Rational Design of Complex Protein Functions by Modulation of Backbone Dynamics

蛋白质在研究、工业和医学中得到了广泛的应用，因为它们能够以极高的精度和效率调节复杂的分子过程。虽然人们通常认为蛋白质的功能是由其三维结构决定的，但越来越多的证据表明，溶液中随时间变化的结构波动(即动力学)对蛋白质的复杂功能是必不可少的。目前，合理地设计这些复杂的功能以满足工业和医学上日益增长的需求是非常具有挑战性的，因为我们缺乏预测将显示必要动态的蛋白质序列的方法。已经发展了计算蛋白质设计(CPD)技术来鉴定能够采用特定的三维结构并具有期望的属性的序列，例如增加的稳定性、改进的结合亲和力或改变的特异性。然而，标准的CPD方法评估单个固定蛋白质结构上的序列，这不允许显式地考虑动力学，从而阻碍了按需合理设计复杂的蛋白质功能。

Proteins have found widespread application in research, industry, and medicine because of their ability to mediate complex molecular processes with extreme precision and efficiency. While it is generally assumed that the function of a protein is dictated by its three-dimensional structure, increasing evidence demonstrates that time-dependent structural fluctuations in solution (i.e. dynamics) are essential to complex functions of proteins. Currently, it is extremely challenging to rationally design these complex functions to meet ever-growing needs in industry and medicine because we lack methods to predict protein sequences that will display the necessary dynamics. Computational protein design (CPD) techniques have been developed to identify sequences that can adopt a specific three-dimensional structure and possess a desired property such as increased stability, improved binding affinity, or altered specificity. However, standard CPD methods evaluate sequences on a single fixed protein structure, which does not allow for the explicit consideration of dynamics, thereby preventing the rational design of complex protein functions on demand.