Multiscale modelization in an icosahedral non-enveloped virus: capsid pH sensing and disassembly induced by alkaline pH

CIC nanoGUNE Seminars

Diego M. Guerin, Instituto Biofisika, UPV
nanoGUNE seminar room, Tolosa Hiribidea 76, Donostia - San Sebastian
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Multiscale modelization in an icosahedral non-enveloped virus: capsid pH sensing and disassembly induced by alkaline pH Triatoma virus (TrV; Dicistroviridae:Triatovirus) is virus very structurally similar to many animal viruses like poliovirus and rhinovirus. These viruses are composed of a spherical capsid that encloses the genome (a single chain of RNA). This type of capsid is built of about 240 proteins displaying icosahedral symmetry, and has a diameter of about 30nm. Experimental results obtaining with TrV show that the capsid of this virus is stable at acidic conditions but disassembles and releases the genome under alkaline environments (i.e. external pH>8)1,2. In this work we show the modelling of three connected processes involved in the capsid destabilization that allow the genome to be released. 1) Using Molecular Dynamic simulations we describe the process by which a structural cation allows the hydration of the hydrophobic cavity along the icosahedral five-fold axis. Whitin the narrowest par of the cavity this hydration forms a water wire, a structure already observed in carbon nanotubes and in cavities of several hydrophobic proteins (membrane proteins). 2) Starting from the hydrated cavity as obtained before, we simulate an ion channel transport using Quantum theoretical Methods (QM). Our analysis shows that protons can escape from the capsid interior along the water wire following a step-by step jumping pathway (called Grotthuss-like mechanism3), and 3) Assuming that the proton's leak produces an internal charge imbalance, by employing a Coarse-grain approximation we model how internal electrostatic forces can destabilize and crack the capsid to allow the genome release. These results are in line with current experimental data on TrV, and could describe the events that drive the disassembly of alkaline pH-labile icosahedral viral capsids. Moreover, our modelizations give base to postulate the existence of proton-diodes in viral capsids, which function would be to sense the environmental pH (Viso el al. 2018 4). **Key words:** Capsid disassembly; hydrophobic gate; Grotthus-like mechanism; Coarse-grain; Triatoma virus **References:** 1\. Agirre J, et al. (2013) J Gen Virol. 94(Pt 5):1058-1068; 2. Snijder J, et al. (2013) Nat Chem 5:502–509; 3. Riccardi D, et al., (2006) JACS 128:16302-16311; 4. Viso, J., et al., 2018. Under revision; 5. Sánchez-Eugenia et al., 2016. J. Gen. Virol. 97:2769-2779 **Host** : A.M. Bittner