Markov State Model of Lassa Virus Nucleoprotein Reveals Large Structural Changes during the Trimer to Monomer Transition.

Lassa virus contains a nucleoprotein (NP) that encapsulates the viral genomic RNA forming the ribonucleoprotein (RNP). The NP forms trimers that do not bind RNA, but a structure of only the NP N-terminal domain was co-crystallized with RNA bound. These structures suggested a model in which the NP forms a trimer to keep the RNA gate closed, but then is triggered to undergo a change to a form competent for RNA binding. Here, we investigate the scenario in which the trimer is disrupted to observe whether monomeric NP undergoes significant conformational changes. From multi-microsecond molecular dynamics simulations and an adaptive sampling scheme to sample the conformational space, a Markov state model (MSM) is constructed. The MSM reveals an energetically favorable conformational change, with the most significant changes occurring at the domain interface. These results support a model in which significant structural reorganization of the NP is required for RNP formation.