Structural insights into the interactions of flavin mononucleotide (FMN) and riboflavin with FMN riboswitch: a molecular dynamics simulation study.

Antibiotics resistance is becoming a serious problem associated with fatalities and suffering patients. New antibiotics that can target the broader spectrum of cellular processes are warranted. One of the recent approaches in this regard is to target the special type of RNA riboswitches in bacteria. In this report, we have explored the mechanistic pathways of ligand-dependent conformational changes of flavin mononucleotide (FMN) riboswitch using molecular dynamics (MD) simulation studies. Cognate ligands FMN and riboflavin (RBF) have shown very different behavior with FMN riboswitch in terms of their role in the gene regulation process. These two ligands have similar scaffold, except the terminal phosphate group in FMN ligand. The MD simulations reveal that the binding of FMN ligand with the riboswitch does not lead to global folding of structure, rather lead to local changes in riboswitch structure. The binding free energy calculated with molecular mechanics Poisson-Boltzmann surface area method suggests the stronger binding of FMN than RBF to the riboswitch and electrostatic energy contributes chiefly to stabilize the complex. Further, the hydrogen bonding analysis identified the key binding site residues G11, G32, G62 of the riboswitch with FMN and RBF. The critical role of the phosphate group in the FMN ligand for binding with the active site of a riboswitch is also borne out in this study. These results unravel the importance of functional groups in natural ligands on designing newer ligands for FMN riboswitch as new antibiotics in the future.Communicated by Ramaswamy H. Sarma.