In recent years, advances in molecular simulations have opened new possibilities to study drugprotein binding in atomistic detail . In particular, although the binding enthalpy can be challenging to compute, a straightforward direct approach has been shown to yield numerically precise (though not necessarily accurate) results for host-guest systems . The direct approach is appealing for its simplicity, as well as its ability to provide a breakdown of enthalpy contributions from various components of the system, such as the ligand and the binding site residues.