Initial viral infection stage: stereo-chemical study of (glico)protein E envelope of the dengue virus

Abstract

The dengue, covering all tropical and subtropical region of the globe and with over 50 million cases reported annually, is considered an emerging problem of growing proportions, especially in Brazil: as a tropical problem, the dengue is practically neglected by the major manufacturers of drugs; the "market failure" syndrome. Thus, actions to create, adapt, and meet conditions to promote advances in the understanding of the virus infection, at the molecular level, can indeed be of great value to meet the challenges imposed by this stage of dengue, as well to be prepared for any future mutants of this and other viral diseases. In this project, focusing on the (glyco)protein E of the envelope of the virus, it is proposed to address the problem of viral infection in various complementary aspects: the consistency of existing hypotheses regarding the mechanisms of the preliminary binding of virus to the cell, having in mind the four different types of viruses, will be examined through numerical simulations of the system, which is consisted of the protein E in several distinct physiological conditions. For this purpose, by means of molecular dynamics analysis, the process of conformational rearrangement of the domain III of protein "E" will be qualified and quantized, for the four types of dengue viruses, as induced by changes in intensive parameters. This conformational rearrangement is known as the precursor of all other events involved in the mechanisms of the virus-cell binding. And in addition, will be studied the events that promote the fusion of viral membrane with the host cell membrane, as described throughout the energy and dynamics of conformational domains II and III of the protein, under several controlled physiological conditions. This study is based on descriptions of the configuracional dynamics of different domains of protein E, obtained by deterministic simulations, like molecular dynamics, and in calculations of the free energy of binding, using the LIE method, Thermodynamic Integration and Free Energy Perturbation. (AU)