Investigating Zika Virus RNA Conformational Switching using Molecular Dynamics

Previous attempts at modeling RNA folding for relatively large systems have demonstrated limited sampling of conformation space due to the presence of kinetic traps. In this work, we used a novel method of molecular dynamics simulations, a 2D replica exchange protocol in which RNA replicas cycle through both temperature variations and base-pairing restraint strength using experimentally determined base-pairing patterns. This method refines the energy landscape, biasing the structure to preserve only the most stable conformations at low temperatures.

Using this approach, we designed all-atom models of sections of the 3’ untranslated region of Zika Virus RNA in order to predict pseudoknot formation between the 3’ dumbbell region and other nearby structures. The dumbbell is theorized to be a driving mechanism that allows switching between the translation and replication phases of the RNA lifecycle. From our simulations, we were able to infer the kinetic and structural favorability of proposed pseudoknots, and investigate potential intermediaries required to trigger switching.