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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

基本信息

批准号：
10330991
负责人：
WILLIAM SETH HORNE
金额：
$ 30.4万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10330991
关键词：
3-Dimensional Address Amino Acids Architecture Award Bee Venoms Behavior Binding Biological Biomimetics Catalysis Cell membrane Characteristics Complex DNA DNA Binding DNA-Binding Proteins Development Disulfides Goals Infection Insecta Ion Channel Life Light Membrane Metals Methods Molecular Nature Outcome Pattern Physiological Progress Reports Property Proteins Reporting Reptiles Research Side Signal Transduction Structure System Tarantula Venoms Technology Tertiary Protein Structure Testing Variant Venoms Vertebral column Work Zinc Fingers analog base biological systems biomacromolecule chronic pain management constriction design frontier inhibitor insight instrument microbial mimetics mimicry molecular recognition programs protein complex protein folding protein function protein structure prototype public health relevance scaffold self assembly stem synthetic protein

项目摘要

PROJECT SUMMARY Proteins are the central functional instruments that enable life, and the development of strategies for protein mimicry is a grand challenge for chemists. Artificial backbones with defined folding propensities, termed “foldamers”, can offer biostable analogues of natural entities; however, challenges related to design create barriers to mimicking complex tertiary folds. Overcoming this barrier promises to open a new frontier and advance foldamers toward the functional versatility of proteins. With support from the initial award, a general method for creating foldamer tertiary structure was developed based on the systematic alteration of backbone covalent structure in natural sequences. An important gap remains in establishing the ability of these mimetics to reproduce and modulate functional properties of prototype proteins on which they are based. A long-term goal of the PI’s research program is to develop principles for the design of artificial backbones capable of reproducing the full panoply of protein folds and functions in nature and to apply these principles to control properties such as folded structure, folded stability, physiological stability, and dynamics. The overall objective of this renewal application is to demonstrate the scope of functions possible in heterogeneous-backbone foldamer tertiary structure mimetics. The central hypothesis guiding this work is that design principles developed in the initial award period can be applied to produce functional analogues of diverse prototype proteins and also used to tune functional characteristics of the native backbone. The rationale for pursuing the proposed research is that pushing beyond structural mimicry to functional mimicry in protein-inspired artificial scaffolds will hone design principles, create valuable bioactive agents, and shed new light on natural systems. In order to test the above central hypothesis, two specific aims will be pursued: (1) develop mimics of zinc finger proteins with native-like molecular recognition characteristics; (2) create mimics of disulfide-rich domains from insect and reptile venoms. In terms of expected outcomes, the proposed work will (1) expand the scope of foldamer tertiary structure mimicry (complex chain topologies, large multidomain proteins); (2) broaden the functional repertoire of these scaffolds (selective recognition of DNA, proteins, and biological membranes); (3) yield new insights into the dynamics of sequence-specific DNA binding by zinc finger proteins; and (4) provide a starting point toward bioactive agents with potential applications in the management of chronic pain and treatment of microbial infections. Collectively, realization of the goals of the project will lead to a vertical advance in the size, structural complexity, and functional diversity possible in synthetic protein mimetics.

项目概要蛋白质是维持生命的核心功能工具，也是制定生命策略的核心工具。蛋白质模拟对化学家来说是一个巨大的挑战。具有明确折叠倾向的人造脊椎，称为“foldamers”，可以提供自然实体的生物稳定类似物；然而，与设计相关的挑战为模仿复杂的三级褶皱制造障碍。克服这一障碍有望开辟新领域并使折叠分子朝着蛋白质功能多功能性的方向发展。在最初奖项的支持下，创建foldamer三级结构的通用方法是基于自然序列中主链共价结构的系统改变而开发。一个在确定这些模拟物复制和调节功能的能力方面仍然存在重要差距它们所基于的原型蛋白质的特性。 PI 研究计划的长期目标是制定能够复制全部蛋白质的人工骨架的设计原则自然界中的折叠和功能，并应用这些原理来控制折叠结构等特性，折叠稳定性、生理稳定性和动力学。此续签申请的总体目标是展示异质骨干折叠体三级结构中可能的功能范围模仿者。指导这项工作的中心假设是最初奖项中制定的设计原则周期可用于生产多种原型蛋白的功能类似物，也可用于调节原生主干的功能特征。进行拟议研究的理由是在蛋白质启发的人造支架中超越结构模仿到功能模仿将得到磨练设计原理，创造有价值的生物活性剂，并为自然系统提供新的视角。为了检验上述中心假设，我们将追求两个具体目标：（1）开发具有类似天然分子识别特征的锌指蛋白； (2) 创建富含二硫键的模拟物昆虫和爬行动物毒液的域。就预期成果而言，拟议的工作将（1）扩大foldamer第三级的范围结构拟态（复杂链拓扑、大型多结构域蛋白质）； (2)拓宽功能这些支架的全部功能（DNA、蛋白质和生物膜的选择性识别）； (3)产量对锌指蛋白序列特异性 DNA 结合动力学的新见解； (4) 提供生物活性剂的起点，在慢性疼痛的治疗和治疗中具有潜在的应用微生物感染的治疗。总的来说，项目目标的实现将导致垂直合成蛋白质模拟物的大小、结构复杂性和功能多样性方面取得了进展。