Unraveling the Role of π-Stacking Interactions in Ligand Binding to the Thiamine Pyrophosphate Riboswitch with High-level Quantum Chemical Calculations and Docking Study

The thiamine pyrophosphate (TPP) riboswitch has emerged as the new target for designing new ligands for antibiotic purpose. Binding of the natural ligand TPP to the TPP riboswitch causes downregulation of the genes responsible for its biosynthesis. We have reported the role of pi-stacking energy contributions to ligand binding with a TPP riboswitch. In conjunction with the docking study, the higher-level quantum chemical calculations performed with the wB97XD and Def2TZVPP basis set in the aqueous phase revealed that the optimum ring size is crucial to attain the effective binding efficiency of ligands with a TPP riboswitch. The pi-stacking energy contributions observed for the ligands studied are largely similar; however, the cases studied with higher pi-stacking energies with larger rings have a weaker ability to displace the radiolabeled thiamine from the riboswitch. The EDA and NCI analyses suggest the role of larger dispersive interactions in stabilizing the pi-stacking rings. The contribution from hydrogen-bonding interactions of the hydrogen-bond donor groups on the A ring augments the binding affinity of the ligand. This study sheds light on various factors that contribute to the design of new ligands for efficient binding with a TPP riboswitch and inhibition of gene expression.