Coupled folding and binding with 2D Window-Exchange Umbrella Sampling.
Coupled folding and binding with 2D Window-Exchange Umbrella Sampling.
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DOI：
10.1002/jcc.24004
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发表时间：
2016-03-05
影响因子：
3
通讯作者：
Brooks CL 3rd
中科院分区：
文献类型：
--
作者：
Dickson A;Ahlstrom LS;Brooks CL 3rd
蛋白质的内部无序区域可以通过与伴侣结合来获得结构。这个耦合折叠和结合的过程是许多重要生物过程的基本部分。基于结构的模型已经证明自己能够揭示耦合折叠和结合如何发生的基本方面，然而，典型的方法，以提高这些过渡的采样，如副本交换，不充分的采样过渡状态区域的这一极其罕见的过程。在这里，我们使用伞采样的一个变体来强制采样的过渡态的耦合折叠和结合的HdeA单体在中性pH值，一个非常罕见的过程，发生在从秒到小时的时间尺度。使用高分辨率的采样在过渡态区域，我们集群状态沿着的主要过渡路径，以获得一个详细的描述耦合绑定和折叠的HdeA二聚体，揭示了新的洞察到合奏的状态，可访问客户端识别。然后，我们证明了伞采样窗口之间的交流，在以前的工作中所做的，显着提高松弛变量正交的约束。总之，这些结果表明，窗口交换伞采样（WEUS）是一种很有前途的方法，表现出灵活的绑定系统，并可以揭示这些系统的过渡态系综的高度详细。
Intrinsically disordered regions of proteins can gain structure by binding to a partner. This process, of coupled folding and binding, is a fundamental part of many important biological processes. Structure-based models have proven themselves capable of revealing fundamental aspects of how coupled folding and binding occurs, however typical methods to enhance the sampling of these transitions, such as replica exchange, do not adequately sample the transition state region of this extremely rare process. Here we use a variant of Umbrella Sampling to enforce sampling of the transition states of coupled folding and binding of HdeA monomers at neutral pH, an extremely rare process that occurs over timescales ranging from seconds to hours. Using high resolution sampling in the transition state region we cluster states along the principal transition path to obtain a detailed description of coupled binding and folding for the HdeA dimer, revealing new insight into the ensemble of states that are accessible to client recognition. We then demonstrate that exchanges between umbrella sampling windows, as done in previous work, significantly improve relaxation in variables orthogonal to the restraints used. Altogether, these results show that Window Exchange Umbrella Sampling (WEUS) is a promising approach for systems that exhibit flexible binding, and can reveal transition state ensembles of these systems in high detail.