The Topology of Peptide/Protein Interaction Space

在高通量、基于阵列的多肽合成方面的最新进展使生成多肽/蛋白质相互作用空间的详细地图成为可能。这样的图谱将被创建用于17个氨基酸多肽与四种特定蛋白质的相互作用。这张图将帮助以精确的方式定义多肽的一级结构(氨基酸序列)如何与其结合特定蛋白质的能力相关。这对于我们理解分子识别(一种分子识别另一种分子的能力)至关重要。分子识别是生物化学几乎所有方面(结合、催化等)的关键要素。理解如何根据分子结构预测分子识别将使无数的实际应用得以实现。用于实现这一点的技术在许多方面都是革命性的。它是由DNA芯片行业的先驱们开发的一种合成方法发展而来的。DNA芯片是通过在有序阵列的玻璃片上一次合成多达数百万种不同的DNA寡核苷酸来制造的。英特尔已经调整和改进了这一工艺，使其与他们的电子芯片制造平台兼容。这使得在硅片上制作多肽成为可能，其分辨率接近图案化电子元件的分辨率(约200纳米)。高密度允许创建多达数亿个多肽的文库。它还允许在电子设备上直接制造多肽，这将为直接电子/生化接口打开大门。广泛影响这项技术的发展对化学、生物化学和生物学具有深远的影响。多肽配体作为生物传感器系统的一部分，用于环境和工业监测，以及作为基础生物学研究的特定分子探针，引起了人们的极大兴趣。除此之外，这种方法的化学比仅仅是多肽化学要普遍得多。事实上，在这些表面上可以制造各种各样的分子，这使得除了肽空间之外还可以探索许多其他的化学空间。这对新催化剂的开发、化学反应的优化、新材料的开发以及与电子器件的分子接口都有明显的意义。该项目还将包括一名博士后研究员，促进该人的职业生涯，并使他/她成为这一发展中领域的领导者。此外，博士后还将在暑期指导一对高中教师/高中生，传授对科学的普遍理解的热情。

Recent advances in high throughput, array-based synthesis of peptides make it possible to generate a detailed map of peptide/protein interaction space. Such a map will be created for the interaction of 17-amino acid peptides with four specific proteins. This map will help define in a precise way how the primary structure (amino acid sequence) of a peptide relates to its ability to bind a specific protein. This is of fundamental importance to our understanding of molecular recognition (the ability of one molecule to specifically recognize another). Molecular recognition is a key element in all almost aspects of biochemistry (binding, catalysis, etc.) and an understanding of how to predict molecular recognition based on the structure of a molecule will empower myriad practical applications.The technology that will be used to accomplish this is in many respects revolutionary. It has grown out of a type of synthetic approach developed by the pioneers of the DNA chip industry. DNA chips are made by synthesizing up to millions of different DNA oligonucleotides at a time on a glass slide in an ordered array. Intel has adapted and improved this process so that it is compatible with their platform for electronic chip manufacturing. This makes it possible to pattern the production of peptides on a silicon wafer with a resolution approaching that of patterned electronic components (on the order of two hundred nanometers). The high density allows the creation of libraries with up to hundreds of millions of peptides. It also allows the fabrication of peptides directly on electronic devices which will open the door for direct electronic/biochemical interfaces.Broader ImpactsThe development of this technology has far reaching implications for chemistry, biochemistry and biology. There is a huge interest in peptide ligands as parts of biosensor systems used in environmental and industrial monitoring and as specific molecular probes for fundamental biological research. Beyond that, the chemistry of this approach is much more general than just peptide chemistry. In fact, a large variety of molecules can be made on these surfaces, allowing the exploration of many other chemical spaces besides peptide space. This has clear implications for the development of new catalysts, the optimization of chemical reactions, the development of new materials, and molecular interfaces with electronics devices. This project will also involve a postdoctoral fellow, advancing that individual's career and preparing him/her as a leader in this developing field. In addition, the postdoc will mentor a high school teacher/high school student pair during the summer, passing on enthusiasm for a general understanding of science.