Every year, the D3R Grand Challenge organizers release pharmaceutically relevant datasets of protein-ligand complexes for the evaluation of ligand pose prediction and binding affinity protocols. This year, we decided to bring together our expertise in pose prediction and binding free energy calculations to participate in the D3R Grand Challenge 4 (GC4) to rank a set of ligands based on their predicted affinities towards the β -Amyloid Cleaving Enzyme 1 (BACE-1) involved in Alzheimer s disease .