A role for both conformational selection and induced fit in ligand binding by the LAO protein.
A role for both conformational selection and induced fit in ligand binding by the LAO protein.
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DOI：
10.1371/journal.pcbi.1002054
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发表时间：
2011-05
影响因子：
4.3
通讯作者：
Huang X
中科院分区：
文献类型：
--
作者：
Silva DA;Bowman GR;Sosa-Peinado A;Huang X
分子识别由蛋白质及其配体的结构和动力学决定，但很难直接评估这些参与者中的每一个的作用。在这项研究中，我们使用马尔可夫状态模型（MSM）建立从原子模拟来阐明赖氨酸，精氨酸，鸟氨酸结合（LAO）蛋白结合到它的配体的机制。我们表明，我们的模型可以预测的结合态，结合自由能，并与合理的准确性，然后使用该模型解剖的结合机制。在过去，这种结合事件通常被认为是通过诱导配合机制发生的，因为蛋白质的结合位点在结合状态下是完全封闭的，使得配体在蛋白质采取封闭构象后不可能进入结合位点。更复杂的机制也被假设，但这些仍然存在争议。在这里，我们能够直接观察LAO结合的构象选择和诱导适合机制的作用。首先，LAO蛋白倾向于通过构象选择形成部分封闭的相遇复合物（即，载脂蛋白可以采样这种状态），尽管诱导的适应机制也可以在这里发挥作用。然后，与配体的相互作用可以诱导向结合态的转变。基于这些结果，我们提出，从原子模拟中构建的MSM可能是剖析配体结合机制的一种有力方式，并可能最终促进对变构的更深入理解以及对新的蛋白质-配体相互作用的预测，这是药物发现的重要一步。蛋白质-配体相互作用对化学、生物学和医学至关重要。人们对蛋白质与配体结合的机制进行了大量的研究，并发展了诱导匹配和构象选择模型。不幸的是，实验探测蛋白质-配体结合机制的原子细节是具有挑战性的。计算机模拟有可能提供分子识别事件的详细图像。在这项研究中，我们构建动力学网络模型，从原子模拟阐明的机制，LAO蛋白结合到它的配体。由于LAO蛋白在结合状态下完全包围其底物，因此通常假设其通过诱导配合机制进行操作。我们发现构象选择和诱导匹配机制在LAO结合中起重要作用。此外，我们已经确定了许多平行的结合途径，所有这些都通过一个单一的看门状态，我们称之为遭遇复合物状态，因为蛋白质是部分关闭的，只有微弱的相互作用与其底物。
Molecular recognition is determined by the structure and dynamics of both a protein and its ligand, but it is difficult to directly assess the role of each of these players. In this study, we use Markov State Models (MSMs) built from atomistic simulations to elucidate the mechanism by which the Lysine-, Arginine-, Ornithine-binding (LAO) protein binds to its ligand. We show that our model can predict the bound state, binding free energy, and association rate with reasonable accuracy and then use the model to dissect the binding mechanism. In the past, this binding event has often been assumed to occur via an induced fit mechanism because the protein's binding site is completely closed in the bound state, making it impossible for the ligand to enter the binding site after the protein has adopted the closed conformation. More complex mechanisms have also been hypothesized, but these have remained controversial. Here, we are able to directly observe roles for both the conformational selection and induced fit mechanisms in LAO binding. First, the LAO protein tends to form a partially closed encounter complex via conformational selection (that is, the apo protein can sample this state), though the induced fit mechanism can also play a role here. Then, interactions with the ligand can induce a transition to the bound state. Based on these results, we propose that MSMs built from atomistic simulations may be a powerful way of dissecting ligand-binding mechanisms and may eventually facilitate a deeper understanding of allostery as well as the prediction of new protein-ligand interactions, an important step in drug discovery. Protein-ligand interactions are crucial to chemistry, biology and medicine. Many studies have been conducted to probe the mechanism of protein-ligand binding, leading to the development of the induced fit and conformational selection models. Unfortunately, experimentally probing the atomistic details of protein-ligand binding mechanisms is challenging. Computer simulations have the potential to provide a detailed picture of molecular recognition events. In this study, we construct kinetic network models from atomistic simulations to elucidate the mechanism by which the LAO protein binds to its ligand. Because the LAO protein completely encompasses its substrate in the bound state, it has generally been assumed that it operates via an induced fit mechanism. We find that both the conformational selection and induced fit mechanisms play important roles in LAO binding. Furthermore, we have identified a number of parallel pathways for binding, all of which pass through a single gatekeeper state, which we refer to as the encounter complex state because the protein is partially closed and only weakly interacting with its substrate.
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