Abstract
Icosahedral virus capsids are closed shells built up with a hexagonal lattice of proteins, which incorporate pentamers at their fivefold vertices. Human adenovirus particles lose pentamers (pentons) during infection under a variety of physicochemical cues, including mechanical pulling of molecular motors and the viscous drag of the cytoplasm. By combining atomic force microscopy experiments with survival analysis and Markovian transition state theory, we investigate the sequence of adenovirus penton disassembly that reveals the aging of the virus structure. We show evidence that the lifetime of pentons gradually decreases, accompanied by capsid softening as neighboring pentons are lost. This cooperative dismantling process, which involves first-neighbor penton-penton distances of at least 45 nm, leads to a 50% increase in the virus disassembling rate of the virus particle. Theory and experiments fit remarkably well, allowing us to obtain the spontaneous escape rate and the energy barrier of penton disassembly (). The observed increase in the penton’s loss rate reveals long-range structural correlations within the capsid. Our estimations suggest that the mechanical cues arising from the strokes of protein motors carrying the virus to the nucleus could help penton disassembly and warrant the timely delivery of weak-enough capsids for adenovirus infection.
- Received 15 October 2020
- Revised 30 December 2020
- Accepted 2 February 2021
DOI:https://doi.org/10.1103/PhysRevX.11.021025
Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.
Published by the American Physical Society
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Popular Summary
Virus particles consist of a protein shell, known as a capsid, that protects its genome from harsh environmental conditions during transmission from host to host. Once inside a cell, the virus sheds its capsid and releases its DNA. Here, we reveal dynamics of this disassembly that allow virus particles to transfer their genome at the right time and place.
Each of the vertices in these polyhedral capsids are formed by proteins known as pentons. Inside a host cell, the virus finely tunes the sequential loss of pentons to render a semidisrupted capsid at the nuclear pore. Viruses with too many pentons would not be able to release their DNA through the cell’s nuclear pore, whereas those with too few pentons would liberate their genome before reaching the nucleus.
We induce penton failure by applying mechanical fatigue on individual virus particles with atomic force microscopy, which mimics the stresses the virus sustains during its journey to the nucleus. Our approach allows us to study the transition kinetics of penton release as a two-state process, from which we derive the spontaneous escape rate and the free energy barrier of a penton. Moreover, survival analysis shows that the loss of one penton increases the release rate of the remaining ones. This aging process accelerates the overall penton escape rate by about 50% with respect to a sequence of independent escape events.
This “aging” effect, demonstrated for the first time in a biomolecular assembly, evidences a cooperative process involving pentons separated by 45 nm, which is probably the largest range ever found in molecular interactions.
