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首页> 外文期刊>Journal of Molecular Biology >Simulation of folding of a small alpha-helical protein in atomistic detail using worldwide-distributed computing.
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Simulation of folding of a small alpha-helical protein in atomistic detail using worldwide-distributed computing.

机译：使用分布在全球的计算模拟小分子α-螺旋蛋白在原子细节上的折叠。

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By employing thousands of PCs and new worldwide-distributed computing techniques, we have simulated in atomistic detail the folding of a fast-folding 36-residue alpha-helical protein from the villin headpiece. The total simulated time exceeds 300 micros, orders of magnitude more than previous simulations of a molecule of this size. Starting from an extended state, we obtained an ensemble of folded structures, which is on average 1.7A and 1.9A away from the native state in C(alpha) distance-based root-mean-square deviation (dRMS) and C(beta) dRMS sense, respectively. The folding mechanism of villin is most consistent with the hydrophobic collapse view of folding: the molecule collapses non-specifically very quickly ( approximately 20ns), which greatly reduces the size of the conformational space that needs to be explored in search of the native state. The conformational search in the collapsed state appears to be rate-limited by the formation of the aromatic core: in a significant fraction of our simulations, the C-terminal phenylalanine residue packs improperly with the rest of the hydrophobic core. We suggest that the breaking of this interaction may be the rate-determining step in the course of folding. On the basis of our simulations we estimate the folding rate of villin to be approximately 5micros. By analyzing the average features of the folded ensemble obtained by simulation, we see that the mean folded structure is more similar to the native fold than any individual folded structure. This finding highlights the need for simulating ensembles of molecules and averaging the results in an experiment-like fashion if meaningful comparison between simulation and experiment is to be attempted. Moreover, our results demonstrate that (1) the computational methodology exists to simulate the multi-microsecond regime using distributed computing and (2) that potential sets used to describe interatomic interactions may be sufficiently accurate to reach the folded state, at least for small proteins. We conclude with a comparison between our results and current protein-folding theory.
机译：通过使用数千台PC和新的全球分布的计算技术，我们已经在原子细节上模拟了从维尔林头饰折叠快速折叠的36个残基的α螺旋蛋白的过程。总模拟时间超过300微米，比以前对这种大小分子的模拟多了几个数量级。从扩展状态开始，我们获得了折叠结构的整体，在基于Cα距离的均方根偏差（dRMS）和Cβ中，与原始状态平均相距1.7A和1.9A dRMS分别表示。 villin的折叠机制与疏水折叠的折叠观点最为吻合：该分子非常迅速地非特异性折叠（约20ns），这大大减小了需要寻找天然状态的构象空间的大小。折叠状态下的构象搜索似乎受芳香核形成的速率限制：在我们的大部分模拟中，C端苯丙氨酸残基与疏水核的其余部分堆积不正确。我们建议这种相互作用的中断可能是折叠过程中决定速率的步骤。根据我们的模拟，我们估计villin的折叠速率约为5微米。通过分析通过仿真获得的折叠合奏的平均特征，我们看到平均折叠结构比任何单个折叠结构都更类似于自然折叠。该发现强调了如果要在模拟和实验之间进行有意义的比较，则需要模拟分子的集合并以类似于实验的方式将结果平均。此外，我们的结果表明，（1）存在使用分布式计算来模拟多微秒机制的计算方法，（2）用于描述原子间相互作用的电势集可能足够准确，至少对于小蛋白质而言，达到折叠状态。我们以我们的结果与当前的蛋白质折叠理论进行比较来得出结论。

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