulated.
• Four distinct molecular mechanics force fields were employed.

Main Results:

• All simulations showed good agreement with experimental folding rates and native state structures.
• Significant variations in folding mechanisms and unfolded state properties were observed across different force fields.
• The choice of force field substantially influenced the simulated folding pathways.

Conclusions:

• Matching experimental folding rates and structures is insufficient to validate MD simulations.
• Force fields critically affect the description of the protein folding free-energy surface.
• MD simulations require careful force field selection for accurate mechanistic insights.