B-cell epitope discovery: The first protein flexibility-based algorithm-Zika virus conserved epitope demonstration.

Antibody-antigen interaction-at antigenic local environments called B-cell epitopes-is a prominent mechanism for neutralization of infection. Effective mimicry, and display, of B-cell epitopes is key to vaccine design. Here, a physical approach is evaluated for the discovery of epitopes which evolve slowly over closely related pathogens (conserved epitopes). The approach is 1) protein flexibility-based and 2) demonstrated with clinically relevant enveloped viruses, simulated via molecular dynamics. The approach is validated against 1) seven structurally characterized enveloped virus epitopes which evolved the least (out of thirty-nine enveloped virus-antibody structures), 2) two structurally characterized non-enveloped virus epitopes which evolved slowly (out of eight non-enveloped virus-antibody structures), and 3) eight preexisting epitope and peptide discovery algorithms. Rationale for a new benchmarking scheme is presented. A data-driven epitope clustering algorithm is introduced. The prediction of five Zika virus epitopes (for future exploration on recombinant vaccine technologies) is demonstrated. For the first time, protein flexibility is shown to outperform solvent accessible surface area as an epitope discovery metric.

Molecular-level characterization of the breathing behavior of the jungle-gym-type DMOF-1 metal-organic framework.

Fundamental insights into the molecular mechanisms that determine the breathing behavior of the jungle-gym-type DMOF-1 metal-organic framework upon adsorption of benzene and isopropyl alcohol are gained from computer simulations. In all cases, good agreement is obtained between the calculated and experimental structural parameters. In the case of benzene adsorption, DMOF-1 is predicted to exist in a narrow pore configuration at high loadings and/or low temperature. A structural transition into a large pore configuration is then observed as the temperature increases and/or the loading decreases, which is directly related to the spatial distribution and molecular interactions of the benzene molecules within the pores. The isopropyl alcohol adsorption simulations indicate that DMOF-1 undergoes two distinct structural transitions (from large pore to narrow pore and then back to large pore) as the number of adsorbed molecules increases, which is explained in terms of the formation of hydrogen bonds between the isopropyl molecules and the framework.

Broad spectrum assessment of the epitope fluctuation--Immunogenicity hypothesis.

Prediction of immunogenicity is a substantial barrier in vaccine design. Here, a molecular dynamics approach to assessing the immunogenicity of nanoparticles based on structure is presented. Molecular properties of epitopes on nonenveloped viral particles are quantified via a set of metrics. One such metric, epitope fluctuation (and implied flexibility), is shown to be inversely correlated with immunogenicity for each of a broad spectrum of nonenveloped viruses. The molecular metrics and experimentally determined immunogenicities for these viruses are archived in the open-source vaccine computer-aided design database. Results indicate the promise of computer-aided vaccine design to bring greater efficiency to traditional lab-based vaccine discovery approaches.