Generation of the configurational ensemble of an intrinsically disordered protein from unbiased molecular dynamics simulation
Generation of the configurational ensemble of an intrinsically disordered protein from unbiased molecular dynamics simulation
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通过无偏分子动力学模拟生成本质上无序的蛋白质的构型系综
DOI：
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发表时间：
2019
影响因子：
11.1
通讯作者：
Loukas Petridis
中科院分区：
文献类型：
--
作者：
Utsab R. Shrestha;Puneet Juneja;Qiu Zhang;V. Gurumoorthy;J. Borreguero;V. Urban;Xiaolin Cheng;S. Pingali;Jeremy C. Smith;H. O’Neill;Loukas Petridis
生物学中的一个主要挑战是表征内在无序蛋白（IDP）的结构灵活性。整体平均的实验数据不提供潜在的蛋白质结构。在这里，我们进行了独立的小角中子和X射线散射实验和无偏分子动力学模拟，以探测IDP的解决方案的结构。我们报告说，增强模拟的采样可以产生一个合奏的IDP结构的散射和NMR定量协议，而不需要偏置模拟或重新加权的结果。建立模拟技术，产生准确的物理模型的灵活的生物系统的演示可能铺平道路，构象的灵活性，生物功能。胞内无序蛋白（IDP）在真核生物蛋白质组中含量丰富，在细胞信号转导中起重要作用，并与人类疾病有关。为了理解IDP功能，确定它们的构型系综是至关重要的，即，它们所采用的三维结构的集合，这仍然是结构生物学中的一个巨大挑战。迄今为止，试图确定这个合奏计算受到阻碍的必要性，重新加权分子动力学（MD）的结果或偏置模拟，以匹配合奏平均的实验观测值，操作，降低所生成的模型的精度，因为不同的结构合奏可能会产生相同的实验观测。在这里，通过采用增强的采样MD，我们重现实验小角中子和X射线散射的配置文件和NMR化学位移的无序N端（SH 4UD）的c-Src激酶没有重新加权或约束的模拟。无偏的模拟结果揭示了一个弱漏斗和崎岖的自由能景观的SH 4UD，这引起了一个不均匀的合奏结构，不能用简单的聚合物理论描述。SH 4UD采用瞬时螺旋，这是发现远离已知的磷酸化位点，并可能在磷酸化所必需的结构区域的稳定中发挥关键作用。我们的研究结果表明，充分采样的分子模拟可以进行灵活的生物系统提供准确的物理模型，从而合理化其生物功能。
Significance A major challenge in biology is characterizing the structural flexibility of intrinsically disordered proteins (IDPs). Ensemble-averaged experimental data do not provide the underlying protein structures. Here, we performed independently small-angle neutron and X-ray scattering experiments and unbiased molecular dynamics simulations to probe the solution structure of an IDP. We report that enhancing the sampling of the simulations can generate an ensemble of IDP structures in quantitative agreement with scattering and NMR, without the need for biasing the simulation or reweighting the results. The demonstration of established simulation technology that produces accurate physical models of flexible biosystems may pave the way to relating conformational flexibility to biological function. Intrinsically disordered proteins (IDPs) are abundant in eukaryotic proteomes, play a major role in cell signaling, and are associated with human diseases. To understand IDP function it is critical to determine their configurational ensemble, i.e., the collection of 3-dimensional structures they adopt, and this remains an immense challenge in structural biology. Attempts to determine this ensemble computationally have been hitherto hampered by the necessity of reweighting molecular dynamics (MD) results or biasing simulation in order to match ensemble-averaged experimental observables, operations that reduce the precision of the generated model because different structural ensembles may yield the same experimental observable. Here, by employing enhanced sampling MD we reproduce the experimental small-angle neutron and X-ray scattering profiles and the NMR chemical shifts of the disordered N terminal (SH4UD) of c-Src kinase without reweighting or constraining the simulations. The unbiased simulation results reveal a weakly funneled and rugged free energy landscape of SH4UD, which gives rise to a heterogeneous ensemble of structures that cannot be described by simple polymer theory. SH4UD adopts transient helices, which are found away from known phosphorylation sites and could play a key role in the stabilization of structural regions necessary for phosphorylation. Our findings indicate that adequately sampled molecular simulations can be performed to provide accurate physical models of flexible biosystems, thus rationalizing their biological function.
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影响因子：
6.8
作者：
Huang J;MacKerell AD Jr
通讯作者：
MacKerell AD Jr
影响因子：
3.4
作者：
Chen, Po-chia;Hub, Jochen S.
通讯作者：
Hub, Jochen S.
影响因子：
6.1
作者：
Franke D;Petoukhov MV;Konarev PV;Panjkovich A;Tuukkanen A;Mertens HDT;Kikhney AG;Hajizadeh NR;Franklin JM;Jeffries CM;Svergun DI
通讯作者：
Svergun DI
DOI：
10.1073/pnas.89.15.7237
发表时间：
1992-08-01
影响因子：
11.1
作者：
SHENOY, S;CHACKALAPARAMPIL, I;SHALLOWAY, D
通讯作者：
SHALLOWAY, D
影响因子：
6.8
作者：
Hub, Jochen S.
通讯作者：
Hub, Jochen S.