Predicting Protein-DNA Interactions with Structural Models

项目摘要/摘要 蛋白质和DNA分子之间的相互作用是广泛的遗传和调控的核心 流程。这项研究项目将改进用于计算预测蛋白质-DNA的工具 仅使用蛋白质序列数据(例如由人类基因组产生的数据)的结构和相互作用 项目)。我们将开发预测络合物三维结构的方法 蛋白质和DNA分子使用实验确定的相关蛋白质的结构。我们的小说 其贡献将是模拟技术的发展，这种技术可以移动 与DNA的复合体中的相关蛋白质更接近于与DNA结合的感兴趣蛋白质的结构。这个 人们普遍认为，缺乏能够完成这一任务的现有技术是阻碍 蛋白质之间结构信息的广泛传递。成功完成该组件的 该项目将大大增加正在进行的结构基因组学项目的影响--这些项目旨在确定 通过实验手段获得一组代表性蛋白质的结构--通过允许高分辨率结构 用于了解未表征蛋白质的结构和功能的数据。 该项目的第二个组件的目标是使用我们生成的结构模型来制作 关于这些蛋白质的生物学功能的具体预测。更准确地说，我们建议 开发预测特定蛋白质将与哪些特定DNA序列结合的方法。我们会去的 通过建立具有各种DNA序列和蛋白质的复合体的结构模型来实现这一点 使用高级力场评估其对这些不同序列的亲和力。成功将取决于 我们用来计算蛋白质与其势之间相互作用能量的力场的准确性 合伙人。更复杂的是，这些DNA分子的结构可能都略有不同，并且 蛋白质本身可以以不同的方式在结构上适应不同的序列，以实现最佳匹配。 在这个项目的最后一部分，我们将应用这些方法来研究一种特殊的蛋白质。 生物学上的重要性。这种名为MyoD的蛋白质被称为骨骼肌发育的“主调节器” 因为它有非凡的能力将各种类型的细胞转化为肌肉细胞。我们将研究其机制。 MyoD在开发期间通过构建结构模型来执行其关键功能 MyoD与基因组中特定位置之间的相互作用。这些模型将包括伙伴分子， 帮助将MyoD定位到生物相关的位置。这些研究的最终目标将是预测地点 在基因组中，MyoD和其他关键调控蛋白发挥作用。

Project Summary/Abstract Interactions between proteins and DNA molecules are central to a wide range of genetic and regulatory processes. This research project will lead to improved tools for computationally predicting protein-DNA structures and interactions using only protein sequence data (such as that generated by the human genome project). We will develop methods for predicting the three-dimensional structures of complexes between proteins and DNA molecules using the experimentally determined structures of related proteins. Our novel contribution will be the development of simulation techniques that can move the three-dimensional structure of the related protein in complex with DNA closer to the structure of the protein of interest bound to DNA. The lack of existing techniques that can achieve this task is widely recognized as a major impediment to the widespread transfer of structural information between proteins. Successful completion of this component of the project would greatly increase the impact of the ongoing structural genomics projects - which aim to determine by experimental means the structures of a representative set of proteins - by allowing high-resolution structural data to be used to understand the structures and functions of uncharacterized proteins. The goal of the second component of this project is to use the structural models we generate to make concrete predictions about the biological functions of the proteins in question. More precisely, we propose to develop methods that will predict which specific sequences of DNA a given protein will bind to. We will go about this by building structural models of the protein in complex with a variety of DNA sequences and evaluating its affinity for these different sequences using advanced force fields. Success will hinge on the accuracy of the force fields we use to calculate the energies of interaction between the protein and its potential partners. As an additional complication, the structures of these DNA molecules may all be slightly different, and the protein itself may adapt structurally to different sequences in different ways to achieve an optimal fit. In the final component of this project, we will apply these methods to study a specific protein of great biological importance. This protein, MyoD, has been called a 'master-regulator' of skeletal muscle development for its remarkable ability to turn cells of a variety of types into muscle cells. We will investigate the mechanisms by which MyoD performs its critical functions during development by building structural models of the interactions between MyoD and specific sites in the genome. These models will include partner molecules that help to target MyoD to biologically relevant sites. The eventual goal of these studies will be to predict the sites in the genome at which MyoD and other key regulatory proteins exert their effect.