Non-Equilibrium Free Energy Calculations for Ligand Optimization

Abstract

Computational methods for rational drug design rely on the estimation of the free energy differences upon a ligand binding to the target biomolecule. Molecular dynamics based alchemical free energy calculations provide a powerful method allowing accurate estimations of relative binding affinities. The alchemical approach requires exploitation of nonphysical pathways over thermodynamic cycles: atoms in the system may be created, morphed or annihilated. A modified form of the soft-cored non-bonded interaction potential is needed for such alchemical transitions when applying the Crooks Fluctuation Theorem. We propose a new soft-core potential suitable for fast non-equilibrium transitions. The new construction of the potential function prevents singularities and additional local minima that may lead to inaccurate estimations of the free energies. We further employ the scheme of thermodynamic integration in combination with the non-equilibrium transitions based on the new soft-core potential to address the problem of lead optimization.