Conformational transition in signal transduction: metastable states and transition pathways in the activation of a signaling protein.
Conformational transition in signal transduction: metastable states and transition pathways in the activation of a signaling protein.
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DOI：
10.1021/acs.jpcb.5b02582
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发表时间：
2015-06
期刊：
影响因子：
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通讯作者：
R. Banerjee;Honggao Yan;R. Cukier
中科院分区：
文献类型：
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作者：
R. Banerjee;Honggao Yan;R. Cukier
信号转导对生物体的生长和适应至关重要。理解生物信号转导机制的关键是阐明其信号蛋白的构象动力学，因为信号蛋白的活化基本上是从非活性状态到活性状态的构象转变过程。在野生环境或宿主体内，细菌感知环境变化的信号转导的主要形式是各种双组分系统，其中响应调节因子（RR）从非活性状态到活性状态的构象转变引发对环境变化的响应。在这里，RR激活已被调查使用RR 468作为一个模型系统，广泛的无偏全原子分子动力学（MD）模拟在明确的溶剂，从快照沿着有针对性的MD轨迹，涵盖构象转变。马尔可夫状态建模、过渡路径理论和对MD数据的丰富几何分析提供了对RR激活的全面描述。它涉及一个亚稳态网络，其中一个亚稳态基本上与非活动状态相同，另一个亚稳态与活动状态非常相似，它们通过一小组中间体连接。五个主要的途径占>75%的非活性状态的构象转变到活性样状态的流量。的热力学稳定性的状态和状态之间的激活势垒被发现，以确定限速步骤。共形转变主要由β3α3环的运动开始，随后是β4α4环和相邻α4螺旋区域的运动，并由β3α3环的额外运动覆盖。一些瞬态的疏水和氢键相互作用被揭示，它们可能是重要的构象转变。
Signal transduction is of vital importance to the growth and adaptation of living organisms. The key to understand mechanisms of biological signal transduction is elucidation of the conformational dynamics of its signaling proteins, as the activation of a signaling protein is fundamentally a process of conformational transition from an inactive to an active state. A predominant form of signal transduction for bacterial sensing of environmental changes in the wild or inside their hosts is a variety of two-component systems, in which the conformational transition of a response regulator (RR) from an inactive to an active state initiates responses to the environmental changes. Here, RR activation has been investigated using RR468 as a model system by extensive unbiased all-atom molecular dynamics (MD) simulations in explicit solvent, starting from snapshots along a targeted MD trajectory that covers the conformational transition. Markov state modeling, transition path theory, and geometric analyses of the wealth of the MD data have provided a comprehensive description of the RR activation. It involves a network of metastable states, with one metastable state essentially the same as the inactive state and another very similar to the active state that are connected via a small set of intermediates. Five major pathways account for >75% of the fluxes of the conformational transition from the inactive to the active-like state. The thermodynamic stability of the states and the activation barriers between states are found, to identify rate-limiting steps. The conformal transition is initiated predominantly by movements of the β3α3 loop, followed by movements of the β4α4-loop and neighboring α4 helix region, and capped by additional movements of the β3α3 loop. A number of transient hydrophobic and hydrogen bond interactions are revealed, and they may be important for the conformational transition.