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. [Display omitted] •Energetically favorable conformational change of Lassa NP is observed in simulations•New conformation has greater accessibility to RNA-binding groove•Findings support model that requires domain-level reorganization for RNP formation•Anton2 simulations and adaptive sampling procedure are combined to build MSM The Lassa virus nucleoprotein binds viral RNA; however, experimental studies have not resolved this structure due to the nucleoprotein propensity to form trimers, which prevent RNA binding. Pattis and May have used advanced molecular simulation techniques to reveal large conformational changes in the nucleoprotein, which may allow for RNA binding.