Abstract
Seasonal flu is an acute respiratory disease that exacts a massive toll on human populations, healthcare systems and economies. The disease is caused by an enveloped Influenza virus containing eight ribonucleoprotein (RNP) complexes. Each RNP incorporates multiple copies of nucleoprotein (NP), a fragment of the viral genome (vRNA), and a viral RNA-dependent RNA polymerase (POL), and is responsible for packaging the viral genome and performing critical functions including replication and transcription. A complete model of an Influenza RNP in atomic detail can elucidate the structural basis for viral genome functions, and identify potential targets for viral therapeutics. In this work we construct a model of a complete Influenza A RNP complex in atomic detail using multiple sources of structural and sequence information and a series of homology-modeling techniques, including a motif-matching fragment assembly method. Our final model provides a rationale for experimentally-observed changes to viral polymerase activity in numerous mutational assays. Further, our model reveals specific interactions between the three primary structural components of the RNP, including potential targets for blocking POL-binding to the NP-vRNA complex. The methods developed in this work open the possibility of elucidating other functionally-relevant atomic-scale interactions in additional RNP structures and other biomolecular complexes.
Highlights
Influenza is a respiratory illness caused by Influenza viruses from the Orthomyxoviridae family, which are in continuous circulation around the world [1]
As we generate the atomic-scale fragments of each supramolecular structure, any bad contacts formed within a single monomeric unit are fixed by repeating the same adjustments on all other monomeric units within the same suprastructure
Despite each RNP target depending on the immediate data sources listed in Table 1, every component is refined using input from the other components that make up its nearest neighbors in the final macromolecular assembly
Summary
Influenza is a respiratory illness caused by Influenza viruses from the Orthomyxoviridae family, which are in continuous circulation around the world [1]. The Influenza A virus, which is responsible for most seasonal cases, and all historical epidemics, will serve as the focus of this project. Influenza A possesses a negativestrand RNA genome that is fragmented into eight segments within the Influenza A virus. Multiple copies of nucleoprotein (NP) form a macromolecular structure that compactifies a section of the viral RNA (vRNA) to form a ribonucleoprotein complex (RNP) [3,4]. Each RNP is in turn complexed with its own RNA-dependent RNA polymerase (POL). Taken together, these complexes contribute to many functional roles in the Influenza
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