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 (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules nucleic acids
- natural sciences biological sciences genetics DNA
- medical and health sciences medical biotechnology genetic engineering
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences molecular biology
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP6-2002-MOBILITY-5
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Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
Italy
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