MP2 and DFT Analysis of the Ligand Selectivity of a Sulfotransferase Enzyme: SULT1A3

Abstract

Sulfotransferase 1A3 (SULT1A3) helps regulate various endogenous and exogenous substrates in the body via sulfation. Dopamine and acetaminophen, for example, are known to be selectively sulfated in a reaction catalyzed by this enzyme. In order to characterize the selectivity of this enzyme, the electronic interaction energies between the SULT1A3 active site and eight dopaminergic ligands, two other structurally similar ligands, and resveratrol 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 eleven 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 side chains where the ligand and protons were optimized; with implicit solvation by water with rigid amino acid side chains; and with implicit solvation by water and relaxed amino acid side chains. Calculations indicate that use of implicit solvent and a relaxed active site offer notable improvement in ligand interaction energies through stronger binding energies. The solvated-relaxed model shows less variability in ligand interaction than the other two models. Further, the influence of point mutations on the selectivity of SULT1A3 was investigated for dopamine, two dopamine analogues, and resveratrol using the solvated-relaxed model. Theoretical results here agree well with published experimental results. Finally, the interaction energy the SULT1A3 active site with salbutamol, a pharmaceutical and feed additive, was investigated, also using the solvated-relaxed model.