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.
Biology (Basel). 2012 Aug 13;1(2):277-96. doi: 10.3390/biology1020277.
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.
HIV-1 转录反式激活因子（Tat）与 p300/（CREB 结合蛋白）相关因子（PCAF）溴结构域之间的结合是 HIV-1 生命周期中的关键步骤。然而，全长乙酰化 Tat 与 PCAF 结合的结构尚未通过实验确定。Tat 残基的乙酰化可以在增强 HIV-1 转录激活中发挥关键作用。在这里，我们结合了完全灵活的蛋白质-蛋白质对接方法和分子动力学模拟，以预测常见的 HIV-1BRU 变体的复合物的结构决定因素。该模型再现了以前通过 NMR 光谱学报道的 Tat 肽 46SYGR（AcK）KKRRQRC56 与 PCAF 溴结构域之间的所有关键接触。此外，包含整个 Tat 蛋白会导致蛋白质-蛋白质界面上的额外接触点。该模型与以前用不太准确的计算方法获得的与罕见的 HIVZ2 变体结合的 PCAF 溴结构域的结构预测一致，并增加了新的信息。对 Tat.PCAF 溴结构域结合的这种改进的描述可能有助于确定涉及赖氨酸乙酰化的其他蛋白质相互作用的结构决定因素。
