A coarse grained protein model with internal degrees of freedom. Application to α-synuclein aggregation
A coarse grained protein model with internal degrees of freedom. Application to α-synuclein aggregation
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DOI：
10.1063/1.4942115
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发表时间：
2016-02-28
影响因子：
4.4
通讯作者：
Briels, Wim J.
中科院分区：
文献类型：
--
作者：
Ilie, Ioana M.;den Otter, Wouter K.;Briels, Wim J.
模拟中的粒子传统上被赋予固定的相互作用。虽然这适用于代表原子或分子的粒子，但具有显著内部动力学的对象--如氨基酸序列甚至整个蛋白质--不能用不变的粒子建模。我们开发了一种高度粗粒度的多晶型片状颗粒，最终目的是在二级结构水平上将蛋白质模拟为颗粒链。构象变化，例如无序和β-片状状态之间的转变，由确定颗粒形状和相互作用特性的内部坐标来调节。内部坐标以及粒子的位置和方向由布朗动力学根据其局部环境进行传播。作为多态粒子提供的潜力的一个例子，我们将参与帕金森病的淀粉样变性固有无序蛋白α-突触核蛋白建模为具有两个内部状态的单个粒子。模拟产生了处于无序状态的粒子的低聚物和处于“错误折叠”的交叉β-折叠状态的粒子的纤维。聚集动力学是复杂的，因为聚集体可以通过直接成核和生长机制形成，也可以通过两种团簇类型之间的转化通过两步成核形成。凝聚动力学是复杂的，由直接成核和生长、通过低聚物转化的两步成核以及这种转化的自动催化形成纤维。(C)2016 AIP出版有限责任公司。
Particles in simulations are traditionally endowed with fixed interactions. While this is appropriate for particles representing atoms or molecules, objects with significant internal dynamics-like sequences of amino acids or even an entire protein-are poorly modelled by invariable particles. We develop a highly coarse grained polymorph patchy particle with the ultimate aim of simulating proteins as chains of particles at the secondary structure level. Conformational changes, e.g., a transition between disordered and beta-sheet states, are accommodated by internal coordinates that determine the shape and interaction characteristics of the particles. The internal coordinates, as well as the particle positions and orientations, are propagated by Brownian Dynamics in response to their local environment. As an example of the potential offered by polymorph particles, we model the amyloidogenic intrinsically disordered protein alpha-synuclein, involved in Parkinson's disease, as a single particle with two internal states. The simulations yield oligomers of particles in the disordered state and fibrils of particles in the "misfolded" cross-beta-sheet state. The aggregation dynamics is complex, as aggregates can form by a direct nucleation-and-growth mechanism and by two-step-nucleation through conversions between the two cluster types. The aggregation dynamics is complex, with fibrils formed by direct nucleation-and-growth, by two-step-nucleation through the conversion of an oligomer and by auto-catalysis of this conversion. (C) 2016 AIP Publishing LLC.