Dynamics and asymmetry in the dimer of the norovirus major capsid protein

Abstract

Noroviruses are the major cause of non-bacterial acute gastroenteritis in humans and livestock worldwide, despite being physically among the simplest animal viruses. The icosahedral capsid encasing the norovirus RNA genome is made of 90 dimers of a single ca 60-kDa polypeptide chain, VP1, arranged with T = 3 icosahedral symmetry. Here we study the conformational dynamics of this main building block of the norovirus capsid. We use molecular modeling and all-atom molecular dynamics simulations of the VP1 dimer for two genogroups with 50% sequence identity. We focus on the two points of flexibility in VP1 known from the crystal structure of the genogroup I (GI, human) capsid and from subsequent cryo-electron microscopy work on the GII capsid (also human). First, with a homology model of the GIII (bovine) VP1 dimer subjected to simulated annealing then classical molecular dynamics simulations, we show that the N-terminal arm conformation seen in the GI crystal structure is also favored in GIII VP1 but depends on the protonation state of critical residues. Second, simulations of the GI dimer show that the VP1 spike domain will not keep the position found in the GII electron microscopy work. Our main finding is a consistent propensity of the VP1 dimer to assume prominently asymmetric conformations. In order to probe this result, we obtain new SAXS data on GI VP1 dimers. These data are not interpretable as a population of symmetric dimers, but readily modeled by a highly asymmetric dimer. We go on to discuss possible implications of spontaneously asymmetric conformations in the successive steps of norovirus capsid assembly. Our work brings new lights on the surprising conformational range encoded in the norovirus major capsid protein.

Glycan-Induced Protein Dynamics in Human Norovirus P Dimers Depend on Virus Strain and Deamidation Status

“…This region is located below the glycan binding cleft in the protein center, so protection from HDX could rather be the result of a long-distance structural change than of direct interaction with fucose. It would be interesting to see how long-distance structural changes would further propagate into the S domain in VLPs and if they would influence the dynamic P domain lift off from the S domain that has been seen for different norovirus strains [ 39 , 40 , 41 ].…”

Generation of Recombinant Rotaviruses Expressing Human Norovirus Capsid Proteins

“…VP1 dimers serve as intermediates in the assembly of the NoV capsid (45). To address whether NoV proteins expressed from recombinant viruses formed dimers, lysates from rSA11/NSP3-2A-fP2, -fP, - fVP1, and -VP1f infected cells were incubated sample buffer at temperatures in which VP1 dimers are stable (25°C) and temperatures in which they are disrupted (95°C).…”

Antiviral Potential of Plants against Noroviruses

“…In non-enveloped viruses, the capsid protects the integrity of the viral nucleic acid. Viral RNA may remain intact, while changes in the structure of the capsid may deactivate the virus [ 58 , 59 ]. Modification of the virus capsid is one of the mechanisms that can lead to the inhibition of the virus adsorption process, which is associated with its deactivation.…”

“…The antiviral activity of plant metabolites is the subject of many scientific studies [ 23 , 41 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 ,…”