Conformational Free-Energy Differences of Large Solvated Systems with the Focused Confinement Method.

Area of Science:

• Computational chemistry
• Molecular dynamics
• Biophysics

Background:

• Calculating conformational free-energy differences is crucial for understanding protein dynamics and function.
• Existing methods often require computationally expensive reaction coordinates.
• Explicit solvent simulations provide a more realistic environment but increase computational cost.

Purpose of the Study:

• To introduce and validate the focused confinement method (FCM) as a reaction coordinate-free approach for free-energy calculations.
• To assess the accuracy and robustness of FCM for large biological systems.
• To develop a general procedure for constructing efficient reference states for FCM.

Main Methods:

• FCM utilizes reference states and partitions the solute into active and inactive regions.
• Calculates desolvation free energies of mixed harmonic-anharmonic states.
• Applies FCM to determine conformational free-energy differences for triosephosphate isomerase (TIM).

Main Results:

• FCM successfully calculated conformational free-energy differences for TIM, matching experimental values.
• The method demonstrated insensitivity to the choice of reference states and partitioning schemes.
• Highly converged desolvation free energies were obtained even for a large system like TIM.

Conclusions:

• FCM is an accurate and robust method for calculating conformational free-energy differences in explicit solvent, particularly for large systems.
• The choice of reference states that capture main structural differences accelerates convergence.
• FCM offers a promising alternative to reaction coordinate-dependent methods.