Schematic overview of de novo design methods to generate peptide binders. De novo design of binders can be broadly categorized into three methods: (a) de novo generation of sequence: In this method, first a diverse pool of sequences is generated and then the best binders are selected based on their sequence ranking followed by binding energy calculation based on downstream structural analysis. (b) De novo generation of structure: In this method structured scaffolds are first generated. They are then used to present and stabilize a select set of hotspot residues at the interface. (c) Joint optimization of sequence and structure: In this method the sequence and structure are generated in one step. This method often starts with a functional group at the interface called the anchor. The peptide structure is generated in the context of the protein pocket, the sequences are optimized, and the structure is adjusted based on the sequence to obtain the best binders. Repeating this process multiple times results in a pool of potential binders.