The Orion workflow then conducted solvation free energy calculations from these input files in a straightforward manner, ultimately using Yank 57 to run free energy calculations as further detailed below. Before input into Yank, however, simulation boxes were built and parameters were assigned. Specifically, starting geometries for simulation boxes were built (in PDB format) from the solute and the specified solvent (as indicated by SMILES strings attached to the input molecule) using the OpenEye toolkits to generate molecular structures and conformers, and PACKMOL (version 17.221) to build boxes consisting of the solvated systems. 58 Force field parameters were then assigned via Antechamber and Ambertools (version 16.16.0), using the GAFF 1.8 small molecule force field and AM1-BCC charges (the latter as assigned by the OpenEye toolkits, version 2018.2.1) to describe solvents and solutes, with the exception of water, which was modeled by using TIP3P. Once parameterized, the resulting systems were stored as ParmEd 63 (version 2.7.3) objects and attached to the OpenEye data record to progress through the workflow.