Predicting Protein-DNA Interactions with Structural Models

项目总结/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机制的核心。 流程.该研究项目将导致改进的计算预测蛋白质-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）。我们将开发预测复合物三维结构的方法， 蛋白质和DNA分子使用相关蛋白质的实验确定的结构。我们的新型 贡献将是模拟技术的发展，可以移动的三维结构的 与DNA复合的相关蛋白质更接近与DNA结合的目的蛋白质的结构。的 缺乏现有的技术，可以实现这一任务被广泛认为是一个主要的障碍， 蛋白质之间结构信息的广泛传递。成功完成本部分的工作， 该项目将大大增加正在进行的结构基因组学项目的影响-旨在确定 通过实验手段，一组代表性的蛋白质的结构-通过允许高分辨率结构 这些数据将用于了解未知蛋白质的结构和功能。 这个项目的第二个组成部分的目标是使用我们生成的结构模型， 对所讨论的蛋白质的生物学功能的具体预测。更准确地说，我们建议 开发出预测特定蛋白质与DNA特定序列结合的方法。我们就去 通过构建蛋白质与各种DNA序列复合的结构模型， 用先进的力场评估它对这些不同序列的亲和力。成功与否取决于 我们用来计算蛋白质与其势能之间相互作用能量的力场的准确性 伙伴作为额外的复杂性，这些DNA分子的结构可能都略有不同， 蛋白质本身可以以不同的方式在结构上适应不同的序列，以实现最佳配合。 在这个项目的最后一部分，我们将应用这些方法来研究一个特定的蛋白质， 生物重要性。这种蛋白质MyoD被称为骨骼肌发育的“主调节器” 因为它具有将各种类型的细胞转化为肌肉细胞的非凡能力。我们将研究 MyoD在开发过程中通过构建结构模型来执行其关键功能， MyoD与基因组中特定位点之间的相互作用。这些模型将包括伙伴分子， 有助于将MyoD靶向生物学相关位点。这些研究的最终目标是预测 在基因组中，MyoD和其他关键调节蛋白发挥作用。

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.