Abstract:

In computational protein design， the amino acid sequence of a protein is rationally chosen through computations so that the resulting molecule is of desired structure and function. Systematic methods for computational protein design have been developed and validated in increasing number of experiments. Exhibiting strong potential for broad applications， computational protein design has been considered as an important enabling technology for Synthetic Biology. Here we briefly review the history of methods for computational design， which are divided into three sections about heuristic design that based on rules， automatic optimization of amino acid sequences， and de novo main chain design respectively. In the next chapter， we introduce the basic approaches and strategies in details. In proteins energy calculation methods， we introduce physical energy terms and statistical energy terms. Based on these energy calculation methods， we introduce sequence and structure design methods including automated optimization of amino acid sequences， de novo design of polypeptide backbones （with fragment assembling method or sequence independent backbone potentials）， designing new interfaces for inter-molecule recognition such as protein-ligand interfaces and protein-protein interfaces， and the concept of negative design. Besides the history and detail of computational protein design methods that mentioned above， we also briefly discuss examples of using computational protein design to support application studies， including enhancing protein structural stability and redesign or de novo design of enzymes， vaccines and protein materials that related to interfaces design. These examples not only present current studies using the computational protein design methods， but also enlighten us on more broader applications in the future. Finally， we analyze some problems that need to be solved in the protein computational design method， such as inefficient in design accuracy， difficulty in characterizing polar interactions， and the need to consider the environment of non-aqueous solvents. We also discuss some aspects of possible application in synthetic biology like biological logic gates design and biosensor design， and application prospects in the medical field such as antibodies， vaccine design， etc.

Key words: protein, methods for computational design, amino acid sequences, polypeptide backbone structure, interface of intermolecular recognition

摘要：

蛋白质计算设计是指通过计算理性地确定蛋白质的氨基酸序列，实现预设的结构和功能。蛋白质计算设计已逐渐形成了一套系统的方法，得到越来越多的实验验证。这些方法既可用于从头设计蛋白，也可以用于既有蛋白的理性改造，具有广泛应用前景，是合成生物学的重要使能技术之一。本文简要回顾蛋白质计算设计方法的历史，并从蛋白质能量计算方法、氨基酸序列自动优化、从头设计主链结构、设计新的分子间识别界面以及负设计等方面介绍蛋白质计算设计的基本方法和思路，还举例讨论了提高结构稳定性、构造新的分子界面等设计方法在酶、疫苗、自组装蛋白质材料等领域的应用，最后分析了蛋白质计算设计方法设计精度不足、难刻画极性相互作用的缺点以及需要考虑非水溶剂环境、界面设计优化等亟待解决的问题，展望了蛋白质计算设计方法未来在合成生物学领域如生物感受器、逻辑门设计等，医学领域如抗体、疫苗设计等的应用前景。

关键词: 蛋白质, 计算设计方法, 氨基酸序列, 多肽主链结构, 分子间识别界面