Ligand binding free-energy calculations with funnel metadynamics

Area of Science:

• Computational chemistry
• Molecular dynamics
• Drug discovery

Background:

• Accurate ligand-target binding mechanism resolution is crucial for drug design.
• Free-energy calculations are essential for determining ligand binding modes.
• Current methods are accurate but lack user-friendliness, limiting their application.

Purpose of the Study:

• To present the Funnel-Metadynamics Advanced Protocol (FMAP), a user-friendly GUI-based tool.
• To enable accurate calculation of absolute ligand-protein binding free energy.
• To elucidate ligand binding mechanisms, including alternative modes and water roles.

Main Methods:

• Developed FMAP, a graphical user interface protocol for funnel metadynamics.
• FMAP guides users through input preparation, simulation, and analysis.
• Utilized a funnel-shape restraint potential for binding free-energy calculations.

Main Results:

• FMAP successfully determined the ligand binding mode and absolute binding free energy.
• The protocol elucidated alternative binding modes and the role of water molecules.
• The benzamidine-trypsin system calculation (~105k atoms) completed in ~2.8 days.

Conclusions:

• FMAP provides a user-friendly approach to complex free-energy calculations.
• The protocol aids in detailed understanding of ligand binding mechanisms.
• FMAP facilitates efficient and accurate drug design through enhanced molecular modeling.