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 蛋白质驱动生命的基本功能以及疾病中的异常功能， 模拟蛋白质的人工分子是生物医学研究中的一个重大挑战。蛋白质的问题 模仿植根于定义蛋白质结构的层次结构中，其中共价连接产生局部 折叠基序、这种基序的单分子排列和多链组装。建设 具有人工骨架和确定的折叠倾向的序列特异性寡聚体是一种有效的方法 肽和蛋白质模拟物。这种支架的大多数先例都集中在孤立的继发性 结构创造更复杂的三级折叠模式是一个巨大的挑战，因为它需要 骨架连接和侧链序列的设计，这将导致多个仿生 以特定方式组装成单链的二级结构。应对这一挑战有可能 将人工蛋白质样链推向生物大分子的功能多样性。 PI实验室研究的一个统一主题是设计，合成和应用 这些分子受到蛋白质的启发，但却超越了共价连接的自然限制。一 这项工作的主要目标是制定战略， 从人工生物启发的主链生产蛋白质三级结构模拟物。核心假设 指导这一努力的是，任何蛋白质都可以被视为具有两个正交序列的化学实体： 侧链官能团和显示这些官能团的第二骨架单元。 对来自自然界的原型序列中的骨架组成进行系统工程改造可以产生一种新的生物学方法。 具有相似折叠和功能异质骨架类似物。在迄今为止的工作中， 设想的建设这样的代理人，影响改变组成折叠检查，和 探索这些分子的功能潜力。本申请寻求推进该程序 通过在四个互补研究领域的持续努力。 从实践的角度来看，人造主链组合物可以赋予有用的性质，例如 增强生物稳定性，调节生物活性。从根本上说，改变骨干特征 以传统诱变不可能的方式，可以进一步了解天然生物大分子。 这项研究所依据的概念的一个重要方面是，它解决了高等教育的问题。 结构模仿的方法是普遍的，作为自然序列作为出发点， 设计自己的模仿者。此外，虽然分子是合成的，但设计原理适用于 新出现的蛋白质样人工链生物生产方法的背景。