利用自组织聚合物模型剖析泛素折叠
Dissecting Ubiquitin Folding Using the Self-Organized Polymer Model
摘要：
利用带有侧链的粗粒自组织聚合物模型，研究了泛素（Ub）在低pH和中性pH以及不同温度下的折叠行为.计算出的回转半径，显示出显着的变化与pH值，是在良好的协议与散射实验。在$T_m$乌布折叠在一个两个状态的方式在低和中性pH值。聚类分析的构象采样在平衡折叠轨迹在$T_m$，折叠和展开状态之间的多个过渡，显示了一个网络的亚稳态连接的本地和展开状态。在低pH和中性pH下，Ub以高概率通过一组优选构象折叠，导致pH依赖性显性折叠途径。折叠动力学表明，在低pH值下的Ub组装发生的多个途径，涉及的成核崩溃和扩散碰撞机制的组合。Ub折叠的机制取决于负责建立长距离接触和Ub崩溃的关键二级结构元件的稳定性。如果这些元素的稳定性是边缘的，成核崩溃机制成立，在高温下的情况下。如果与这些结构化微区相关的寿命是数百个$μsec$的数量级，则Ub折叠遵循具有中间体的扩散碰撞机制，其中许多中间体与在平衡中发现的中间体一致。折叠在中性pH值是一个连续的过程，与人口中间类似，在平衡采样。使用$P_{fold}$分析获得的过渡态结构是均匀的和球状的，其中大部分二级和三级结构是天然的。我们的许多发现不仅与实验一致，而且还提供了在标准实验中无法解决的缺失细节。
英文摘要：
Folding of Ubiquitin (Ub) is investigated at low and neutral pH at different temperatures using simulations of the coarse-grained Self-Organized-Polymer model with side chains. The calculated radius of gyration, showing dramatic variations with pH, is in excellent agreement with scattering experiments. At $T_m$ Ub folds in a two-state manner at low and neutral pH. Clustering analysis of the conformations sampled in equilibrium folding trajectories at $T_m$, with multiple transitions between the folded and unfolded states, show a network of metastable states connecting the native and unfolded states. At low and neutral pH, Ub folds with high probability through a preferred set of conformations resulting in a pH-dependent dominant folding pathway. Folding kinetics reveal that Ub assembly at low pH occurs by multiple pathways involving a combination of nucleation-collapse and diffusion collision mechanism. The mechanism by which Ub folds is dictated by the stability of the key secondary structural elements responsible for establishing long range contacts and collapse of Ub. Nucleation collapse mechanism holds if the stability of these elements are marginal, as would be the case at elevated temperatures. If the lifetimes associated with these structured microdomains are on the order of hundreds of $μsec$ then Ub folding follows the diffusion-collision mechanism with intermediates many of which coincide with those found in equilibrium. Folding at neutral pH is a sequential process with a populated intermediate resembling that sampled at equilibrium. The transition state structures, obtained using a $P_{fold}$ analysis, are homogeneous and globular with most of the secondary and tertiary structures being native-like. Many of our findings are not only in agreement with experiments but also provide missing details not resolvable in standard experiments.
机构、总结、中文摘要均由AI分析而来，可能存在错误，请以论文正文为准。
