Poster abstracts
Poster number 20 submitted by Sahil Chhabra
Modeling RNA-ligand Structures using chemical shifts
Sahil Chhabra (University of Michigan), Aaron Frank (University of Michigan)
Abstract:
Over the last couple of decades, it has become clear that RNAs can regulate many processes within the cell. Also, it has been discovered that RNA dysregulation is associated with many humans diseases. Acquiring accurate structural information of disease-associated RNAs in complex with small drug-like molecules is crucial in the rational design and discovery of potential therapeutics. Here we examine whether, starting from the sequence of an RNA, computational methods can be used to sample the correct 3D structure of RNA-ligand complex, and whether assigned chemical shifts could be used to discriminate between the correct structures and non-native decoy structures. Using the influenza A virus promoter RNA complex with a small-molecule (PDBID 2LWK, BMRBID 18633) that inhibits viral replication as a model system, we have discovered that not only can computational methods sample native-like conformations of the holo RNA, but more importantly, the modeled RNA structure that best agree with holo chemical shift data are within 2.5 Å of the NMR structure. Moreover, when the ligands are docked onto this structure, we can sample models of the full complex that are within 2.5 Å of the correct structure. To better assess the resolving-power of holo chemical shifts in the context of modeling RNA-ligand complexes, we will carry out similar analysis on additional RNA-ligand complexes for which both chemical shifts and NMR structures are available.
Keywords: RNA, Chemical Shifts, Modeling