DFT and MP2 study of the effects of mutations on the binding of ligands within the SULT1A3 active site

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Sulfotransferases (SULTs) are important in the metabolism and regulation of xenobiotics and endogenous substrates, such as neurotransmitters. In this study, we apply a previously validated model chemistry (Bigler et al., 2014) to study the role of specific active site amino acid residues in the selectivity of SULT1A3 for particular ligands. Experimental work (Brix et al., 1999; Liu et al., 2000) has verified the importance of two amino acid residues in the binding of ligands to this active site (E146 and D86); the current work provides a molecular-level explanation for the observed results and then offers further interpretation of specific interactions important to ligand binding. A suite of ligands were optimized in three mutant SULT1A3 active sites using M062X/6-31G with relaxed amino acid side chains and implicit solvation. M062X/6-311+G∗ and MP2/6-311+G∗ were used to calculate counterpoise-corrected interaction energies between the ligands and the mutant active site residues. These results were found to agree well with the experimental site-directed mutagenesis studies of SULT1A3.