Department of Chemistry and Applied Biosciences, Eidgenössische Technische Hochschule Zürich, CH-8093 Zurich, Switzerland.
Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14237-42. doi: 10.1073/pnas.1313548110. Epub 2013 Aug 12.
Allosteric regulation plays an important role in a myriad of biomacromolecular processes. Specifically, in a protein, the process of allostery refers to the transmission of a local perturbation, such as ligand binding, to a distant site. Decades after the discovery of this phenomenon, models built on static images of proteins are being reconsidered with the knowledge that protein dynamics plays an important role in its function. Molecular dynamics simulations are a valuable tool for studying complex biomolecular systems, providing an atomistic description of their structure and dynamics. Unfortunately, their predictive power has been limited by the complexity of the biomolecule free-energy surface and by the length of the allosteric timescale (in the order of milliseconds). In this work, we are able to probe the origins of the allosteric changes that transcription factor mixed lineage leukemia (MLL) causes to the interactions of KIX domain of CREB-binding protein (CBP) with phosphorylated kinase inducible domain (pKID), by combing all-atom molecular dynamics with enhanced sampling methods recently developed in our group. We discuss our results in relation to previous NMR studies. We also develop a general simulations protocol to study allosteric phenomena and many other biological processes that occur in the micro/milliseconds timescale.
变构调节在众多生物大分子过程中起着重要作用。具体来说，在蛋白质中，变构过程是指将局部扰动（如配体结合）传递到远处的过程。在发现这一现象几十年后，随着人们认识到蛋白质动力学在其功能中起着重要作用，基于蛋白质静态图像的模型正在被重新考虑。分子动力学模拟是研究复杂生物分子系统的一种有价值的工具，它提供了对其结构和动力学的原子级描述。不幸的是，由于生物分子自由能面的复杂性和变构时间尺度（毫秒量级）的限制，它们的预测能力受到了限制。在这项工作中，我们通过结合全原子分子动力学和我们小组最近开发的增强采样方法，能够探测转录因子混合谱系白血病（MLL）引起的变构变化的起源，这些变化涉及 CREB 结合蛋白（CBP）的 KIX 结构域与磷酸化激酶诱导结构域（pKID）的相互作用。我们将讨论我们的结果与以前的 NMR 研究的关系。我们还开发了一种通用的模拟方案，用于研究发生在微/毫秒时间尺度的变构现象和许多其他生物过程。
