Abstract
Norwalk virus causes severe gastroenteritis for which there is currently no specific anti-viral therapy. A stage of the infection process is uncoating of the protein capsid to expose the viral genome and allow for viral replication. A mechanical characterization of the Norwalk virus may provide important information relating to the mechanism of uncoating. The mechanical strength of the Norwalk virus has previously been investigated using atomic force microscopy (AFM) nanoindentation experiments. Those experiments cannot resolve specific molecular interactions, and therefore, we have employed a molecular modeling approach to gain insights into the potential uncoating mechanism of the Norwalk capsid. In this study, we perform simulated nanoindentation using a coarse-grained structure-based model, which provides an estimate of the spring constant in good agreement with the experimentally determined value. We further analyze the fracture mechanisms and determine weak interfaces in the capsid structure, which are potential sites to inhibit uncoating by stabilization of these weak interfaces. We conclude by identifying potential target sites at the junction of a weak protein–protein interface.
Highlights
Norwalk virus is a worldwide human health threat, which causes acute gastroenteritis, resulting in approximately 200,000 annual deaths (Patel et al, 2008)
Unlike the previous studies on Norwalk virus, we investigate the symmetry/geometrical effects on the capsid mechanics, dissect the molecular interactions, and identify which interfaces in the capsid are most resistant to mechanical stress and which are most responsive
Mechanical Properties We performed a total of nine nanoindentation simulations on a CG model of an Norwalk VLP (NVLP)
Summary
Norwalk virus (genus Norovirus) is a worldwide human health threat, which causes acute gastroenteritis, resulting in approximately 200,000 annual deaths (Patel et al, 2008). In the US alone, Norwalk virus infects approximately 21 million humans annually, resulting in 800 deaths (Lopman et al, 2012). Norwalk virus is a small (~38 nm diameter), icosahedral non-enveloped virus with a positivesense single stranded (ss) RNA genome. The genome encodes for a polyprotein that is posttranslationally processed to produce six or seven non-structural proteins (NS1–7) and two structural proteins, VP1 and VP2, the major and minor capsid proteins, respectively. Expression of just the major capsid protein, VP1, will lead to self-assembled virus-like particles (VLPs), which are morphologically and antigenically indistinguishable from native virus (Jiang et al, 1992). A high resolution structure of the Norwalk VLP (NVLP) was determined by X-ray crystallography to 3.4 Å resolution (Prasad et al, 1999)
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