Theoretical investigations on ligand- and RNA-protein complexes of pharmaceutical relevance

The following chapter provides a brief overview of the main findings of my thesis work. The first paragraph is devoted to the description of a study on the enzyme-substrate-drug interaction in InhA of Mycobacterium tuberculosis. Theoretical results of both, ab initio and classical molecular dynamics are confronted against experimental data on dissociation constants and_ crystallographic data from the literature. The second paragraph is referred to the structural characterization through classical molecular dynamics of Tat, a viral protein of HIV- 1, which is crucial for viral replication, and constitute a very attractive possibility for anti AIDS chemotherapeutic intervention. The third paragraph concerns the study of several mutants of the Tat protein in residues that are very recently been reported as target of posttranslational modification. Finally, and within the same framework, we have also explored the interaction of Tat protein with its RNA target. A very simple methodology using vacuum MD allowing to partially overcome the problem of limited time sampling is presented. The theoretical model obtained matches most of the experimental data available in literature (Calnan et al. 199la;Calnan et al. 199lb;Puglisi et al. 1992;Sumner-Smith et al. 199l;Wang and Rana 1998;Naryshkin et al. 1997;Puglisi et al. 1992;Sumner-Smith et al. 199l;Wang and Rana 1998). In the later two cases theoretical studies have been conducted simultaneously with experiments, working in colaboration with Prof. Mauro Giacca's Laboratory of Molecular Medicine at the International Centre for Genetic Engeering and Biotechnology (ICGEB).