Cheng Shanmei, Yang Yuedong, Wang Wenrui, Liu Haiyan
Key Laboratory of Structural Biology, School of Life Sciences, University of Science and Technology of China (USTC), and Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, 230026, China.
J Phys Chem B. 2005 Dec 15;109(49):23645-54. doi: 10.1021/jp0517798.
Folding pathways of the B domain of staphylococcal protein A have been sampled with a distributed computing approach. Starting from an extended structure, the method employs an index measuring topological similarity to the native structure to selectively sample trajectory branches leading to the native fold. Unperturbed and continuous folding trajectories are drawn on a physics-based atomic potential energy surface with an implicit solvent. The sampled folding trajectories demonstrate a similar sequence of events: the earlier stage involves a partial formation of helix 2 and to a less extent of helix 1 at their N terminals, followed by the hydrophobic collapse between residues F14, I17, and L18 on helix 1 and residues R28, F31, and I32 on helix 2, which results in the rigidification of the helix turn from R28 to I32. Helix 2 is then able to extend, allowing for the formation to turn 2. The above description explains one experimental result why a G30A mutant of the protein was observed to be the fastest folder among proteins of its size. And the ensemble of structures right before the final collapse is in good agreement with the transition state ensemble mapped by another recent experiment with Fersht Phi values. We emphasize that because the approach here does not provide quantifications of the free energy landscape, our model of the transition state ensemble emerges from comparisons of simulations and previous experimental results rather from the simulation results alone. On the other hand, as our approach does not rely on a low-dimensional free energy surface, it can complement methods based on the construction of free energy surfaces.
已采用分布式计算方法对葡萄球菌蛋白A的B结构域的折叠途径进行了采样。该方法从一个伸展结构开始，利用一种测量与天然结构拓扑相似性的指标，有选择地对通向天然折叠的轨迹分支进行采样。在具有隐式溶剂的基于物理的原子势能面上绘制无扰动且连续的折叠轨迹。采样得到的折叠轨迹展示了相似的事件序列：早期阶段涉及螺旋2在其N端部分形成，螺旋1在较小程度上形成，随后螺旋1上的残基F14、I17和L18与螺旋2上的残基R28、F31和I32之间发生疏水塌缩，这导致从R28到I32的螺旋转角刚性化。然后螺旋2能够延伸，从而形成转角2。上述描述解释了一个实验结果，即为何观察到该蛋白的G30A突变体在其大小的蛋白质中是折叠最快的。并且在最终塌缩之前的结构集合与另一个最近使用Fersht Phi值的实验所绘制的过渡态集合高度一致。我们强调，由于这里的方法没有提供自由能景观的量化，我们的过渡态集合模型是通过模拟与先前实验结果的比较得出的，而不是仅从模拟结果得出的。另一方面，由于我们的方法不依赖于低维自由能面，它可以补充基于自由能面构建的方法。
