Computational Design of Protein Structures and Complexes

蛋白质结构和复合物的计算设计

• 批准号: 10433948
• 负责人: BRIAN A KUHLMAN
• 金额: $ 79.13万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433948
• 关键词: Area; Binding Proteins; Binding Sites; Biological Process; Code; Communities; Computer software; Computers; Computing Methodologies; Development; Disease; Engineering; Environment; Goals; Ligand Binding; Maintenance; Medicine; Methods; Nature; Persons; Protein Engineering; Proteins; Reagent; Research; Running; Sampling; Sum; Surface; Tertiary Protein Structure; Testing; Therapeutic; anti-cancer therapeutic; anticancer activity; base; design; enzyme activity; improved; molecular modeling; novel strategies; programs; protein complex; protein folding; protein protein interaction; protein structure

Project Summary/Abstract Protein design is a rigorous test of our understanding of protein structure and stability and can be used to create proteins that have important applications in research and medicine. This project focuses on three topics in computer-based protein design: (1) the design of protein–protein interfaces, (2) de novo protein design, and (3) development of the molecular modeling program Rosetta. Protein–protein interactions are essential to almost all biological processes. We have developed new adaptive sampling strategies within Rosetta for designing interaction surfaces between protein domains that do not naturally interact. We will continue to improve this method while testing it on diverse design goals such as engineering autoinhibitory domains to regulate the activity of anti-cancer therapeutics and enhancing enzyme activity via the incorporation of substrate recognition domains. Our second area of focus is de novo protein design, and more particularly, an approach that we call requirement-driven protein design, in which the goal is to create well-folded proteins that match a set of user- defined requirements. To perform requirement-driven protein design, we have created a computational method called SEWING for designing proteins from pieces of naturally occurring proteins. We will explore a variety of design requirements with SEWING, including the incorporation of ligand-binding sites and protein interaction motifs. The third area of concentration for this project is the improvement and maintenance of the molecular modeling software Rosetta. We will continue long-standing activities aimed at supporting the large community of Rosetta developers and users. These include running Rosetta “boot camps” that teach people how to code in the Rosetta environment and spearheading code-cleanup activities to improve the extensibility of the software. In addition, we will develop new approaches for rapidly calculating the energy of a protein and create core methods that will allow the community to take better advantage of hardware advances in GPUs. In sum, by pursuing this project, we will expand the capabilities of computational protein design and create molecules that can be used to understand or treat disease.

项目摘要/摘要 蛋白质设计是对我们对蛋白质结构和稳定性的理解的严格测试，可用于创建 在研究和医学中具有重要应用的蛋白质。该项目侧重于三个主题 基于计算机的蛋白质设计：（1）蛋白质 - 蛋白界面的设计，（2）从头蛋白质设计和（3） 分子建模程序Rosetta的开发。蛋白质 - 蛋白质相互作用对于几乎所有人都是必不可少的 生物过程。我们已经在Rosetta中开发了新的自适应抽样策略来设计 不自然相互作用的蛋白质结构域之间的相互作用表面。我们将继续改善这一点 在对潜水员设计目标（例如工程自动抑制域）进行测试时的方法以调节活动 通过融合底物识别的抗癌治疗和增强酶活性 域。我们的第二个重点是从头蛋白质设计，尤其是我们称之为一种方法 需求驱动的蛋白质设计，其目标是创建折叠良好的蛋白质，使一组用户与 定义的要求。为了执行需求驱动的蛋白质设计，我们创建了一种计算方法 被称为缝制用于设计自然存在的蛋白质碎片的蛋白质。我们将探索各种各样的 缝纫的设计要求，包括结合配体结合位点和蛋白质相互作用 主题。该项目的第三个浓度区域是分子的改进和维护 建模软件Rosetta。我们将继续旨在支持大型社区的长期活动 Rosetta开发人员和用户。其中包括运行Rosetta“新兵训练营”，这些“新兵训练营”教人们如何编码 在Rosetta环境和率先进行代码清洁活动，以提高软件的可扩展性。 此外，我们将开发新的方法来快速计算蛋白质的能量并创建核心 可以使社区更好地利用GPU中硬件进步的方法。总而言之 追求这个项目，我们将扩展计算蛋白设计的功能，并创建分子 可用于理解或治疗疾病。