Abstract
Riboswitches are naturally occurring RNA elements that control bacterial gene expression by binding to specific small molecules. They serve as important models for RNA-small molecule recognition and have also become a novel class of targets for developing antibiotics. Here, we carried out conventional and enhanced-sampling molecular dynamics (MD) simulations, totaling 153.5 μs, to characterize the determinants of binding free energies and unbinding paths for the cognate and synthetic ligands of a PreQ1 riboswitch. Binding free energy analysis showed that two triplets of nucleotides, U6-C15-A29 and G5-G11-C16, contribute the most to the binding of the cognate ligands, by hydrogen bonding and by base stacking, respectively. Mg2+ ions are essential in stabilizing the binding pocket. For the synthetic ligands, the hydrogen-bonding contributions of the U6-C15-A29 triplet are significantly compromised, and the bound state resembles the apo state in several respects, including the disengagement of the C15-A14-A13 and A32-G33 base stacks. The bulkier synthetic ligands lead to significantly loosening of the binding pocket, including extrusion of the C15 nucleobase and a widening of the C15-C30 groove. Enhanced-sampling simulations further revealed that the cognate and synthetic ligands unbind in almost opposite directions. Our work offers new insight for designing riboswitch ligands.
Highlights
Noncoding RNAs mediate essential cellular processes such as gene expression and their dysregulation is linked to infectious diseases and cancer [1,2]
We carried out extensive molecular dynamics simulations of a PreQ1 riboswitch bound to either cognate or synthetic ligands
We carried out a total of 153.5 μs molecular dynamics (MD) simulations for the Thermoanaerobacter tengcongensis (Tte) PreQ1 riboswitch aptamer bound with the cognate ligand Q1 or Q0, or with the synthetic ligand L1, L2, or L3, or in the apo form (Table 1)
Summary
Noncoding RNAs mediate essential cellular processes such as gene expression and their dysregulation is linked to infectious diseases and cancer [1,2]. They can fold into intricate threedimensional structures with pockets that potentially serve as binding sites for small molecules [3,4]. Ligands range from nucleobases, cofactors, and amino acids to metal ions [8,9,10,11,12,13,14,15] Riboswitches bind their cognate ligands with high affinity and high selectivity. These important properties make riboswitches prime targets for developing small-molecule antibiotics and chemical tools [16,17,18,19,20,21,22,23]
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