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HIV-1 Tat Binding to PCAF Bromodomain: Structural Determinants from Computational Methods
Computational Biophysics, German Research School for Simulation Sciences, Computational Biomedicine, Institute for Advanced Simulation (IAS-5), Forschungszentrum Jülich, Jülich D-52425, Germany
Institut Pasteur de Montevideo, Mataojo 2020, Montevideo CP 11400, Uruguay
Institute for Research in Biomedicine and Barcelona Supercomputing Center Joint Research Program on Computational Biology, Baldiri I Reixac 10, Barcelona S-08028, Spain
Jülich Supercomputing Centre, Forschungszentrum Jülich, Jülich D-52425, Germany
International Centre for Genetic Engineering and Biotechnology, Trieste 34149, Italy
* Author to whom correspondence should be addressed.
Received: 8 June 2012; in revised form: 9 July 2012 / Accepted: 26 July 2012 / Published: 13 August 2012
Abstract: The binding between the HIV-1 trans-activator of transcription (Tat) and p300/(CREB-binding protein)-associated factor (PCAF) bromodomain is a crucial step in the HIV-1 life cycle. However, the structure of the full length acetylated Tat bound to PCAF has not been yet determined experimentally. Acetylation of Tat residues can play a critical role in enhancing HIV-1 transcriptional activation. Here, we have combined a fully flexible protein-protein docking approach with molecular dynamics simulations to predict the structural determinants of the complex for the common HIV-1BRU variant. This model reproduces all the crucial contacts between the Tat peptide 46SYGR(AcK)KRRQRC56 and the PCAF bromodomain previously reported by NMR spectroscopy. Additionally, inclusion of the entire Tat protein results in additional contact points at the protein-protein interface. The model is consistent with the available experimental data reported and adds novel information to our previous structural predictions of the PCAF bromodomain in complex with the rare HIVZ2 variant, which was obtained with a less accurate computational method. This improved characterization of Tat.PCAF bromodomain binding may help in defining the structural determinants of other protein interactions involving lysine acetylation.
Keywords: Tat; PCAF BRD; HIV-1; docking; protein-protein interaction
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Quy, V.C.; Pantano, S.; Rossetti, G.; Giacca, M.; Carloni, P. HIV-1 Tat Binding to PCAF Bromodomain: Structural Determinants from Computational Methods. Biology 2012, 1, 277-296.
Quy VC, Pantano S, Rossetti G, Giacca M, Carloni P. HIV-1 Tat Binding to PCAF Bromodomain: Structural Determinants from Computational Methods. Biology. 2012; 1(2):277-296.
Quy, Vo Cam; Pantano, Sergio; Rossetti, Giulia; Giacca, Mauro; Carloni, Paolo. 2012. "HIV-1 Tat Binding to PCAF Bromodomain: Structural Determinants from Computational Methods." Biology 1, no. 2: 277-296.