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

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... nal 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.