Cytosolic sulfotransferases (SULTs) acting as phase II metabolic enzymes can be used in the sulfonation of small molecules by transferring a sulfonate group from the unique co-factor 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to the substrates. In the present study, molecular dynamics (MD) simulations and ensemble docking study were employed to theoretically characterize the mechanism for the effect of co-factor (PAP) and ligands (LCA, raloxifene, α-hydroxytamoxifen, ouabain, and 3′-phosphoadenylyl sulfate) on structural stability and selectivity of SULT2A1 from the perspective of the dynamic behavior of SULT2A1 structures. Structural stability and network analyses indicated that the cooperation between PAP and LCA may enhance the thermal stability and compact communication in enzymes. During the MD simulations, the obviously rigid region and inward displacement were detected in the active-site cap (loop16) of the conformation containing PAP, which may be responsible for the significant changes in substrate accessibility and catalytic activity. The smaller substrates such as LCA could bind stably to the active pocket in the presence of PAP. However, the substrates or inhibitors with a large spatial structure needed to bind to the open conformation (without PAP) prior to PAPS binding.

Xanthine oxidase (XO), which can catalyze the formation of xanthine or hypoxanthine to uric acid, is the most important target of gout. To explore the conformational changes for inhibitor binding, molecular dockings and molecular dynamics simulations were performed. Docking results indicated that three inhibitors had similar pose binding to XO. Molecular dynamics simulations showed that the binding of three inhibitors influenced the secondary structure changes in XO. After binding to the inhibitor, the peptide Phe798-Leu814 formed different degrees of unhelix, while for the peptide Glu1065-Ser1075, only a partial helix region was formed when allopurinol was bound. Through the protein structure analysis in the simulation process, we found that the distance between the active residues Arg880 and Thr1010 was reduced and the distance between Glu802 and Thr1010 was increased after the addition of inhibitors. The above simulation results showed the similarities and differences of the interaction between the three inhibitors binding to the protein. MM-PBSA calculations suggested that, among three inhibitors, allopurinol had the best binding effect with XO followed by daidzin and puerarin. This finding was consistent with previous experimental data. Our results can provide some useful clues for further gout treatment research.

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Adenosine deaminase (ADA), an important enzyme related to purine nucleoside metabolism, can be divided into open conformation and closed conformation according to the inhibitors of binding.