School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK.
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK; School of Biochemistry, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK; BrisSynBio, University of Bristol, Life Sciences Building, Tyndall Avenue, Bristol BS8 1TQ, UK.
Curr Opin Chem Biol. 2019 Oct;52:102-111. doi: 10.1016/j.cbpa.2019.06.011. Epub 2019 Jul 20.
Our ability to design completely de novo proteins is improving rapidly. This is true of all three main approaches to de novo protein design, which we define as: minimal, rational and computational design. Together, these have delivered a variety of protein scaffolds characterised to high resolution. This is truly impressive and a major advance from where the field was a decade or so ago. That all said, significant challenges in the field remain. Chief amongst these is the need to deliver functional de novo proteins. Such designs might include selective and/or tight binding of specified small molecules, or the catalysis of entirely new chemical transformations. We argue that, whilst progress is being made, solving such problems will require more than simply adding functional side chains to extant de novo structures. New approaches will be needed to target and build structure, stability and function simultaneously. Moreover, if we are to match the exquisite control and subtlety of natural proteins, design methods will have to incorporate multi-state modelling and dynamics. This will require more than black-box methodology, specifically increased understanding of protein conformational changes and dynamics will be needed.
我们设计全新蛋白质的能力正在迅速提高。这适用于我们定义的三种全新蛋白质设计主要方法：最小化设计、理性设计和计算设计。这些方法共同提供了各种高分辨率的蛋白质支架。这确实令人印象深刻，是该领域在十年前左右的重大进展。尽管如此，该领域仍然存在重大挑战。其中最重要的是需要提供具有全新功能的蛋白质。此类设计可能包括对特定小分子的选择性和/或紧密结合，或催化全新的化学转化。我们认为，尽管正在取得进展，但要解决此类问题，仅仅向现有全新结构添加功能性侧链是不够的。需要新的方法来同时靶向和构建结构、稳定性和功能。此外，如果我们要与天然蛋白质的精密控制和微妙性相匹配，设计方法将必须包含多态建模和动力学。这将需要不仅仅是黑盒方法，还需要具体地增加对蛋白质构象变化和动力学的理解。
