现代化学生物学的研究中需要使用化学方法合成一些难以通过生物技术得到的蛋白质，包括翻译后修饰蛋白质和赋予人造功能的蛋白质。本项目拟围绕蛋白质化学合成展开研究，发展建立新一代蛋白质化学合成方法，力求大幅度提高蛋白质化学合成的效率，并产生自主知识产权的核心技术。以蛋白质化学合成新方法为基础，制备生物医学领域几类重要的蛋白质分子并研究其生物化学功能及机制，在检验化学方法的实用性同时，拓展蛋白质化学合成的应用研究。具体计划是：（1）发展建立新一代蛋白化学合成方法，克服目前蛋白合成存在的连接效率低、分离纯化困难等挑战；（2）化学合成含有翻译后修饰（多聚泛素化）、获取困难（膜蛋白）、以及具有人造功能的蛋白质（如同位素标记的蛋白、D-型蛋白质）；（3）使用化学合成的蛋白质研究阐明一些重要生物化学机制问题，例如去泛素化酶的选择性机制、泛素识别过程的分子机制、泛素链的动态结构等。

In the development of chemical biology, it is important to develop chemical methods to synthesize proteins with post-translational modifications or with artificial functionality. In the proposed project, we plan to carry out systematic studies on the development of next-generation methods for protein chemical synthesis. With the new methods in hand, we plan to synthesize important proteins and study their biochemical functions and mechanisms. Specifically,we plan to carry out the following studies: 1) Develop novel methods of protein chemical syntheis with the aim of improving ligation efficiency and purification yield; 2) Synthesize three types of target protein molecules including post-translationally modified proteins (e.g. polyubiquitinated proteins), difficult-to-obtain proteins (e.g. membrane proteins) and artificial functional proteins (e.g. isotope-labeled proteins and enantiomeric proteins); 3) Use chemically synthesized proteins to elucidate molecular mechanisms of important biological processes, such as linkage-selective deubiquitination, ubiquitin code identification, and structural dynamics of polyubiquitin chains.