Flavin mononucleotide
riboswitches are common among many pathogenic
bacteria and are therefore considered to be an attractive target for
antibiotics development. The riboswitch binds riboflavin (RBF, also
known as vitamin B2), and although an experimental structure
of their complex has been solved with the ligand bound deep inside
the RNA molecule in a seemingly unreachable state, the binding mechanism
between these molecules is not yet known. We have therefore used our
Multicanonical Molecular Dynamics (McMD)-based dynamic docking protocol
to analyze their binding mechanism by simulating the binding process
between the riboswitch aptamer domain and the RBF, starting from the
apo state of the riboswitch. Here, the refinement stage was crucial
to identify the native binding configuration, as several other binding
configurations were also found by McMD-based docking simulations.
RBF initially binds the interface between P4 and P6 including U61
and G62, which forms a gateway where the ligand lingers until this
gateway opens sufficiently to allow the ligand to pass through and
slip into the hidden binding site including A48, A49, and A85.