Enhanced Sampling of Interdomain Motion Using Map-Restrained Langevin Dynamics and NMR: Application to Pin1.
Enhanced Sampling of Interdomain Motion Using Map-Restrained Langevin Dynamics and NMR: Application to Pin1.
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DOI：
10.1016/j.jmb.2018.05.007
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发表时间：
2018-07-06
影响因子：
5.6
通讯作者：
Peng JW
中科院分区：
文献类型：
--
作者：
Bouchard JJ;Xia J;Case DA;Peng JW
许多信号蛋白由球状结构域组成，由灵活的连接物连接，允许大量的结构域运动。由于这些结构域经常作为互补的功能模块，因此可能出现功能重要的结构域运动。为了探索这种可能性，我们需要了解通过区域间运动采样的蛋白质构象的集合。主干氢键的核磁共振残余偶极偶联（RDCs）的测量提供了域间动力学的每残基表征，因为偶极偶联对畴取向敏感。实现这一潜力的一个挑战是需要将rdc解释为域构象动态集合的平均值。在这里，我们通过引入一种有效的协议来生成适合灵活的多结构域蛋白质的构象集成来解决这一挑战。该协议使用地图约束的自制导朗格万动力学模拟来促进集体，域间运动，同时将内域运动抑制到接近刚性。关键的是，模拟保留了全原子描述，以便于包含特定位点的NMR RDC约束。结果是快速生成与RDC数据一致的构象系综。我们在人类Pin1（一种与癌症和阿尔茨海默病相关的双结构域肽酰脯氨酸异构酶）上说明了这一方案。结果包括Pin1采样的结构域方向集合，以及功能失调变体I28A-Pin1的结构域方向集合。综聚体之间的差异证实了我们之前的自旋弛豫结果，即I28A变体的结构域间接触相对于野生型减弱。我们的方案扩展了我们探索蛋白质结构域运动的功能意义的能力。
Many signaling proteins consist of globular domains connected by flexible linkers that allow for substantial domain motion. Because these domains often serve as complementary functional modules, the possibility of functionally important domain motions arises. To explore this possibility, we require knowledge of the ensemble of protein conformations sampled by interdomain motion. Measurements of NMR residual dipolar couplings (RDCs) of backbone NH bonds offer a per-residue characterization of interdomain dynamics, as the couplings are sensitive to domain orientation. A challenge in reaching this potential is the need to interpret the RDCs as averages over dynamic ensembles of domain conformations. Here, we address this challenge by introducing an efficient protocol for generating conformational ensembles appropriate for flexible, multi-domain proteins. The protocol uses map-restrained self-guided Langevin dynamics simulations to promote collective, interdomain motion while restraining the internal domain motion to near rigidity. Critically, the simulations retain an all-atom description for facile inclusion of site-specific NMR RDC restraints. The result is the rapid generation of conformational ensembles consistent with the RDC data. We illustrate this protocol on human Pin1, a two-domain peptidyl-prolyl isomerase relevant for cancer and Alzheimer’s disease. The results include the ensemble of domain orientations sampled by Pin1, as well as those of a dysfunctional variant, I28A-Pin1. The differences between the ensembles corroborate our previous spin relaxation results that showed weakened interdomain contact in the I28A variant relative to wild type. Our protocol extends our abilities to explore the functional significance of protein domain motions.
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影响因子：
4.8
作者：
Jacobs, DM;Saxena, K;Fiebig, KM
通讯作者：
Fiebig, KM
影响因子：
15
作者：
BRUSCHWEILER, R;ROUX, B;ERNST, RR
通讯作者：
ERNST, RR
DOI：
10.1038/nrm2904
发表时间：
2010-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
16
作者：
Follis AV;Llambi F;Merritt P;Chipuk JE;Green DR;Kriwacki RW
通讯作者：
Kriwacki RW
影响因子：
3.3
作者：
Fisher, Charles K.;Zhang, Qi;Al-Hashimi, Hashini M.
通讯作者：
Al-Hashimi, Hashini M.