Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations
Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations
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DOI：
10.1021/jacs.6b02016
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发表时间：
2016-07-20
影响因子：
15
通讯作者：
Gustavo Turjanski, Adrian
中科院分区：
文献类型：
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作者：
Esteban Ithuralde, Raul;Roitberg, Adrian Enrique;Gustavo Turjanski, Adrian
内在无序蛋白（IDPs）是一类在溶液中缺乏明确二级结构的蛋白质。国内流离失所者在与伴侣结合时可以获得三级结构；因此，识别过程也必须涉及蛋白质折叠。过渡态（TS）的性质（结构化或非结构化）决定了结合机制。由于扩散、识别和结合与折叠相结合，表征TS已成为实验技术和分子模拟方法的主要挑战。在这项工作中，我们提出了原子分子动力学（MD）模拟，对转录因子c-myb与共转录因子CREB结合蛋白（CBP）的耦合折叠和结合的自由能表面进行了采样。最近对这一过程进行了研究，并成为研究国内流离失所者的一种模式。尽管有大量的可用信息，我们仍然不知道c-myb是如何与CBP结合的。我们进行了一组总运行15.6 μ s的原子偏态MD模拟。我们的结果表明，c-myb在与CBP结合后折叠非常快，没有独特的结合途径。该过程可以通过具有相似概率的结构化或非结构化TS进行。这一发现与之前看似不同的实验结果相一致。我们还对几个结构化和非结构化模型进行了G (o) over bar型粗粒度MD，表明耦合折叠和结合遵循原生接触机制。据我们所知，这是第一次对IDPs的耦合折叠和结合过程的自由能面进行原子MD模拟。
Intrinsically disordered proteins (IDPs) are a set of proteins that lack a definite secondary structure in solution. IDPs can acquire tertiary structure when bound to their partners; therefore, the recognition process must also involve protein folding. The nature of the transition state (TS), structured or unstructured, determines the binding mechanism. The characterization of the TS has become a major challenge for experimental techniques and molecular simulations approaches since diffusion, recognition, and binding is coupled to folding. In this work we present atomistic molecular dynamics (MD) simulations that sample the free energy surface of the coupled folding and binding of the transcription factor c-myb to the cotranscription factor CREB binding protein (CBP). This process has been recently studied and became a model to study IDPs. Despite the plethora of available information, we still do not know how c-myb binds to CBP. We performed a set of atomistic biased MD simulations running a total of 15.6 mu s. Our results show that c-myb folds very fast upon binding to CBP with no unique pathway for binding. The process can proceed through both structured or unstructured TS's with similar probabilities. This finding reconciles previous seemingly different experimental results. We also performed G (o) over bar -type coarse-grained MD of several structured and unstructured models that indicate that coupled folding and binding follows a native contact mechanism. To the best of our knowledge, this is the first atomistic MD simulation that samples the free energy surface of the coupled folding and binding processes of IDPs.