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的前沿挑战。蛋白质功能是三维折叠构象的直接结果。因此，创造一种模拟特定蛋白质功能的分子需要该分子表现出原型折叠状态的关键结构特征。在简单二级结构的模拟方面已经取得了重大进展;然而，对于能够产生显示与天然蛋白质相同的复杂三级折叠的非天然物种的设计策略存在未满足的需求。PI实验室的长期研究目标是发明一套用于设计天然蛋白质类似物的工具，这些天然蛋白质类似物在具有增强的折叠和/或生理稳定性的支架上表现出原型的关键结构和功能特征。本提案的总体目标是 开发一种基于序列的方法，通过非天然骨架模拟蛋白质三级折叠，并将这种方法应用于两个生物医学上重要的靶标，其中三级折叠对功能至关重要。指导这项工作的中心假设是，任何天然蛋白质序列都可以作为设计其自身非天然类似物的起点，只要存在骨架修饰的系统规则。激发这项工作的基本原理是，一种真正基于序列的非天然骨架模拟蛋白质三级折叠的通用方法将为解决任意复杂性的折叠提供可能性。本论文将通过三个具体目标来验证中心假设：（1）建立基于序列的非天然骨架寡聚体模拟蛋白质三级折叠的设计原则;（2）开发将噬菌体衍生的亲和配体转化为蛋白酶抗性类似物的通用方法，并将该方法应用于肿瘤显像剂的制备;（3）设计疟疾和弓形虫病疾病进展中常见的保守蛋白质-蛋白质相互作用的抑制剂。拟议工作的预期成果包括设计蛋白酶抗性物种的一般策略，这些物种表现出天然蛋白质的三级折叠模式， 这是一种将基于噬菌体的序列选择与非天然骨架、识别癌症相关细胞表面蛋白的肿瘤成像剂以及靶向疟疾和其他寄生虫感染中的共同途径的寡聚体连接起来的范例。这项研究的重要性源于丰富的新功能，当复杂的三级折叠模式可以被非自然主链所利用时，这些功能将成为可能。所提出的想法的创新源于解决三级结构模拟的重要挑战，通过基于序列的设计方法，该方法可推广到本提案中讨论的蛋白质之外。