Computer Simulation Theory of Globular Protein Dynamics

我们的长期目标是开发强大的算法，可以预测蛋白质的三级结构， 四级结构的DNA-蛋白质复合物，并应用于重要的蛋白质组的方法。 蛋白质结构是重要的，因为它们可以帮助阐明蛋白质的功能。这是必不可少 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 最近开发的和有前途的TASSER结构预测算法，采用线程 确定模板以提供连续的结构片段和预测的三级接触， 折叠组装/细化方案。TASSER为约70%的单域提供了合理的模型 与具有解析结构的蛋白质弱同源的蛋白质，并且通常提供显著的 对输入螺纹对齐的改进。为了推广这一做法， 针对单结构域蛋白质，本文提出了以下具体目标：（1）对单结构域蛋白质， TASSER中的模板自由限制将得到改善。目前，这是TASSER的主要弱点。（二） TASSER将被扩展以更好地预测膜蛋白的三级结构。（3）TASSER将是 扩展到明确包括辅基，金属离子和蛋白质建模中的小配体 程序，目的是产生更准确的结构预测。(4)TASSER将扩展到 更好地治疗多结构域蛋白质。目前，预测的成功取决于是否域方向 在目标和模板结构是相似的。(5)TASSER将被扩展到预测的结构 与DNA结合的蛋白质然后，我们将应用最近开发的算法，预测蛋白质是否 将结合DNA，如果是这样，最终在蛋白质组学规模上模拟DNA-蛋白质复合物的结构。 (6)选择性剪接对单结构域蛋白质结构的影响将被探讨。(7)叔 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代表了方法上的进步，而具体目标6和1旨在应用 改进的TASSER算法用于解决生物学中的重要问题。针对所有具体目标，全面 将制定基准，包括参与未来的CASP。所有开发的算法，工具， 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/.