De novo approach, also known as the inverse protein folding problem, involves designing proteins from scratch. De novo protein design has proven a powerful method for understanding protein folding and function, and for mimicking or even bettering the properties of natural proteins. De novo protein design mainly involves the generation of target backbone, the design of sequences whose lowest energy states are the target backbones, and the optimization followed by computational and experimental validation of selected sequence-structure pair.

De novo protein design has been widely used in the field of synthetic biology. Its goal is to create proteins that do not exist in nature and can be successfully folded and given specific functions. Unlike in the structure-prediction and fixed-backbone design, both the sequence and the exact structure of the backbone are unknown for de novo protein design. In other words, it is the generation of new proteins based on physical principles with sequences unrelated to those in nature.

Figure 1. Schematic showing the various steps involved in De novo Protein Design. (Poluri K M & Gulati K, 2017)