MOLECULAR MODELING OF EBOLA VIRUS INHIBITORS

In this PhD thesis computational methods have been employed in order to study different biologically relevant systems. In the first part of the thesis two Ebola virus proteins were studied, namely Viral Protein 24 (VP24) and Viral Protein 35 (VP35), responsible for the inhibition of the immune response . After a brief theoretical introduction to the main computational methods employed in the thesis, a study of VP35 in complex with small organic molecules is presented. These compounds are able to inhibit the interaction between VP35 and viral nucleoprotein. This study confirms the experimental findings highlighting new important key interactions between the protein the inhibitors. Moreover, an Essential Dynamics analysis points out an interesting collective motion of the apo-form that is hindered by the presence of the ligands. Afterwards, the protein-protein interaction VP24-Karyopherin (KPNA) is studied. An atomistic analysis of the interactions at the interface leads to the design of a nonapeptide with VP24 binding capability. The peptide is derived from a KPNA subsequence and could potentially inhibit the VP24-KPNA interaction. Subsequently an analysis on the pockets present on VP24 surface in different solvents is performed. Once the most promising pocket has been located, a virtual screening on a subset of ZINC database is carried out, leading to the identification of few classes of molecules potentially able to bind VP24. Finally the effect of the osmolytes on VP24 protein structure is studied, pointing out how osmoprotectants and urea have opposite effects on the protein, the former stabilizing the folded state and the latter shifting the equilibrium to the denatured state. In the second part of the manuscript the study of the interaction of an antimicrobial peptide with a lipid membrane is presented. This work was carried out in the University of Groningen under the supervision of Prof. Siewert Jan Marrink in order to deepen the Coarse Grain method.