Paper Citing NAMD - Abstract
Singharoy, Abhishek; Polavarapu, Abhigna; Joshi, Harshad; Baik, Mu-Hyun; Ortoleva, Peter
Epitope Fluctuations in the Human Papillomavirus Are Under Dynamic Allosteric Control: A Computational Evaluation of a New Vaccine Design Strategy
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 135:18458-18468, DEC 11 2013
The 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 angstrom 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.
