posted on 2021-07-26, 21:29authored byIndrajit Deb, Hazel Wong, Colleen Tacubao, Aaron T. Frank
Estimating
the binding energies of small molecules to RNA could
help uncover their molecular recognition characteristics and be used
to rationally design RNA-targeting chemical probes. Here, we leveraged
the ability of the fragment molecular orbital (FMO) method to provide
detailed pairwise energetic information to examine the interactions
between the aptamer domain of the flavin mononucleotide (FMN)-responsive
riboswitch and small-molecule ligands. After developing an efficient
protocol for executing high-level FMO calculations on RNA–ligand
complexes, we applied our protocol to nine FMN-aptamer–ligand
complexes. We then used the results to identify “hot-spots”
within the aptamer and decomposed pairwise interactions between the
hot-spot residues and the ligands. Interestingly, we found that several
of these hot-spot residues interact with the ligands via atypical
CH···O hydrogen bonds and anion−π contacts,
as well as (face-to-edge) T-shaped π–π interactions.
We envision that our results should pave the way for the wider and
more prominent use of FMO calculations to study structure–energy
relationships in diverse RNA–ligand systems, which in turn
may provide a basis for dissecting the molecular recognition characteristics
of RNAs.