Computational Design of Protein Structures and Complexes

联系PD/PI：Kuhlman，Brian A 项目概要/摘要 蛋白质设计是对我们对蛋白质结构和稳定性理解的严格测试，可用于创建 在研究和医学上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-蛋白质界面的设计，（2）从头蛋白质设计，和（3） 分子模拟程序Rosetta的开发。蛋白质-蛋白质相互作用对几乎所有 生物过程。我们在Rosetta中开发了新的自适应采样策略， 蛋白质结构域之间的相互作用表面不自然相互作用。我们将继续改进这一点 方法，同时测试它对不同的设计目标，如工程自动抑制域，以调节活动 抗癌治疗和增强酶的活性，通过纳入底物识别 域.我们的第二个重点领域是从头蛋白质设计，更具体地说，我们称之为 需求驱动的蛋白质设计，目标是创建与一组用户相匹配的折叠良好的蛋白质 明确的要求。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 叫做“缝纫”，它是从天然蛋白质中设计蛋白质的。我们将探索各种 SEWING的设计要求，包括配体结合位点和蛋白质相互作用的掺入 图案该项目的第三个集中领域是分子的改进和维护， 建模软件Rosetta。我们将继续开展旨在支持广大社区的长期活动 Rosetta的开发者和用户。这些措施包括运行罗塞塔“靴子营地”，教人们如何编码 在Rosetta环境中，并带头进行代码清理活动，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 这些方法将允许社区更好地利用GPU中的硬件进步。总之，由 通过这个项目，我们将扩大计算蛋白质设计的能力，并创造出 可以用来了解或治疗疾病。 第6页 项目概要/摘要

Contact PD/PI: Kuhlman, Brian A 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. Page 6 Project Summary/Abstract