Mechanistic Insights into the Effect of Ligands on Structural Stability and Selectivity of Sulfotransferase 2A1 (SULT2A1)

[Image: see text] 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.