ja407489r_si_001.pdf (1.57 MB)
Epitope Fluctuations in the Human Papillomavirus Are Under Dynamic Allosteric Control: A Computational Evaluation of a New Vaccine Design Strategy
journal contribution
posted on 2013-12-11, 00:00 authored by Abhishek Singharoy, Abhigna Polavarapu, Harshad Joshi, Mu-Hyun Baik, Peter OrtolevaThe
dynamic properties of the capsid of the human papillomavirus
(HPV) type 16 were examined using classical molecular dynamics simulations.
By systematically comparing the structural fluctuations of the capsid
protein, a strong dynamic allosteric connection between the epitope
containing loops and the h4 helix located more than 50 Å away
is identified, which was not recognized thus far. Computer simulations
show that restricting the structural fluctuations of the h4 helix
is key to rigidifying the epitopes, which is thought to be required
for eliciting a proper immune response. The allostery identified in
the components of the HPV is nonclassical because the mean structure
of the epitope carrying loops remains unchanged, but as a result of
allosteric effect the structural fluctuations are altered significantly,
which in turn changes the biochemical reactivity profile of the epitopes.
Exploiting this novel insight, a new vaccine design strategy is proposed
wherein a relatively small virus capsid fragment is deposited on a
silica nanoparticle in such a way that the fluctuations of the h4
helix are suppressed. The structural and dynamic properties of the
epitope carrying loops on this hybrid nanoparticle match the characteristics
of epitopes found on the full virus-like particle precisely, suggesting
that these nanoparticles may serve as potent, cost-effective, and
safe alternatives to traditionally developed vaccines. The structural
and dynamic properties of the hybrid nanoparticle are examined in
detail to establish the general concepts of the proposed new design.
History
Usage metrics
Categories
Keywords
50 Åfluctuationtype 16Dynamic Allosteric ControlComputational Evaluationvaccine design strategyreactivity profileEpitope FluctuationsHuman Papillomaviruscapsid proteinsilica nanoparticlecomputer simulations showHPVallosteric effectvirus capsid fragmenth 4 helixallosteric connectionNew Vaccine Design StrategyThedynamics simulationsnovel insightepitopeloop
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC