FMAP

FMAP performs ligand–protein binding free-energy calculations using funnel metadynamics to determine ligand binding modes and compute absolute binding free energies.

Key Features:

• Funnel metadynamics method: Implements funnel metadynamics to enhance sampling of ligand binding and unbinding.
• Funnel-shaped restraint potential: Employs a funnel-shaped restraint potential to confine ligand exploration within the binding funnel.
• Absolute binding free energy calculation: Computes absolute ligand–protein binding free energies.
• Binding mode and water interaction analysis: Outputs ligand binding modes, alternative binding modes, and the role of water molecules in the binding process.
• Computational demonstration: Demonstrated on the benzamidine-trypsin system of approximately 105,000 atoms with a reported runtime of about 2.8 days on the Cray XC50 piz Daint cluster.

Scientific Applications:

• Drug design optimization: Provides absolute binding free energies and binding modes to support optimization of ligands for improved efficacy and specificity.
• Mechanistic studies of binding: Elucidates alternative binding modes and water-mediated interactions to inform interpretation of ligand–protein binding mechanisms.

Methodology:

Applies funnel metadynamics with a funnel-shaped restraint potential to sample ligand binding and unbinding and to compute absolute binding free energies and binding modes; demonstrated on the benzamidine-trypsin system (~105,000 atoms) with a reported runtime of about 2.8 days on the Cray XC50 piz Daint cluster.