Chapter 12. Viruses
A prototypical example of a large-scale system is a virus. Typical viral
protein coats range from 0.5 million atoms up; with the addition of viral RNA
or DNA, atom counts can easily exceed one million. Understanding the structure
of viral protein coats is essential for investigating antigenic sites amenable
to recognition by natural or synthetic agents and for understanding the process
of coat assembly and disassembly that is critical to the viral life cycle.
Much as with large finite simulations improving on small periodic simulations,
full atomistic simulations of viruses can improve substantially on current
technology, which imposes simplifying assumptions such as symmetry
As a start towards more sophisticated analyses of viral coat structure, a
specific viral structure was simulated: human rhinovirus-14 (RHV). This viral
coat is composed of sixty protomers arranged with icosahedral symmetry; each
protomer is in turn composed of multiple subunits.
The subunit structure at a resolution of 3.0 Å was obtained from the
Brookhaven protein databank (file 4RHV) . The atom types and forcefield
parameters were selected from the AMBER forcefield , and connectivities were
generated to match standard amino acids. Investigation of the fitting of
asymmetric units showed that several charged groups on the surface of the
protomer appeared to form salt bridges with oppositely-charged groups on the
opposing surface of a neighboring protomer. After accounting for these, a net
charge of +5 remained, composed of 10 positively charged groups and 15
negatively charged groups. Counterions (sodium or chloride) were positioned
near each of these charged residues. Finally, the protein coat, consisting of
60 copies of the asymmetric unit, was then built using the crystallographic
symmetry operations from the structure deposited with the protein databank.
The final structure contained 512,760 atoms including crystallographic waters
and the added counterions.
The structure was then minimized to better position the counterions and to
attempt to find the best, symmetry-free, relaxed structure for the coat. This
also served to test whether the coat was stable in the absence of the viral
genome. Dynamics at 0 K was used to perform the minimization. A CMM level of
6 was used with a bounding cube 360 Å on a side. The farfield was
updated every 5 minimization steps.
After 6000 steps of minimization, the RMS force reached a value of 0.2
kcal/mol. The energy of the final structure was -1.03x10^6
The RMS difference in coordinates between the initial and final structures was
0.495 Å, but there was no change in the radius of gyration during the
course of the minimization.
Note that the structure remained relatively stable, despite the absence of RNA
in the interior. This suggests that the RNA does not play an essential role in
maintaining the integrity of the protein coat, though it does undoubtedly
affect the structure of the internal portions of the protomer units.
We have demonstrated that building a symmetry-constraint-free model of a viral
protein coat is now practical.
The coat structure is stable with respect to minimization from the X-ray
geometry, suggesting that there is sufficient strength in the interactions
between protomers to hold the coat together, even in the absence of RNA.
Future work on this project will include studying the pH dependence of the
stability of the system, as experiments have suggested that acid-induced
changes may be relevant to uncoating for rhinovirus-14 , but perhaps not for
poliovirus . The temperature dependence of the stability can also be
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