Decoding the Identification Mechanism of an SAM-III Riboswitch on Ligands through Multiple Independent Gaussian-Accelerated Molecular Dynamics Simulations

S-Adenosyl-l-methionine (SAM)-responsive riboswitches
play a central role in the regulation of bacterial gene expression
at the level of transcription attenuation or translation inhibition.
In this study, multiple independent Gaussian-accelerated molecular
dynamics simulations were performed to decipher the identification
mechanisms of SAM-III (SMK) on ligands SAM, SAH, and EEM.
The results reveal that ligand binding highly affects the structural
flexibility, internal dynamics, and conformational changes of SAM-III.
The dynamic analysis shows that helices P3 and P4 as well as two junctions
J23 and J24 of SAM-III are highly susceptible to ligand binding. Analyses
of free energy landscapes suggest that ligand binding induces different
free energy profiles of SAM-III, which leads to the difference in
identification sites of SAM-III on ligands. The information on ligand–nucleotide
interactions not only uncovers that the π–π, cation−π,
and hydrogen bonding interactions drive identification of SAM-III
on the three ligands but also reveals that different electrostatic
properties of SAM, SAH, and EEM alter the active sites of SAM-III.
Meanwhile, the results also verify that the adenine group of SAM,
SAH, and EEM is well recognized by conserved nucleotides G7, A29,
U37, A38, and G48. We expect that this study can provide useful information
for understanding the applications of SAM-III in chemical, synthetic
RNA biology, and biomedical fields.