Exploring the Impact of Altered Backbone Composition on Protein Folding and Function

探索主链组成改变对蛋白质折叠和功能的影响

• 批准号: 10622073
• 负责人: WILLIAM SETH HORNE
• 金额: $ 30.37万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622073
• 关键词: Address; Area; Award; Behavior; Biological; Biomedical Research; Biomimetics; Characteristics; Chemicals; Complex; Development; Disease; Engineering; Goals; Laboratories; Life; Light; Mutagenesis; National Institute of General Medical Sciences; Nature; Pattern; Peptides; Production; Property; Proteins; Research; Structure; Tertiary Protein Structure; Vertebral column; Work; analog; biomacromolecule; design; functional group; mimetics; mimicry; programs; protein complex; protein folding; protein function; protein structure; prototype; public health relevance; scaffold; stem

PROJECT SUMMARY Proteins drive essential functions of life as well as aberrant functions in disease, making the development artificial molecules that mimic proteins a significant challenge in biomedical research. The problem of protein mimicry is rooted in the hierarchy that defines protein structure, where covalent connectivity gives rise to local folding motifs, unimolecular arrangements of such motifs, and multi-chain assemblies. The construction of sequence-specific oligomers with artificial backbones and defined folding propensities is a powerful approach to peptide and protein mimetics. Most precedent with such scaffolds has focused on isolated secondary structure. Creating more complex tertiary folding patterns presents a formidable challenge, as it requires the design of both backbone connectivity and side-chain sequence that will result in multiple biomimetic secondary structures that pack in a defined way in a single chain. Addressing this challenge has the potential to advance artificial protein-like chains toward the functional versatility of biomacromolecules. A unifying theme underlying research in the PI’s laboratory is the design, synthesis, and application of molecules that are inspired by proteins but expand beyond natural constraints of covalent connectivity. A major goal in this work, supported in prior awards from NIGMS, has been the development of strategies for producing protein tertiary structure mimetics from artificial bio-inspired backbones. The central hypothesis guiding this effort is that any protein can be treated as a chemical entity with two orthogonal sequences: one of side-chain functional groups and a second of backbone units that display those functional groups. Systematic engineering of backbone composition in a prototype sequence from nature can yield a heterogeneous-backbone analogue with similar fold and function. In work to date, design rules have been conceived for the construction of such agents, the impacts of altered composition on folding examined, and the functional potential of these molecules explored. The present application seeks to advance this program through continued effort across four complementary research areas. From a practical standpoint, artificial backbone composition can impart useful properties, such as enhanced biostability, and tune biological activity. In fundamental terms, changing backbone characteristics in ways not possible with traditional mutagenesis can further understanding of natural biomacromolecules. An important aspect of the concept underlying the research is that it addresses the problem of tertiary structure mimicry by an approach that is generalizable, as natural sequences serve as the starting point for design of their own mimics. Further, while the molecules are synthetic, the design principles are applicable in the context of new emerging approaches to biological production of protein-like artificial chains.

项目摘要 蛋白质推动生命的基本功能以及疾病的异常功能，使发展 模仿蛋白质的人工分子在生物医学研究中是重大挑战。蛋白质问题 模仿植根于定义蛋白质结构的层次结构，共价连通性产生了局部 折叠基序，此类基序的单分子排列和多链组件。构造 具有人工骨架和定义的折叠建议是一种强大的方法 给胡椒和蛋白质模拟物。这种脚手架的最先例已集中在孤立的次级上 结构。创建更复杂的三级折叠模式提出了巨大的挑战，因为它需要 骨干连通性和侧链序列的设计，这将导致多种仿生 以单个链中定义的方式包装的二级结构。解决这一挑战具有潜力 促进人造蛋白质的链条朝着生物大分子的功能多功能性。 PI实验室中的一个统一主题是设计，合成和应用 受蛋白质启发但超越共价连通性的自然约束的分子。一个 这项工作中的主要目标是NIGMS的先前奖项的支持，是制定策略的 由人工生物启发的骨架产生蛋白质三级结构。中心假设 指导这项工作是任何蛋白质都可以视为具有两个正交序列的化学实体：一个 侧链官能团和显示这些功能组的骨干单元的第二个。 来自自然的原型序列中骨干组成的系统工程可以产生 具有相似折叠和功能的异质 - 贝克骨类似物。迄今为止的工作，设计规则已经 构思为建造这种药物的构造，成分改变对折叠的影响，以及 这些分子的功能潜力探索了。本申请旨在推进此计划 通过在四个完整的研究领域的持续努力。 从实际的角度来 增强的生物稳定性和调整生物学活性。从基本的角度来看，改变骨干特征 传统诱变无法以可能的方式进一步理解天然的生物大分子。 该研究基础的概念的一个重要方面是它解决了第三级问题 通过一种可推广的方法模仿结构，因为自然序列是 他们自己的模仿的设计。此外，虽然分子是合成的，但设计原理适用于 新的新兴方法的背景是蛋白质样人造链的生物产生。