Fig. 1. Design of peptide macrocycles targeting PD-1. (A) Schematic design protocol for PD-i3 (top) and PD-i6 (bottom). Starting from a fixed hotspot residue (I), a cyclic poly-Gly backbone is built and thousands of conformations are sampled with kinematic closure (II); ultimately, low-energy conformations are selected and side-chain designed (III) to maximize favorable contacts with the target protein. (B) Energy landscape calculations show convergence towards low-energy structures that are close to the design. (C) Superposition of the lowest-energy energy structure (in green) with the target-templated design (in blue). For the sake of clarity, only the backbone and Pro residues are shown.