Synthesis and Applications of functional Macromolecules

描述（由申请人提供）：大自然依赖于蛋白质和催化RNA形式的结构大分子，这些大分子折叠成特定的三维结构，并在精确的星座中呈现反应功能，以进行生命的化学过程。这些分子的结构性质以及我们从蛋白质中了解到的结构/功能关系表明，如果有能力构建大分子并控制它们的三维结构，我们可以开发具有仿生能力和全新化学功能的大分子。我们的目标是开发一种新的基础技术，用于合成具有设计三维形状的大分子，并能够以可控的方式呈现多个化学反应基团，以执行新功能。我们的方法是合成小而坚硬的分子构建块（双氨基酸），并通过对酰胺键将它们偶联以创建阶梯低聚物。每个单体包含多个立体中心，这些立体中心是在构建块合成中设置的。双氨基酸在固体载体上或溶液中以特定的顺序组装，形成具有特定结构的精确大分子。我们提出以下具体目标。1)我们将利用我们的原型单体合成几种具有有趣结构的支架，并确定它们的结构。2)我们将测量线性和弓形脚手架的柔韧性。3)我们将开发其他单体的合成。4)我们将合成具有与蛋白质活性位点相当尺寸的空腔的大分子，并确定其结构。5)我们将发现选择性结合这些腔体和支架的肽，并通过结构测定和结合自由能的测量来表征相互作用。6)我们将开发双氨基酸的合成，显示一个类似于氨基酸侧链的附加官能团。7)我们将开发一种通用方法来设计具有仿生功能的复杂官能团阵列，并可用于纳米级分子器件的开发。

DESCRIPTION (provided by applicant): Nature relies on structured macromolecules in the form of proteins and catalytic RNA's that fold into specific three-dimensional structures and present reactive functionality in precise constellations in order to carry out the chemical processes of life. The structured nature of these molecules and what we have learned from proteins about structure/function relationships suggests that given the ability to construct macromolecules and control their three-dimensional structures, we could develop macromolecules with biomimetic capabilities and with entirely new chemical functions. Our goal is to develop a novel, basic technology for synthesizing macromolecules with designed three-dimensional shapes and capable of presenting multiple chemically reactive groups in controlled ways to perform new functions. Our approach is to synthesize small, rigid molecular building blocks (bis-amino acids) and couple them through pairs of amide bonds to create ladder oligomers. Each monomer contains multiple stereocenters that are set in the building block synthesis. The bis-amino acids are assembled on solid support, or in solution, in specific sequences to form constitutionally precise macromolecules with specific structures. We propose the following specific goals. 1) We will utilize our prototype monomer to synthesize several scaffolds with interesting structures and determine their structures. 2) We will measure the flexibility of linear and bow-shaped scaffolds. 3) We will develop syntheses of additional monomers. 4) We will synthesize macromolecules that display cavities with dimensions comparable to those of protein active sites and determine their structures. 5) We will discover peptides that selectively bind these cavitand scaffolds and characterize the interaction through structure determination and measurement of binding free energies. 6) We will develop syntheses for bis-amino acids that display an additional functional group akin to the side chain of an amino acid. 7) We will develop a general approach to the design of complex functional group arrays that are capable of biomimetic function and could be used for the development of nanoscale molecular devices.