Thesis (Ph.D.) - Indiana University, Chemistry, 2015Allostery is defined as the change in the structure, function or activity of a specific site on a protein, due to the binding of a substrate or effecter on a different site of the same protein. This phenomenon has been observed and studied in two different protein systems of therapeutic importance. CsoR protein in Mycobacterium tuberculosis adopts classical allostery to regulate the concentration of Cu(I) inside the cell. Cu(I) is speculated to bind in an unusual trigonal planar geometry with two cysteines and one histidine. When CsoR is bound to copper an overall structural change (allostery) is envisioned and its affinity to DNA is lost. In the current computational exploration we focus on the binding mode of Cu(I) and identify different protonation states of copper bound cysteines. MD simulations were performed on the apo and copper bound form with a starting structure from QM/MM calculations to predict the allosteric structural transition. The dynamic properties of the capsid of the human papillomavirus (HPV) type 16 were also examined using classical molecular dynamics simulations. The allostery identified in the components of the HPV is non-classical because the mean structure of the epitope carrying loops remains unchanged as the result of allosteric effect, but 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, where a relatively small virus 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.