Retention of local conformational compactness in unfolding of barnase; Contribution of end-to-end interactions within quasi-modules.
Retention of local conformational compactness in unfolding of barnase; Contribution of end-to-end interactions within quasi-modules.
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DOI：
10.2142/biophysics.3.1
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发表时间：
2007-01-01
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影响因子：
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通讯作者：
Go, Mitiko
中科院分区：
文献类型：
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作者：
Shinoda, Kazuki;Takahashi, Ken-Ichi;Go, Mitiko
为了理解蛋白质如何减少要搜索的天然结构的构象空间，关键是要表征折叠过程中的构象集合，特别是连接在广泛展开状态和具有天然样整体链拓扑结构的状态之间的相对长范围结构的集合。为了分析这种中间构象，我们在498K下对芽孢杆菌RNA酶进行了多次解折叠分子动力学模拟。一些短程结构如部分螺旋和转角得到了很好的保持，而大部分二级结构和疏水核心最终丢失，这与其他实验和计算研究结果一致。最重要的新发现是持久的远程相对紧凑的子结构，这是利用模块的概念捕获。模块最初被引入来描述天然状态下球状蛋白质的层次结构。模块在概念上是这样的相对紧凑的亚结构，其通过将球状蛋白的天然结构完全划分为具有最少延伸构象的几个连续片段而产生。我们应用这个概念的模块来检测一个可能的层次结构的每个快照结构的展开过程中。沿着这个概念的扩展，这种检测到的相对紧凑的子结构被称为准模块。我们发现几乎完美的持久性的准模块的边界定位接近本地模块的边界在整个展开轨迹。相对紧凑的构象的准模块似乎主要保留由位于每个模块内的两个末端区域的残基之间形成的疏水相互作用。根据这些结果，我们提出了一个假设，即准模块早期形成的分层折叠有效地减少了原生结构的搜索空间。
To understand how protein reduces the conformational space to be searched for the native structure, it is crucial to characterize ensembles of conformations on the way of folding processes, in particular ensembles of relatively long-range structures connecting between an extensively unfolded state and a state with a native-like overall chain topology. To analyze such intermediate conformations, we performed multiple unfolding molecular dynamics simulations of barnase at 498K. Some short-range structures such as part of helix and turn were well sustained while most of the secondary structures and the hydrophobic cores were eventually lost, which is consistent with the results by other experimental and computational studies. The most important novel findings were persistence of long-range relatively compact substructures, which was captured by exploiting the concept of module. Module is originally introduced to describe the hierarchical structure of a globular protein in the native state. Modules are conceptually such relatively compact substructures that are resulted from partitioning the native structure of a globular protein completely into several contiguous segments with the least extended conformations. We applied this concept of module to detect a possible hierarchical structure of each snapshot structure in unfolding processes as well. Along with this conceptual extension, such detected relatively compact substructures are named quasi-modules. We found almost perfect persistence of quasi-module boundaries that are positioned close to the native module boundaries throughout the unfolding trajectories. Relatively compact conformations of the quasi-modules seemed to be retained mainly by hydrophobic interactions formed between residues located at both terminal regions within each module. From these results, we propose a hypothesis that hierarchical folding with the early formation of quasi-modules effectively reduces search space for the native structure.