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Computational design of new protein structures and interactions

新蛋白质结构和相互作用的计算设计

基本信息

批准号：
10396457
负责人：
Tanja Kortemme
金额：
$ 34.89万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396457
关键词：
Address Algorithms Amino Acids Behavior Benchmarking Binding Proteins Binding Sites Biological Biological Process Biology Biomedical Engineering Biomedical Research Biosensor Biotechnology Cell physiology Cells Chemicals Combinatorial Optimization Communities Complex Computing Methodologies Crystallization Custom Development Dimerization Disease Elements Engineering Environment Design Family Foundations Gene Expression Geometry Health Industrialization Intuition Knowledge Length Ligand Binding Ligands Manuals Medicine Methodology Methods Molecular Molecular Conformation Nature Production Protein Engineering Protein Fragment Proteins Regulation Research Scaffolding Protein Side Signal Transduction Signaling Molecule Signaling Protein Site Structure System Technology Testing Variant Vertebral column Work cancer therapy cell behavior data repository design improved innovation metabolic engineering neurotensin mimic 2 novel strategies novel therapeutics practical application protein function protein structure response scaffold sensor small molecule tool

项目摘要

PROJECT SUMMARY/ABSTRACT Computational design has immense potential to create new protein functions with applications in biotechnology, biology, and medicine. However, despite exciting progress in designing proteins with de novo structures, our ability to design proteins with new functions lags behind. A key reason for this discrepancy is that function typically requires protein geometries that deviate from the “idealized” folds of de novo designed structures and that are hence more difficult to design. The long-term objective of our work is to advance computational design to make predictive design of more complex functions possible. The specific objective of this proposal is to address the generally unsolved problem of designing proteins that bind new small molecule ligands. A particular application is the design of new sensor/actuators: proteins that can detect a user-defined small molecule signal and trigger a biological response (such as protein signaling or gene expression). Significant applications of such sensor/actuators include maximizing production of industrially valuable chemicals in metabolic engineering, creating precise tools for dissecting biological processes in cell signaling, and achieving tight regulation in emerging cancer therapies. Our work in the prior project period has advanced methods for binding site design and applied them to engineer the first computationally designed chemically-induced protein dimerization system, which senses and responds to a new ligand in living cells; a crystal structure confirmed the accuracy of the de novo designed binding site. Despite this key progress, there are significant barriers to generalize the approach. The first step in engineering new ligand binding sites is generally to identify desired binding site geometries (constellations of amino acid side chains coordinating the ligand). The second step is then to place those geometries into a suitable protein termed “scaffold”. This approach is critically limited by available geometries, both for binding sites and scaffolds to accommodate them. To address these problems, we propose two key methodological innovations: Aim 1 will establish and experimentally test a new computational method to generate millions of possible binding site geometries de novo that can be built into proteins. Aim 2 will develop and test a new computational approach to build “de novo fold families” (sets of custom-shaped de novo designed proteins) by systematically varying the geometries of structural elements within a given fold topology, to be used as scaffolds. Feasibility is supported by preliminary results for both aims; we have designed new binding sites (prior period), and have solved structures of 3 de novo designed proteins with the same fold but distinct geometries. The proposed studies innovate in creating both new methods and new molecules that expand designable structures and functions and overcome problems with current approaches limited by available geometries. Ultimately, these studies will lead to advanced computational design methods that we will make freely available, new knowledge on strengths and limitations of these methods to drive further developments, and new tools to control cellular behavior in biological engineering and to probe basic and disease biology.

项目总结/摘要计算设计具有创造新蛋白质功能的巨大潜力，可应用于生物技术，生物学和医学。然而，尽管在设计具有从头结构的蛋白质方面取得了令人兴奋的进展，设计具有新功能的蛋白质的能力落后。这种差异的一个关键原因是，通常需要偏离从头设计结构的“理想化”折叠的蛋白质几何形状，因此更难设计。我们工作的长期目标是推进计算设计使更复杂功能的预测设计成为可能。这项建议的具体目标是解决了设计结合新的小分子配体的蛋白质的通常未解决的问题。特定应用是设计新的传感器/执行器：可以检测用户定义的小分子信号的蛋白质并触发生物反应（如蛋白质信号或基因表达）。重要应用这样的传感器/致动器包括在代谢工程中最大限度地生产工业上有价值的化学品，创造了精确的工具，用于解剖细胞信号传导中的生物过程，并实现了细胞信号传导的严格调控。新兴的癌症疗法。我们在前期的工作中有着先进的装订场地设计方法并将其应用于第一个计算机设计的化学诱导蛋白质二聚化系统，它能感知活细胞中的一种新配体并对其作出反应;晶体结构证实了这种检测的准确性。 novo设计的结合位点。尽管取得了这一关键进展，但推广这一方法仍存在重大障碍。工程化新配体结合位点的第一步通常是鉴定所需的结合位点几何形状（配位配体的氨基酸侧链的星座）。第二步是将这些几何形状转变成合适的蛋白质，称为“支架”。这种方法受到可用几何形状的严重限制，用于结合位点和容纳它们的支架。为了解决这些问题，我们提出了两个关键方法创新：目标1将建立并实验测试一种新的计算方法，从头产生数百万种可能的结合位点几何形状，可以构建到蛋白质中。Aim 2将开发并测试一种新的计算方法，以建立“从头折叠家庭”（一套定制形状的从头设计，通过系统地改变给定折叠拓扑结构内的结构元件的几何形状，作为脚手架。两个目标的初步结果支持可行性;我们设计了新的结合位点（前期），并解决了3个从头设计的蛋白质的结构，具有相同的折叠，但不同几何学拟议中的研究在创造新方法和新分子方面进行了创新，可设计的结构和功能，并克服现有方法的问题，几何学最终，这些研究将导致先进的计算设计方法，我们将使免费提供关于这些方法的优势和局限性的新知识，以推动进一步发展，以及在生物工程中控制细胞行为和探索基础和疾病生物学的新工具。