ITR: Collaborative Research: (ASE+NHS+EVS)-(sim+dmc+int): In Silico De Novo Protein Design: A Dynamically Data Driven, (DDDAS), Computational and Experimental Framework

ITR：协作研究：(ASE NHS EVS)-(sim dmc int)：计算机从头蛋白质设计：动态数据驱动、(DDDAS)、计算和实验框架

• 批准号: 0426691
• 负责人: Christodoulos Floudas
• 金额: --
• 依托单位: Princeton University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0426691&HistoricalAwards=false
• 关键词: ITR; Collaborative; Research; ASE+NHS+EVS; sim+dmc+int

ABSTRACTPI: Christodoulos Floudas Institution: Princeton UniversityProposal Number: 0426691Research: A challenge in computational protein design is the discovery of novel proteins, which are compatible with either target template structures or arbitrarily three dimensional structures. This research is a dynamically data driven application systems, (DDDAS), effort through an integrative research framework, (i.e., computational, physicochemical, and biochemical approaches) for the in silico de novo design of peptides and proteins. The primary aims of the project are (i) in silico sequence selection and folding specificity calculations through a novel computational framework that is based on mixed-integer optimization and deterministic global optimization, (ii) in vitro and in silico characterization via NMR, structure determination, and molecular dynamics, (iii) protein expression, structural characterization and activity measurements of predicted sequences, and (iv) the development of a web-based WorkBench support system for de novo peptide/protein design which will be freely available to all researchers. The biological systems for testing and validating the proposed framework include the C3a anaphylatoxin (aims (i)-(iv)), and human beta defensins (aims (i), molecular dynamics of (ii) and (iv)). Intellectual Merit:The planned effort involves an interdisciplinary team (Floudas, Lambris, Morikis) from three institutions (Princeton, U. Penn, U. California at Riverside). Their expertise spans the fields of complement biology, protein chemistry, structural biology, mathematical modeling and analysis, combinatorial and global optimization, scientific computing, and bioengineering, and the project is an integrative computational and experimental effort. These developments can expedite significantly the drug discovery process, address important tasks in the design of new drugs, and the proposed novel concept of a web-based WorkBench will be the first such service to the scientific community. Broader Impacts: Using IT and DDDAS techniques, in a uniquely symbiotic computational and experimental framework, this project will lay the groundwork for making significant advances in the discovery of new drugs. This framework for in silico prediction of new sequences which fold selectively to structural templates and their experimental validation will allow rapid screening of novel alternatives and will lead into better and faster drug discovery which has direct impact in our society. The proposed effort integrates participation of graduate students, postdoctoral students, and undergraduate students into the research, thereby providing multidisciplinary training opportunities. The co-PIs have records in research with undergraduate students as part of their junior independent work, as well as senior thesis work. All three institutions have policies for attracting students and employees from traditionally under-represented groups. The co-PIs are committed to working with these students and will work pro-actively to attract them to this research project, the seminar series, the journal club, and the graduate level course. The co-PIs have strong records of educating undergraduate and graduate students, and post-doctoral associates from under-represented groups. The results of the research will be disseminated to the entire scientific community through publications in archival journals, refereed proceedings, and via presentations at conferences. Furthermore, the development of the web-based WorkBench for the de novo design of peptide/proteins will provide, for the first time, service to the scientific community.

AbstractPI：Christodoulos Floudas机构：普林斯顿大学港口编号：0426691研究：计算蛋白设计中的挑战是发现新型蛋白质，它们与目标模板结构或任意三维结构兼容。这项研究是一种动态数据驱动的应用系统（DDDAS），它是通过综合研究框架（即计算，理化和生化方法）的努力，用于从头设计的肽和蛋白质。 The primary aims of the project are (i) in silico sequence selection and folding specificity calculations through a novel computational framework that is based on mixed-integer optimization and deterministic global optimization, (ii) in vitro and in silico characterization via NMR, structure determination, and molecular dynamics, (iii) protein expression, structural characterization and activity measurements of predicted sequences, and (iv) the development of a web-based WorkBench support从头肽/蛋白质设计的系统系统将为所有研究人员免费使用。用于测试和验证所提出框架的生物系统包括C3a过敏毒素（AIMS（I） - （IV））和人β防御素（Aims（i），（II）的分子动力学（II）和（IV））。知识分子的优点：计划中的工作涉及来自三个机构（普林斯顿，美国宾夕法尼亚州，美国加利福尼亚州里弗斯岛）的一个跨学科团队（Floudas，Lambris，Morikis）。它们的专业知识涵盖了补体生物学，蛋白质化学，结构生物学，数学建模和分析，组合和全球优化，科学计算以及生物工程的领域，并且该项目是一体的计算和实验性工作。这些发展可以显着加快药物发现过程，解决新药设计中的重要任务，而拟议的基于网络的工作台的新颖概念将成为科学界的首次这样的服务。 更广泛的影响：在独特的共生计算和实验框架中，使用IT和DDDAS技术将为在发现新药的发现方面取得重大进步奠定基础。在新序列的硅硅预测中，该框架有选择地折叠到结构模板及其实验验证将允许快速筛选新型替代方案，并将导致更快，更快的药物发现，从而直接影响我们的社会。拟议的努力将研究生，博士后学生和本科生的参与纳入了研究，从而提供了多学科的培训机会。 Co-Pis作为初级独立工作以及高级论文工作的一部分与本科生有关的研究记录。这三个机构均制定了吸引传统代表性不足团体的学生和员工的政策。 Co-Pis致力于与这些学生合作，并将积极地吸引他们参加该研究项目，研讨会系列，期刊俱乐部和研究生级课程。该副研究有很强的记录记录，教育本科生和研究生，以及来自代表性不足的团体的博士后同伙。该研究的结果将通过档案期刊中的出版物，审计程序和会议的演讲将其传播给整个科学界。此外，基于网络的工作台开发肽/蛋白质的从头设计将首次为科学界提供服务。