Protein refolding versus aggregation: computer simulations on an intermediate-resolution protein model.
Protein refolding versus aggregation: computer simulations on an intermediate-resolution protein model.
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蛋白质重折叠与聚集：中等分辨率蛋白质模型的计算机模拟。
DOI：
10.1006/jmbi.2001.4845
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Hall,CK
中科院分区：
文献类型：
--
作者：
Smith,AV;Hall,CK
进行计算机模拟的系统上的八个模型肽链研究蛋白质的重折叠和聚集之间的竞争如何影响的最佳条件的重折叠的四螺旋束。不连续的分子动力学算法是利用沿着与中间分辨率的蛋白质模型，我们开发了这项工作。物理上，该模型比迄今为止用于模拟蛋白质聚集的任何模型都要详细得多。每个模型残基由详细的三珠骨架和简化的单珠侧链组成。排除体积，氢键和疏水相互作用建模与不连续（即硬球和方井）的潜力。模拟有效地采样构象空间，从随机的初始配置，两个四螺旋束的完整折叠轨迹是可能在两天内在一个单一的处理器工作站。束的折叠遵循两个主要途径，一个通过三聚体中间体，另一个通过具有两个二聚体的中间体。遵循每条路线的轨迹的比例是显着不同的八肽系统在这项工作中比以前研究的四肽系统，产生一个四螺旋束，这表明，正如我们以前的模拟，蛋白质折叠特性的强烈影响的存在下，其他蛋白质。束的折叠在固定的温度范围内是最佳的，其中高温边界是待折叠的蛋白质（或寡聚体）的复杂性的函数，低温边界是蛋白质环境的复杂性的函数。在折叠的最佳温度范围以上，模型链倾向于展开;在最佳温度范围以下，模型链倾向于聚集。如前所述，聚集体具有大量的天然二级结构，表明聚集体主要由部分折叠的中间体组成，而不是变性链。
Computer simulations are performed on a system of eight model peptide chains to study how the competition between protein refolding and aggregation affects the optimal conditions for refolding of four-helix bundles. The discontinuous molecular dynamics algorithm is utilized along with an intermediate-resolution protein model that we developed for this work. Physically, the model is much more detailed than any model used to date for simulations of protein aggregation. Each model residue consists of a detailed, three-bead backbone and a simplified, single-bead side-chain. Excluded volume, hydrogen bond, and hydrophobic interactions are modeled with discontinuous (i.e. hard-sphere and square-well) potentials. Simulations efficiently sample conformational space, and complete folding trajectories from random initial configurations to two four-helix bundles are possible within two days on a single processor workstation. Folding of the bundles follows two main pathways, one through a trimeric intermediate and the other through an intermediate with two dimers. The proportion of trajectories that follow each route is significantly different for the eight-peptide system in this work than in a previously studied four-peptide system, which yields one four-helix bundle, suggesting, as our previous simulations have, that protein folding properties are strongly influenced by the presence of other proteins. Folding of the bundles is optimal within a fixed temperature range, with the high-temperature boundary a function of the complexity of the protein (or oligomer) to be folded and the low-temperature boundary a function of the complexity of the protein’s environment. Above the optimal temperature range for folding, the model chains tend to unfold; below the optimal range, the model chains tend to aggregate. As has been seen previously, aggregates have substantial levels of native secondary structure, suggesting that aggregates are composed largely of partially folded intermediates, not denatured chains.