The PDB files for ethane and ethanol were generated using the SMILES method in the ANTECHAMBER module. The initial coordinates for the protein-ligand complex, specifically Tyk2 (JH1) in complex with 2,6-Dichloro-N{2-[(cyclopropanecarbonyl)amino]pyridin- (ejm 55) using the VMD package. For the cAMP to Rp-cAMPS system, solvation was conducted using the TIP3P water model. For the ethane-ethanol system and the protein-ligand complex, the TIP4P-EW water model was employed. Sodium ions (Na + ) and chloride ions (Cl -) were added to achieve a salt concentration of 150 mM in the protein-ligand complex. The pdb4amber tool was used to clean the PDB structures, while tleap was employed for generating topology and parameter files. To generate the topology for HMR, ParmEd () 54 was utilized. Table presents the water model, the force field of the small molecule, the protein, and the salt concentration for the various systems.