Chemical Signatures for the Discovery of Protein Function

化学系的生命过程化学项目获得这一奖项，支持东北大学的Mary Jo Ondrechen博士和Penny J.Beuning博士开发、实施和验证一种预测蛋白质生化功能的新方法。这个项目利用计算化学工具，以一种创新的基于化学性质的方法来发现蛋白质结构的生化功能。它始于这样一个前提，即活性部位的局部结构特征比整体折叠更能预测生化功能。首先，证明了结构相似的蛋白质组可以根据生化功能，利用计算的化学性质预测的活性部位残基，对它们进行结构比对，并根据化学相似性对它们进行评分。因此，对于每个功能亚基，定义了特征化学特征。接下来，使用计算的化学特征并寻找与先前表征的蛋白质的化学特征匹配的结构基因组蛋白质，分析和注释结构基因组蛋白质，并识别错误注释的结构基因组蛋白质。对于被确定为错误注释的结构基因组学蛋白质的选定案例，或其生化功能被新预测的案例，预测的功能通过动力学分析和结合研究进行实验验证。在过去的15年里，基因组测序和结构基因组学的努力提供了关于数千种蛋白质的丰富的新信息。虽然基因组研究为未来的重大社会利益带来了巨大的希望，但实现这一潜力的关键一步是能够确定数以千计的蛋白质结构的功能，这些结构的生化功能目前尚不清楚或不确定；该项目解决了目前的挑战。更好地了解蛋白质的功能在化学以外的领域有许多潜在的好处，包括农业、生物技术、医药、生物燃料和“绿色”工业过程。更好地了解支配蛋白质如何如此选择性和有效地工作的局部结构、静电和化学模式，将为新的商业应用打开大门。这些推动新的高科技商业应用的基本知识对我们区域和国家经济的未来增长非常重要。该项目还将开发一个知识库和工具，使其他发现和应用成为可能。在这个项目中，一群不同种族的本科生和博士生接受了计算化学、计算生物学和生物化学方法的培训。这些领域的经验对美国在全球经济中的竞争力至关重要。拥有这样的知识和培训的人在学术界和工业界都很受欢迎。

With this award the Chemistry of Life Processes Program in the Chemistry Division supports Drs. Mary Jo Ondrechen and Penny J. Beuning from Northeastern University to develop, implement, and verify a novel method for predicting the biochemical function of proteins. This project utilizes computational chemistry tools in an innovative chemical-properties-based method to discover the biochemical function of protein structures. It begins with the premise that local structural features at the active site constitute better predictors of biochemical function than does the overall fold. First it is shown that sets of structurally similar proteins may be sorted into subgroups according to biochemical function, using the active site residues predicted from computed chemical properties, structurally aligning them, and scoring them according to chemical similarity. Thus for each functional subgroup, a characteristic chemical signature are defined. Next, structural genomics proteins are analyzed and annotated, using their calculated chemical signatures and seeking matches with the chemical signatures of the previously characterized proteins, and misannotated structural genomics proteins are identified. For selected cases of structural genomics proteins that have been determined to be misannotated, or for which biochemical function is newly predicted, the predicted functions are verified experimentally by kinetics assays and binding studies. Genome sequencing and structural genomics efforts over the past 15 years have provided a wealth of new information about thousands of proteins. While genome research holds tremendous promise for major future benefits to society, a key step toward the realization of this potential is the ability to determine the function of the thousands of protein structures whose biochemical functions are currently unknown or uncertain; this project addresses that current challenge. Greater understanding of protein function has many potential benefits in fields outside of chemistry, including agriculture, biotechnology, medicine, biofuels, and "green" industrial processes. A better understanding of the local structural, electrostatic, and chemical patterns that govern how proteins work so selectively and efficiently will open the door to novel commercial applications. Such basic knowledge to drive novel high-tech commercial application is important to the future growth of our regional and national economies. This project also will develop a knowledge base and tools that will enable other discoveries and applications. In this project a racially diverse group of both undergraduate and doctoral students are trained in methods of computational chemistry, computational biology, and biochemistry. Experience in these areas is a vital ingredient for United States competitiveness in the global economy. Individuals with such knowledge and training are in high demand in both academia and industry.