In the current work we use the NEQ approach to demonstrate the feasibility of accurate absolute binding free energy calculations for a large number of protein-ligand systems, showing accuracy on par with the relative binding free energy estimates. To achieve this, we introduce methodological advancements that allow for an efficient treatment of the ligand in its decoupled state and careful considerations of the protein in its apo state. This allows for identification of protein states that have a drastic effect on ligand binding affinity, such as e.g. a flip of a single amino acid rotamer. Our calculation strategy also allows identify-ing the most representative structure for a protein's apo state for the cases where multiple likely candidates (structures in their local free energy minima, X-ray structures) are available.