Using Selectively Scaled Molecular Dynamics Simulations to Assess Ligand Poses in RNA Aptamers

Predicting the structure (or pose) of RNA-ligand complexes is an important problem in RNA structural biology. Although one could use computational docking to rapidly sample putative poses of RNA-ligand complexes, accurately discriminating the native-like poses from non-native, decoy poses remains a formidable challenge. Here, we started from the assumption that native-like RNA-ligand poses are less likely to dissociate during molecular dynamics simulations, and then we used enhanced simulations to promote ligand unbinding for diverse poses of a handful of RNA aptamer-ligand complexes. By fitting unbinding profiles obtained from the simulations to a single exponential, we identified the characteristic decay time (τ) as particularly effective at resolving native poses from decoys. We also found that a simple regression model trained to predict the simulation-derived parameters directly from structure could also discriminate ligand poses for similar RNA aptamers. Characterizing the unbinding properties of individual poses may thus be an effective strategy for enhancing pose prediction for ligands interacting with RNA aptamers. A similar strategy might be applicable to other ligandable RNAs; however, further analysis will be required to confirm this hypothesis.