Addressing sub-optimal poses in non-equilibrium alchemical calculations

Alchemical transformations can be used to quantitatively estimate absolute binding free energies at reasonable computational cost. However, most of the approaches currently in use require knowledge of the correct (crystallographic) bond position. In this paper we present a combined Hamiltonian replica exchange non-equilibrium alchemical method that allows to reliably calculate absolute binding free energies, even when starting from sub-optimal initial binding poses. Performing a preliminary Hamiltonian replica exchange enhances the sampling of slow degrees of freedom of the ligand and the target allowing the system to populate the correct binding pose when starting from an approximate docking pose. We apply the method on 6 ligands of the first bromodomain of the BRD4 bromodomain containing protein. For each ligand, we start non-equilibrium alchemical transformations from both the crystallographic pose and the top-scoring docked pose that are often significantly different. We show that the method produces statistically equivalent binding free energies making it a useful tool for computational drug discovery pipelines.