Effects of implicit solvent and relaxed amino acid side chains on the MP2 and DFT calculations of ligand–protein structure and electronic interaction energies of dopaminergic ligands in the SULT1A3 enzyme active site

The electronic interaction energies between eight dopaminergic ligands and resveratrol and the SULT1A3 active site have been calculated using MP2 and M062X with the 6-311+G∗ basis set. The SULT1A3 active site was isolated from the crystal structure with dopamine bound (PBD ID 2A3R). Structures for the nine ligands bound in the active site were obtained by three different optimization approaches with M062X/6-31G: by optimization in vacuo with rigid amino acid residue side chains (i.e. using the side chain structures from the crystal structure; the ligand and all protons were optimized), with implicit solvation by water with rigid amino acid residue side chains, and with implicit solvation by water and relaxed amino acid residue side chains (i.e. the ligand and all amino acid residue side chains were optimized). The calculations show that the use of implicit solvent and a relaxed active site offer considerable improvement in ligand interaction energies (more strongly binding), and that the solvated-relaxed model shows less variability in ligand interaction than the other two models. Finally, 6-carboxydopamine was shown to be the most strongly binding of the nine ligands, with an interaction energy over 100 kcal/mol stronger than its nearest neighbor. Four of the eight non-dopamine ligands studied interact with SULT1A3 more strongly than the endogenous ligand, dopamine, in the solvated-relaxed model.