An Analysis of Biomolecular Force Fields for Simulations of Polyglutamine in Solution
An Analysis of Biomolecular Force Fields for Simulations of Polyglutamine in Solution
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DOI：
10.1016/j.bpj.2015.07.018
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发表时间：
2015-09-01
影响因子：
3.4
通讯作者：
de Pablo, Juan J.
中科院分区：
文献类型：
--
作者：
Fluitt, Aaron M.;de Pablo, Juan J.
聚谷氨酰胺（polyQ）肽是蛋白质折叠和聚集的生物物理研究的一个有用的模型系统，既因为它们有趣的聚集特性，也因为它们自身与人类疾病的相关性。多q束的遗传扩增引发淀粉样蛋白聚集体的形成，与九种神经退行性疾病相关。几个明确可识别和可分离的因素，特别是多q束的长度，影响聚集机制、相关动力学和形成的结构集合。原子模拟可以很好地回答关于多聚体折叠和聚集的热力学和动力学的开放性问题。另外，水的显式表示允许对溶剂动力学的作用进行更深入的研究，并允许将模拟结果与红外光谱实验进行直接比较。产生有意义的模拟结果取决于满足两个基本标准：获得足够的构象采样以得出统计上有效的结论，并准确地再现控制系统结构和动力学的分子间力。在这项工作中，我们研究了12个生物分子力场在显式水中重现一个简单的30个残基多肽（Q(30)）特性的能力。除了二级和三级结构外，我们还考虑了聚合物的一般结构特性，这些特性为分析分子的高度简并无序状态提供了额外的维度。我们发现这12个力场产生了广泛的预测。我们发现AMBER ff99SB、AMBER ff99SB*和OPLS-AA/L是最适合研究多q折叠和聚集的。
Polyglutamine (polyQ) peptides are a useful model system for biophysical studies of protein folding and aggregation, both for their intriguing aggregation properties and their own relevance to human disease. The genetic expansion of a polyQ tract triggers the formation of amyloid aggregates associated with nine neurodegenerative diseases. Several clearly identifiable and separable factors, notably the length of the polyQ tract, influence the mechanism of aggregation, its associated kinetics, and the ensemble of structures formed. Atomistic simulations are well positioned to answer open questions regarding the thermodynamics and kinetics of polyQ folding and aggregation. The additional, explicit representation of water permits deeper investigation of the role of solvent dynamics, and it permits a direct comparison of simulation results with infrared spectroscopy experiments. The generation of meaningful simulation results hinges on satisfying two essential criteria: achieving sufficient conformational sampling to draw statistically valid conclusions, and accurately reproducing the intermolecular forces that govern system structure and dynamics. In this work, we examine the ability of 12 biomolecular force fields to reproduce the properties of a simple, 30-residue polyQ peptide (Q(30)) in explicit water. In addition to secondary and tertiary structure, we consider generic structural properties of polymers that provide additional dimensions for analysis of the highly degenerate disordered states of the molecule. We find that the 12 force fields produce a wide range of predictions. We identify AMBER ff99SB, AMBER ff99SB*, and OPLS-AA/L to be most suitable for studies of polyQ folding and aggregation.