Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA; UC Berkeley-UCSF Graduate Program in Bioengineering, University of California San Francisco, San Francisco, CA, USA.
Curr Opin Struct Biol. 2022 Feb;72:71-78. doi: 10.1016/j.sbi.2021.08.004. Epub 2021 Sep 16.
Protein switches perform essential roles in many biological processes and are exciting targets for de novo protein design, which aims to produce proteins of arbitrary shape and functionality. However, the biophysical requirements for switch function - multiple conformational states, fine-tuned energetics, and stimuli-responsiveness - pose a formidable challenge for design by computation (or intuition). A variety of methods have been developed toward tackling this challenge, usually taking inspiration from the wealth of sequence and structural information available for naturally occurring protein switches. More recently, modular switches have been designed computationally, and new methods have emerged for sampling unexplored structure space, providing promising new avenues toward the generation of purpose-built switches and de novo signaling systems for cellular engineering.
蛋白质开关在许多生物过程中发挥着重要作用,是从头设计蛋白质的激动人心的目标,旨在产生具有任意形状和功能的蛋白质。然而,开关功能的生物物理要求——多个构象状态、精细的能量学和刺激响应性——对计算(或直觉)设计构成了巨大的挑战。已经开发了多种方法来应对这一挑战,通常从大量现有的天然蛋白质开关的序列和结构信息中汲取灵感。最近,已经通过计算设计了模块化开关,并且出现了用于采样未探索结构空间的新方法,为用于细胞工程的定制开关和从头信号系统的生成提供了有前途的新途径。