Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction.
Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction.
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DOI：
10.1038/srep37532
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发表时间：
2016-12-01
影响因子：
4.6
通讯作者：
Kmiecik S
中科院分区：
文献类型：
--
作者：
Ciemny MP;Debinski A;Paczkowska M;Kolinski A;Kurcinski M;Kmiecik S
蛋白质-多肽相互作用往往与大规模的构象变化有关，这些变化无论是通过经典的分子建模还是通过实验都很难研究。最近，我们开发了用于蛋白质-多肽柔性对接的CABS-DOCK方法，使蛋白质链的大规模重排成为可能。在这项研究中，我们使用CABS-DOCK来研究P53-MDM2复合体的结合，这是细胞周期调节系统的一个元件，对抗癌药物设计至关重要。实验数据表明，P53-MDM2结合受到LID区域显著重排的影响，该区域是N端高度灵活的MDM2片段；然而，细节尚不清楚。高度灵活的MDM2片段的大小使得p53-MDM2难以用原子模型进行详尽的结合动力学研究。我们使用CABS-DOCK方法进行了广泛的动力学模拟，包括对MDM2柔性区的大规模结构重排。在没有对P53肽结构或其结合位置的先验知识的情况下，我们获得了P53-MDM2复合体的近天然模型。模拟结果与实验数据吻合得很好，并为LID片段在p53结合中的可能作用提供了新的见解。案例研究表明，CABS-DOCK方法为蛋白质-多肽与蛋白质受体结构的大规模变化对接开辟了新的机会。
Protein-peptide interactions are often associated with large-scale conformational changes that are difficult to study either by classical molecular modeling or by experiment. Recently, we have developed the CABS-dock method for flexible protein-peptide docking that enables large-scale rearrangements of the protein chain. In this study, we use CABS-dock to investigate the binding of the p53-MDM2 complex, an element of the cell cycle regulation system crucial for anti-cancer drug design. Experimental data suggest that p53-MDM2 binding is affected by significant rearrangements of a lid region - the N-terminal highly flexible MDM2 fragment; however, the details are not clear. The large size of the highly flexible MDM2 fragments makes p53-MDM2 intractable for exhaustive binding dynamics studies using atomistic models. We performed extensive dynamics simulations using the CABS-dock method, including large-scale structural rearrangements of MDM2 flexible regions. Without a priori knowledge of the p53 peptide structure or its binding site, we obtained near-native models of the p53-MDM2 complex. The simulation results match well the experimental data and provide new insights into the possible role of the lid fragment in p53 binding. The presented case study demonstrates that CABS-dock methodology opens up new opportunities for protein-peptide docking with large-scale changes of the protein receptor structure.
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