Probabilistic Modeling of RNA Ensembles Using NMR Chemical Shifts.

NMR-derived chemical shifts are structural fingerprints that are sensitive to the underlying conformational distributions of molecules. Thus, chemical shift data are now routinely used to infer the dynamical or conformational ensembles of peptides and proteins. However, for RNAs, techniques for inferring their conformational ensembles from chemical shift data have received less attention. Here, we used chemical shift data and the Bayesian/maximum entropy (BME) approach to model the secondary structure ensembles of several single-stranded RNAs. Inspection of the resulting ensembles indicates that the secondary structure of the highest weighted (most probable) conformer in the ensemble typically resembled the known NMR structure. Furthermore, using apo chemical shifts measured for the HIV-1 TAR RNA, we found that our framework reproduces the expected structure yet predicts the existence of a previously unobserved base pair, which we speculate may be sampled transiently. We expect that the chemical shift-based BME (CS-BME) framework we describe here should find utility as a general strategy for modeling RNA ensembles using chemical shift data.