Design of hierarchical recognition motifs

我们建议在特拉华州大学（UD）建立一个卓越的生物医学研究中心（COBRE）：设计的l-lierabieal识别基序。该中心的研究方向旨在开发识别元件，包括从小分子到蛋白质到中尺度组件的结构控制的原子级相互作用。将开发新的设计范例，用于研究小分子-蛋白质相互作用，膜环境中的蛋白质组装，人工糖蛋白支架的构建以显示多价识别基序，以及基于肽的生物材料的制备，其结构和功能对环境线索有响应。将寻求新的合成方法来制备非天然氨基酸，用于掺入蛋白质中以赋予独特的结构和功能。拟议的COBRE中心将建立一个专业知识库， 适当的基础设施，将解决生物医学问题，确定分子设计原则，承担有关的问题，识别功能的生物分子和合成能力，以控制分子拓扑结构。将开展五个分项目，其中包括基础研究和应用研究。所有这些项目都需要关于结构基序相互作用的详细信息。这些基序的范围从特征性的大分子表面、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，并进一步了解生物分子识别。这些项目的名称是：小分子（Z-螺旋模拟物; II.具有环境敏感形态的肽基生物材料; III.用于合成非天然氨基酸的应变分子; IV。人工糖蛋白结构在材料和生物学中的应用，以及V.完整膜蛋白的稳定性和组装的决定因素。这些项目是由化学和生物化学系（DCB）和材料科学与工程系（MSEG）最近聘请的终身助理教授提出的。一般而言，项目一和项目五是结构生物学领域，项目二和项目四是通过材料进行生物工程。项目III通过开发用于制备非天然氨基酸的新合成方法来补充这两个一般领域，这些方法将引起新的蛋白质结构和功能特征。重要的是，拟议中的中心将有助于 将新成立的材料科学与工程系以及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令中。 此外，该中心不仅将有力地补充NIH发起的蛋白质结构倡议（PSI），还将补充校园和周边机构的其他生物医学研究工作。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州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.