Molecular bases and specificity behind the activation of the immune system OAS/RNAse L pathway by viral RNA.

Abstract

The first line of defense against invading pathogens usually relies on the innate immune systems. In this context the recognition of exogenous RNA structure is primordial to fight, notably, against RNA viruses. One of the most efficient immune response pathways is based on the sensing of RNA double helical motifs by the oligoadenylate synthase (OAS) proteins, which in turns triggers the activity of RNase L and, thus, cleaving cellular and viral RNA. In this contribution by using long range molecular dynamics simulation, complemented with enhanced sampling techniques, we elu-cidate the structural features leading to the activation of OAS by interaction with a model double strand RNA oligomer mimicking a viral RNA. We characterize the allosteric regulation induced by the nucleic acid leading to the population of the active form of the protein. Furthermore, we also identify the free energy profile connected to the active vs. inactive conformational transitions in presence and absence of RNA. Finally, the role of two RNA mutations, identified as able to down-regulate OAS activation, in shaping the protein/nucleic acid interface and the conformational land-scape of OAS are also analyzed.