Computer Simulation Theory of Globular Protein Dynamics

我们的长期目标是开发能够预测蛋白质三级结构和 DNA-蛋白质复合体的四级结构，并将该方法学应用于重要的蛋白质组。 蛋白质结构很重要，因为它们可以帮助阐明蛋白质的功能。这是必不可少的 因为在给定的蛋白质组中，大约一半的蛋白质的功能是未知的。拟议的研究建立了 基于线程的TASTER结构预测算法研究 识别模板以提供连续的结构片段和预测的三级接触，随后 折叠装配/改进协议。Tasser为-70%的单一领域提供了合理的模型 与具有已解决结构的蛋白质弱同源的蛋白质，并且通常提供显著的 对输入线程对齐的改进。以扩展此方法并解决已确定的 针对其不足之处，提出了以下具体目标：(1)对于单域蛋白，其性能 Tasser中的模板自由限制将得到改进。目前，这是Tasser的一大软肋。(2) Tasser将被扩展到更好地预测膜蛋白的三级结构。(3)TASTER将被 扩展到在蛋白质模型中显式地包括假体基团、金属离子和小配体 程序，目的是产生更准确的结构预测。(4)TASTER将扩展至 更好地处理多结构域蛋白质。目前，预测的成功与否取决于是否存在领域取向 在目标和模板结构上是相似的。(5)TASTER将扩展到预测结构 与DNA结合的蛋白质。然后，我们将应用最近开发的一种算法来预测蛋白质是否 将结合DNA，如果是这样的话，最终在蛋白质组学的规模上对DNA-蛋白质复合体的结构进行建模。 (6)探讨选择性剪接对单域蛋白结构的影响。(7)第三级 将对大量蛋白质组中长度小于300个残基的蛋白质进行结构预测。 具体目标1-5代表方法上的进步，而具体目标6和1旨在应用 生物重要问题的改进Tasser算法。对于所有具体目标，全面 将制定基准，包括参与未来的CASP。所有开发的算法、工具和 结果将在我们的网站http://cssb.biology.gatech.edu/skolnick/.上公布。

Our long-term objectives are to develop robust algorithms that can predict protein tertiary structure and the quaternary structure of DNA-protein complexes and to apply the methodology to important proteomes. Protein structures are important because they can assist in the elucidation of protein function. This is essential as the functions of roughly half the proteins in a given proteome are unknown. The proposed research builds on the recently developed and promising TASSER structure prediction algorithm that employs threading identified templates to provide continuous structural fragments and predicted tertiary contacts followed by fold assembly/refinement protocols. TASSER provides reasonable models for -70% of the single domain proteins that are weakly homologous to proteins with solved structures and often provides a significant improvement over the input threading alignment. To extend this approach and to address identified weaknesses, the following Specific Aims are proposed: (1) For single domain proteins, the performance of TASSER in the template free limit will be improved. At present, this is the major weakness of TASSER. (2) TASSER will be extended to better predict the tertiary structure of membrane proteins. (3)TASSER will be extended to explicitly include prosthetic groups, metal ions and small ligands in the protein modeling procedure, with the goal of producing more accurate structural predictions. (4) TASSER will be extended to better treat multidomain proteins. Currently, prediction success depends on whether the domain orientations in the target and template structures are similar. (5) TASSER will be extended to predict the structure of proteins bound to DNA. Then, we shall apply a recently developed algorithm that predicts whether a protein will bind DNA, and if so, model the structure of the DNA-protein complex, ultimately on a proteomic scale. (6) The effect of alternative splicing on the structure of single domain proteins will be explored. (7) Tertiary structure prediction of proteins less than 300 residues in length in a large number of proteomes will be done. Specific Aims 1-5represent methodological advances, whereas Specific Aims 6 & 1 are designed to apply the improved TASSER algorithm to biologically important problems. For all Specific Aims, comprehensive benchmarking that includes participation in future CASPs will be done. All developed algorithms, tools, and results will be made available on our website, http://cssb.biology.gatech.edu/skolnick/.