Smith A V, Hall C K
Department of Chemical Engineering, North Carolina State University, Raleigh, NC 27695-7905, USA.
J Mol Biol. 2001 Sep 7;312(1):187-202. doi: 10.1006/jmbi.2001.4845.
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.
对由八条模型肽链组成的系统进行计算机模拟，以研究蛋白质重折叠与聚集之间的竞争如何影响四螺旋束重折叠的最佳条件。采用了不连续分子动力学算法以及我们为此工作开发的中等分辨率蛋白质模型。从物理角度来看，该模型比迄今为止用于蛋白质聚集模拟的任何模型都要详细得多。每个模型残基由一个详细的三珠主链和一个简化的单珠侧链组成。排除体积、氢键和疏水相互作用用不连续（即硬球和方阱）势进行建模。模拟能够有效地对构象空间进行采样，并且在单处理器工作站上，两天内就可以从随机初始构型获得完整的折叠轨迹，形成两个四螺旋束。束的折叠遵循两条主要途径，一条通过三聚体中间体，另一条通过具有两个二聚体的中间体。在这项工作中，八肽系统中遵循每条途径的轨迹比例与之前研究的产生一个四螺旋束的四肽系统有显著差异，正如我们之前的模拟所表明的，这表明蛋白质折叠特性受到其他蛋白质存在的强烈影响。束的折叠在一个固定温度范围内是最佳的，高温边界是待折叠蛋白质（或寡聚体）复杂性的函数，低温边界是蛋白质环境复杂性的函数。在折叠的最佳温度范围之上，模型链倾向于展开；在最佳范围之下，模型链倾向于聚集。如之前所见，聚集体具有大量的天然二级结构，这表明聚集体主要由部分折叠的中间体组成，而非变性链。
