Design of hierarchical recognition motifs

我们建议在特拉华大学(UD)建立一个生物医学研究卓越中心(COBRE)：设计L-腹部识别主题。该中心内的研究指令旨在开发包含原子级相互作用的识别元件，以实现从小分子到蛋白质再到中尺度组装的结构控制。新的设计范式将被开发用于研究小分子-蛋白质相互作用，膜环境中的蛋白质组装，构建展示多价识别基序的人造糖蛋白支架，以及制备其结构和功能对环境线索响应的多肽生物材料。人们将寻求新的合成方法来制备非天然氨基酸，并将其融入蛋白质中，以赋予其独特的结构和功能。拟建的科布雷中心将建立一个专业基础， 适当的基础设施，将通过确定与生物分子的识别功能和控制分子拓扑的合成能力有关的分子设计原则来解决生物医学问题。将执行五个子项目，包括基础研究部分和应用研究部分。所有这些项目都需要关于结构主题相互作用的详细信息。这些基序的范围从特有的大分子表面、结构域和支架到特定氨基酸侧链残基的功能意义。重要的是，在每个单独项目中建立的设计原则可以应用于所有项目，以增强当前的设计策略，并进一步加深对生物分子识别的一般理解。这些项目的标题是：I.小分子(z-螺旋模拟；ii.具有环境敏感形态的多肽生物材料；伊利诺伊州。用于合成非天然氨基酸的应变分子；IV.在材料和生物学中应用的人造糖蛋白结构；V.整膜蛋白的稳定性和组装的决定因素。这些项目是由化学与生物化学系(DCB)和材料科学与工程系(MSEG)最近聘用的终身教职助理教授提出的。一般而言，项目I和项目V属于结构生物学领域，项目II和项目IV属于通过材料进行生物工程。项目III通过开发新的合成方法来制备非天然氨基酸，从而补充了这两个一般领域，这些非天然氨基酸将产生新的蛋白质结构和功能特征。重要的是，拟建的中心将有助于 将新成立的材料科学与工程系和化学与生物化学系的有机部门整合到大学内与生物医学相关的研究指导中。此外，该中心不仅将有力地补充美国国立卫生研究院发起的蛋白质结构倡议(PSI)，还将有力地补充校园和周边机构的其他生物医学研究努力。作为Cobre的一部分，将提供的核心设施将加强目前在校园内建立的设施，并有助于加强特拉华大学的所有生物医学研究工作。

We propose to establish a Center of Biomedical Research Excellence (COBRE) at the University of Delaware (UD): Design of l-Iierarebieal Recognition Motifs. Research directives within this center are aimed at developing recognition elements that encompass atomic-level interactions for structural control from small molecules to proteins to mesoscale assemblies. Novel design paradigms will be developed for the study of small molecule-protein interactions, protein assembly in membrane environments, the construction of artificial glycoprotein scaffolds to display multivalent recognition motifs, and the preparation of peptide-based biomaterials whose structures and functions are responsive to environmental cues. Novel synthetic methodology will be pursued to prepare non-natural amino acids for incorporation into proteins to impart unique structure and function. The proposed COBRE center will create an expertise base with appropriate infrastructure that will address biomedical questions by identifying molecular design principles that bear on questions related to the recognition function of biomolecules and the synthetic capability to control molecular topology. Five subprojects will be carried out that incorporate both fundamental and applied research components. All of these projects require detailed information about the interplay of structural motifs. These motifs range from characteristic macromolecular surfaces, domains, and scaffolds to the functional significance of specific amino acid side chain residues. Importantly, design principles established within each individual project can be applied across all of the projects to enhance current design strategies and further the general understanding of biomolecular recognition. The titles of these projects are: I. Small Molecule (z-helix Mimics; II. Peptide-based Biomaterials with Environmentally Sensitive Morphologies; Ill. Strained Molecules for the Synthesis of Unnatural Amino Acids; IV. Artificial Glycoprotein Architectures for Applications in Materials and Biology and V. Determinants of Stability and Assembly of Integral Membrane Proteins. These projects are proposed by recently hired, tenure-track assistant professors in the Department of Chemistry and Biochemistry (DCB) and the Department of Materials Science and Engineering (MSEG). Broadly speaking, projects I and V are in the area of structural biology, and II and IV are in bioengineering through materials. Project III complements these two general areas by developing novel synthetic methodology for the preparation of non-natural amino acids that will elicit new protein structural and functional features. Importantly, the proposed center will serve to integrate the newly established Materials Science and Engineering department and the Organic division of the Chemistry and Biochemistry department into biomedical-related research directives within the University. In addition, this Center will strongly complement not only the Protein Structure Initiative (PSI) launched by the NIH, but also other biomedical research efforts on campus and surrounding institutions. Core facilities to be provided as part of this COBRE will enhance those currently being established on campus and serve to strengthen all of the biomedical research efforts at the University of Delaware.