Computing free energies of protein conformations from explicit solvent simulations

Area of Science:

• Computational chemistry
• Molecular dynamics
• Biophysics

Background:

• Calculating conformational free energy differences for polymers is computationally challenging.
• Existing methods struggle with sampling issues, particularly for unfolded states.

Purpose of the Study:

• To develop a general and efficient technique for computing conformational free energy differences of polymer chains.
• To address the long-standing challenge of accurate free energy calculations in explicit solvent simulations.

Main Methods:

• Introduced a novel path coordinate variable to continuously connect different polymer conformations.
• Implemented an artificial confinement 'tube' in phase space to prevent molecular unfolding during simulations.
• Applied the method to calculate free energy differences for the Trp-cage protein using the CHARMM force field.

Main Results:

• The new method accurately computes free energy differences between polymer conformations.
• The technique proved highly computationally efficient compared to traditional methods.
• Results for the Trp-cage protein were validated against independent, more resource-intensive calculations.

Conclusions:

• The developed technique offers an accurate and computationally efficient solution for polymer conformational free energy calculations.
• This method significantly advances the simulation of molecular conformations in explicit solvent.
• The approach has broad applicability for studying polymer dynamics and thermodynamics.