Objective Nature uses acetylation of lysine residues to modulate the affinity of a variety of nucleic acid binding proteins for their target DNA or RNA. Important examples of such acetylation-based signalling activation processes include the acetylation of Lys residues in histones and the activation of HIV-1 integrase for enhancing the binding affinity to DNA. Surprisingly, no systematic study aimed at understanding the basic molecular mechanisms of acetylation has been performed so far. Here we propose a combined computational chemistry and molecular biology approach, which will uncover several aspects of the Lys acetylation process. The proponent will carry out the computations at the International School for Advanced Studies within a close collaboration with the Molecular Medicine Lab of the International Centre for Genetic Engineering and Biotechnology directed by Mauro Giacca.Specifically:(i) I will provide the description of the molecular mechanism of tGcn5 enzyme-catalysed Lys acetylation process using hybrid Car-Parrinello QM/MM method;(ii) I will characterize the structural rearrangements associated to acetylation in tGcn5-histone complex will be carried out using classical molecular dynamics simulations;(iii) I will construct a structural model for DNA-acetylated protein HIV-1 integrase. Each computational study will be accompanied by experimental mutagenesis data, which will be used to validate my results.Results of this highly interdisciplinary work will provide a description of fundamental aspects of Lys acetylation-based signalling as well as provide a structural model of the DNA-HIV-1 integrase complex, which in turn can be used as a template for designing potential anti-AIDS drugs. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acidsnatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesmedical biotechnologygenetic engineeringnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesmolecular biology Keywords Acetylation Biophysics Molecular Dynamics Protein Activation Protein Modeling QM/MM Site Site-Directed Mutagenesis Programme(s) FP6-MOBILITY - Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006 Topic(s) MOBILITY-2.1 - Marie Curie Intra-European Fellowships (EIF) Call for proposal FP6-2002-MOBILITY-5 See other projects for this call Funding Scheme EIF - Marie Curie actions-Intra-European Fellowships Coordinator INTERNATIONAL SCHOOL OF ADVANCED STUDIES Address Italy See on map EU contribution € 0,00
