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.

中文翻译：

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致力于从头设计的蛋白质。

我们设计完全从头蛋白质的能力正在迅速提高。从头开始设计蛋白质的所有三种主要方法都是如此，我们将其定义为：最小，合理和计算设计。这些共同提供了多种具有高分辨率特征的蛋白质支架。这确实是令人印象深刻的，并且是该领域大约十年前取得的重大进步。综上所述，该领域仍然存在重大挑战。其中最主要的是需要递送从头蛋白。这样的设计可能包括特定小分子的选择性和/或紧密结合，或全新化学转化的催化作用。我们认为，尽管正在取得进展，但解决此类问题将不仅仅需要向现有的从头结构中添加功能性侧链。将需要同时针对和建立结构，稳定性和功能的新方法。而且，如果我们要匹配天然蛋白质的精致控制和微妙之处，则设计方法将必须结合多状态建模和动力学。这不仅需要黑盒方法，还需要更多地了解蛋白质构象变化和动力学。