String Method for Protein-Protein Binding Free-Energy Calculations.

Area of Science:

• Computational chemistry
• Biophysics
• Molecular modeling

Background:

• The geometric route using molecular dynamics (MD) simulations is a powerful strategy for determining macromolecular binding constants.
• Current methods often rely on a predefined rectilinear pathway for complex separation, which can be suboptimal and slow to converge.

Purpose of the Study:

• To develop a more reliable and computationally efficient theoretical framework for binding free-energy calculations.
• To introduce a novel approach utilizing an optimal curvilinear minimum free-energy path (MFEP) determined by the string method.

Main Methods:

• Employed explicit-solvent molecular dynamics (MD) simulations.
• Utilized the string method to determine the optimal curvilinear minimum free-energy path (MFEP).
• Validated the framework by comparing rectilinear and curvilinear pathways for host-guest and protein-protein complexes.

Main Results:

• Calculations using both rectilinear and string-based curvilinear pathways yielded quantitatively similar results.
• The curvilinear pathway demonstrated faster convergence compared to the traditional rectilinear pathway.
• Multi-microsecond MD calculations were performed for validation.

Conclusions:

• The novel theoretical framework using curvilinear paths offers a more efficient approach to binding free-energy calculations.
• This method improves upon traditional rectilinear pathway limitations in molecular dynamics simulations.
• The findings suggest a more robust computational strategy for studying molecular interactions.