Conformational ensemble of native -synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations
Conformational ensemble of native -synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations
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DOI：
10.1371/journal.pcbi.1006859
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发表时间：
2019-03-01
影响因子：
4.3
通讯作者：
Borchers, Christoph H.
中科院分区：
文献类型：
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作者：
Brodie, Nicholas I.;Popov, Konstantin I.;Borchers, Christoph H.
将结构蛋白质组学实验数据与计算方法相结合，是蛋白质结构预测的有力工具。在这里，我们应用了最近开发的一种新的蛋白质结构测定方法，该方法基于在离散分子动力学模拟（CL-DMD）中结合短距离交联数据作为约束来确定溶液中内在无序蛋白质-突触核蛋白的构象系。预测的结构与氢-氘交换、圆二色性、表面修饰和长距离交联数据一致。我们发现-synuclein在溶液中作为一个相当紧凑的球状构象的集合存在，具有不同的拓扑结构和残基间的接触，这很好地代表了大环的运动和少数瞬态二级结构元素的形成。非淀粉样蛋白组分和c端区域一致发现含有-结构元素和发夹。随着人口老龄化，神经退行性疾病，如帕金森病将成为许多国家日益严重的问题。蛋白-突触核蛋白的聚集是帕金森病的主要原因，但关于这种蛋白的天然非聚集形式的结构信息仍然缺乏。更好地了解天然蛋白的结构状态可能有助于设计新的治疗方法来对抗这种疾病。为了获得更多关于该蛋白的结构信息，我们最近建立了天然-synuclein蛋白的模型。这些模型是用一种结合了蛋白质交联和离散分子动力学模拟的新方法生成的。我们发现-synuclein蛋白可以采用几种形状，它们都具有相似的拓扑结构，就像一个三指闭合的爪子。研究发现，在这些构象中，蛋白质聚集的一个重要区域不受周围生物环境的影响，这些结构的稳定可能是未来减轻帕金森病病因和影响的药物研究的有效途径。
Combining structural proteomics experimental data with computational methods is a powerful tool for protein structure prediction. Here, we apply a recently-developed approach for de novo protein structure determination based on the incorporation of short-distance crosslinking data as constraints in discrete molecular dynamics simulations (CL-DMD) for the determination of conformational ensemble of the intrinsically disordered protein -synuclein in the solution. The predicted structures were in agreement with hydrogen-deuterium exchange, circular dichroism, surface modification, and long-distance crosslinking data. We found that -synuclein is present in solution as an ensemble of rather compact globular conformations with distinct topology and inter-residue contacts, which is well-represented by movements of the large loops and formation of few transient secondary structure elements. Non-amyloid component and C-terminal regions were consistently found to contain -structure elements and hairpins.Author summary As the population ages, neurodegenerative diseases such as Parkinson's disease will become an increasing problem in many countries. Aggregation of the protein -synuclein is the primary cause of Parkinson's disease, but there is still a dearth of structural information pertaining to the native, non-aggregating form of this protein. A better understanding the structural state of the native protein may prove useful for the design of new therapeutics to combat this disease. In order to obtain more structural information on this protein, we have recently modelled the native -synuclein protein. These models were generated using a novel approach which combines protein crosslinking and discrete molecular dynamics simulations. We have found that the -synuclein protein can adopt several shapes, all with a similar topology, resembling a three fingered closed claw. A region of the protein important for aggregation was found to be protected from the surrounding biological environment in these conformations, and the stabilization of these structures may be a fruitful avenue for future drug research into mitigating the cause and effect of Parkinson's disease.