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首页> 外文期刊>Biophysical Chemistry: An International Journal Devoted to the Physical Chemistry of Biological Phenomena >Conformational dynamics and free energy of BHRF1 binding to Bim BH3
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Conformational dynamics and free energy of BHRF1 binding to Bim BH3

机译：BHRF1与BH3结合的构象动态和自由能

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Abstract The interaction between the Bim BH3 peptide and the viral protein BHRF1 is pivotal to understanding the fundamental molecular details of the mechanism used by the Epstein-Barr virus to trick the mammalian immune system. Here, we study the mechanism of binding/unbinding and compute the free energy for the association of the Bim peptide to the BHRF1 protein. Key elements of the binding mechanism are the conformational rearrangement together with a main free energy barrier of 11.5kcal/mol. The simulations show complete unbinding and rebinding of the Bim peptide to BHRF1. The peptide slowly dissociates, disrupting the hydrophobic contacts, then tilting to one side. The peptide then completely disrupts all the remaining interactions and moves into the bulk solvent. The rebinding of the peptide from the solvent to the receptor binding site occurs slowly. This is because the helix partially unfolds in the unbound state. Rebinding involves an intermediate state, in which the peptide interacts with the hydrophobic binding pocket, which mainly involves Leu 62, Arg 63, Ile 65, and Phe 69. This novel intermediate structure forms 65 contacts with the receptor before the peptide again reaches the bound state. The standard binding free energy value is close to the experimental Kd in the nanomolar range. Finally, we observe how the breathing motions of α 3- α 4 are coupled with the binding/unbinding of the Bim BH3 peptide. The structure of the intermediate can be used for designing novel peptide inhibitors of the BHRF1 protein. Graphical Abstract Display Omitted Highlights ? Molecular simulations show unbinding and rebinding of Bim BH3 to BHRF1. ? The standard free energy is in the nanomolar range. ? Simulations show molecular details of the conformational rearrangment of BHRF1 upon unbinding. ? Leu 62, Arg 63, Ile 65, and Phe 69 of the peptide are the hot spots in the peptide-protein interaction.
机译：摘要BIM BH3肽与病毒蛋白BHRF1之间的相互作用是枢转的，以了解Epstein-Barr病毒用于欺骗哺乳动物免疫系统的机制的基本分子细节。在这里，我们研究了结合/解除粘合的机制，并计算了BIM肽与BHRF1蛋白结合的自由能。绑定机构的关键元件是构象重新排列在一起，具有11.5kcal / mol的主要自由能屏障。模拟显示了BIM肽的完全解界和重新绑定到BHRF1。肽缓慢解离，破坏疏水触点，然后倾斜到一侧。然后肽完全破坏所有剩余的相互作用并进入散装溶剂。将肽从溶剂旋转到受体结合位点的旋转发生缓慢。这是因为螺旋在未结合状态下部分展开。 Rebinding涉及中间状态，其中肽与疏水结合口袋相互作用，其主要涉及Leu 62，Arc 63，ILE 65和PHE 69.在肽再次达到束缚之前，这种新的中间结构与受体形成65触点状态。标准结合能量值接近纳米摩尔范围内的实验KD。最后，我们观察α3-α4的呼吸运动如何与BIM BH3肽的结合/解除耦合。中间体的结构可用于设计BHRF1蛋白的新型肽抑制剂。图形抽象显示省略了亮点？分子模拟显示了BIM BH3至BHRF1的解界和重新绑定。还标准的自由能在纳米摩尔范围内。还模拟显示在解除界面时BHRF1的构象重新排列的分子细节。还肽的Leu 62，Arc 63，ILE 65和PHE 69是肽 - 蛋白质相互作用中的热点。

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