Binding Free Energy Calculations Based on the Path Collective Variable along a String Pathway.

Area of Science:

• Computational chemistry and biophysics
• Molecular dynamics simulations
• Drug discovery and design

Background:

• Accurate calculation of binding free energy is essential for drug discovery.
• Molecular dynamics (MD) simulations are a powerful tool for studying molecular interactions.
• Existing methods for binding free energy calculation have limitations.

Purpose of the Study:

• To develop and validate a novel "geometrical route" for calculating binding free energy.
• To rigorously map the ligand-receptor separation process onto a defined pathway.
• To compare the novel method with established alchemical approaches.

Main Methods:

• Utilizing the string method to construct a curvilinear separation pathway.
• Employing Path Collective Variable (PCV) to define longitudinal and orthogonal order parameters.
• Calculating potential of mean force along the defined pathway.
• Applying the method to a glycogen synthase kinase-3 beta (GSK-3β) inhibitor.

Main Results:

• Successfully mapped the entire ligand-receptor dissociation process onto a curvilinear pathway.
• Demonstrated the ability to calculate binding free energy using PCV along this pathway.
• Achieved comparable results to the standard alchemical double decoupling approach for a GSK-3β inhibitor.

Conclusions:

• The proposed geometrical route offers a rigorous and effective method for binding free energy calculations.
• This approach provides a valuable alternative to alchemical methods in molecular dynamics simulations.
• The study validates the utility of PCV and the string method for complex molecular binding studies.