Trypsin-ligand binding free energies from explicit and implicit solvent simulations with polarizable potential

Area of Science:

• Computational Chemistry
• Molecular Dynamics
• Drug Discovery

Background:

• Understanding ligand-protein interactions is crucial for drug design.
• Accurate prediction of binding free energies guides inhibitor development.

Purpose of the Study:

• To calculate binding free energies of benzamidine-like inhibitors to trypsin.
• To compare explicit and implicit solvent models for predicting binding affinity.
• To analyze the influence of ligand properties on binding and solvation.

Main Methods:

• Molecular dynamics simulations with a polarizable force field.
• Free energy perturbation calculations in explicit and implicit solvent.
• Analysis of molecular dipole moments and atomic multipoles.

Main Results:

• Explicit solvent simulations yielded binding free energies within experimental accuracy.
• Ligand binding affinity showed weak dependence on molecular dipole moments.
• Solvation energy varied significantly with ligand modification, but binding affinity changes were minimal due to cancellation.
• The MM-PMPB/SA implicit solvent model also showed good agreement with experimental data.

Conclusions:

• Polarizable force field simulations with explicit solvent accurately predict trypsin inhibitor binding free energies.
• Ligand modifications impact solvation more than binding affinity.
• Implicit solvent models offer a viable alternative for binding free energy calculations.