Multiscale modelization in a small virus: Mechanism of proton channeling and its role in triggering capsid disassembly

In this work, we assess a previously advanced hypothesis that predicts the existence of ion channels in the capsid of small and non-enveloped icosahedral viruses. With this purpose we examine Triatoma Virus (TrV) as a case study. This virus has a stable capsid under highly acidic conditions but disassembles and releases the genome in alkaline environments. Our calculations range from a subtle sub-atomic proton interchange to the dismantling of a large-scale system representing several million of atoms. Our results provide structure-based explanations for the three roles played by the capsid to enable genome release. First, we observe, for the first time, the formation of a hydrophobic gate in the cavity along the five-fold axis of the wild-type virus capsid, which can be disrupted by an ion located in the pore. Second, the channel enables protons to permeate the capsid through a unidirectional Grotthuss-like mechanism, which is the most likely process through which the capsid senses pH. Finally, assuming that the proton leak promotes a charge imbalance in the interior of the capsid, we model an internal pressure that forces shell cracking using coarse-grained simulations. Although qualitatively, this last step could represent the mechanism of capsid opening that allows RNA release. All of our calculations are in agreement with current experimental data obtained using TrV and describe a cascade of events that could explain the destabilization and disassembly of similar icosahedral viruses.Author summary: Plant and animal small non-enveloped viruses are composed of a capsid shell that encloses the genome. One of the multiple functions played by the capsid is to protect the genome against host defenses and to withstand environmental aggressions, such as dehydration. This highly specialized capsule selectively recognizes and binds to the target tissue infected by the virus. In the viral cycle, the ultimate function of the capsid is to release the genome. Observations of many viruses demonstrate that the pH of the medium can trigger genome release. Nevertheless, the mechanism underlying this process at the atomic level is poorly understood. In this work, we computationally modeled the mechanism by which the capsid senses environmental pH and the destabilization process that permits genome release. Our calculations predict that a cavity that traverses the capsid functions as a hydrophobic gate, a feature already observed in membrane ion channels. Moreover, our results predict that this cavity behaves as a proton diode because the proton transit can only occur from the capsid interior to the exterior. In turn, our calculations describe a cascade of events that could explain the destabilization and dismantling of an insect virus, but this description could also apply to many vertebrate viruses.