Molecular Mimics of Protein Tertiary Folding from Primary Sequence Information

从一级序列信息模拟蛋白质三级折叠的分子模拟

• 批准号: 8558491
• 负责人: WILLIAM SETH HORNE
• 金额: $ 24.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8558491
• 关键词: 3-Dimensional; Address; Affinity; Amides; Amino Acid Sequence; Antimalarials; Apicomplexa; Bacterial Proteins; Bacteriophages; Base Sequence; Binding; Biological; Cell Surface Proteins; Cells; Chemistry; Complex; Data; Disease; Disease Progression; Elements; Event; Goals; Health; Human; Image; Indium; Infection; Lead; Life; Ligands; Malaria; Malignant Neoplasms; Membrane Proteins; Methods; Modeling; Modification; Molecular; Molecular Conformation; Outcome; Parasites; Pathway interactions; Pattern; Peptide Hydrolases; Peptide Sequence Determination; Peptides; Physiological; Prevalence; Protein Binding; Proteins; Reporting; Research; Resistance; Scaffolding Protein; Science; Side; Structure; Surface; Technology; Testing; Toxoplasmosis; Training; Vertebral column; Work; analog; base; design; frontier; in vivo; inhibitor/antagonist; innovation; mimicry; programs; protein folding; protein function; protein protein interaction; prototype; public health relevance; scaffold; stem; therapeutic target; tool; tumor

DESCRIPTION (provided by applicant): Inhibiting protein-protein binding interactions with designed molecules is a frontier challenge in biomedical science. Protein function is a direct result of 3-dimensional folded conformation. Thus, creating a molecule that mimics the function of a particular protein requires that the molecule manifest key structural features of the folded state of the prototype. Significant advances have been made in the mimicry of simple secondary structures; however, there is an unmet need for a design strategy capable of generating unnatural species that show the same complex tertiary folds as natural proteins. A long-term goal of research in the PI's lab is to invent a suite of tools for the design of natural protein analogues that manifest key structural and functional features of the prototype on scaffolds with enhanced folded and/or physiological stability. The overall objective of the present proposal is to develop a sequence-based method for the mimicry of protein tertiary folding by unnatural backbones and to apply this method to two biomedically significant targets where a tertiary fold is essential for function. The central hypothesis guiding the work is that any natural protein sequence can serve as the starting point for the design of its own unnatural analogue, provided systematic rules for backbone modification exist. The rationale motivating this work is that a general method for mimicry of protein tertiary folding by unnatural backbones that is truly sequence-based will open the possibility to address folds of arbitrary complexity. The central hypothesis will be tested through pursuit of three specific aims: (1) Establish design principles for sequence-based mimicry of protein tertiary folding by unnatural-backbone oligomers; (2) Develop a general method for the conversion of phage-derived affinity ligands to protease-resistant analogues and apply this method to create tumor imaging agents; (3) Design inhibitors of a conserved protein-protein interaction common to disease progression in malaria and toxoplasmosis. Expected outcomes of the proposed work include a general strategy for the design of protease-resistant species that manifest tertiary folding patterns of natural proteins, a paradigm to connect phage-based sequence selection to unnatural backbones, tumor imaging agents that recognize cancer-associated cell-surface proteins, and oligomers that target a common pathway in infection by malaria and other parasites. The significance of the research stems from the wealth of new functions that will become possible when complex tertiary folding patterns are accessible to unnatural backbones. The innovation of the proposed idea arises from addressing the important challenge of tertiary structure mimicry by a design approach that is sequence-based and generalizable to proteins beyond those discussed in the present proposal.

描述（由申请人提供）：抑制与设计分子的蛋白质 - 蛋白质结合相互作用是生物医学科学中的领域挑战。蛋白质功能是三维折叠构象的直接结果。因此，创建一个模拟特定蛋白质功能的分子要求该分子表现出原型折叠状态的关键结构特征。在简单的二级结构的模仿中取得了重大进展。但是，对于能够产生与天然蛋白质相同复杂的第三折叠的不自然物种的设计策略的需求未满足。 PI的实验室研究的长期目标是发明一套用于设计天然蛋白质类似物的工具，该工具在脚手架上表现出原型的关键结构和功能特征，并具有增强的折叠和/或生理稳定性。本提案的总体目标是 开发一种基于序列的方法，用于通过非天然骨架模仿蛋白质第三折叠的折叠，并将此方法应用于两个生物医学显着的靶标，而三级折叠对于功能至关重要。指导工作的中心假设是，任何天然蛋白质序列都可以作为设计其自然类似物的设计的起点，如果存在系统的骨干修饰规则。促使这项工作的基本原理是，通过不自然的骨架模仿蛋白质三级折叠的一般方法，这是真正基于序列的，将打开解决任意复杂性折叠的可能性。中心假设将通过追求三个特定目的来检验：（1）建立基于序列的模仿蛋白质三级折叠的设计原理； （2）开发一种通用方法，用于将噬菌体衍生的亲和力配体转化为抗蛋白酶的类似物，并应用此方法来创建肿瘤成像剂； （3）疟疾和弓形虫病中疾病进展的保守蛋白质蛋白相互作用的设计抑制剂。拟议作品的预期结果包括一种抗蛋白酶的物种设计的一般策略，该物种表现出天然蛋白的第三折叠模式，一种 将基于噬菌体的序列选择连接到不自然的骨架的范式，识别与癌症相关的细胞表面蛋白的肿瘤成像剂以及针对疟疾和其他寄生虫感染中常见途径的低聚物。研究的意义源于新功能的财富，当不自然的骨架可以访问复杂的三级折叠模式时，这些功能将成为可能。提出的思想的创新是通过通过一种基于序列的设计方法来解决三级结构的重要挑战而产生的，该设计方法基于序列，并且可以推广到本提案中讨论的蛋白质之外的蛋白质。