Computational design of mixed chirality peptide macrocycles with internal symmetry.

Publication Type:

Journal Article


Protein Sci (2020)


<p>Cyclic symmetry is frequent in protein and peptide homo-oligomers, but extremely rare within a single chain, as it is not compatible with free N- and C-termini. Here we describe the computational design of mixed-chirality peptide macrocycles with rigid structures that feature internal cyclic symmetries or improper rotational symmetries inaccessible to natural proteins. Crystal structures of three C2- and C3-symmetric macrocycles, and of six diverse S2-symmetric macrocycles, match the computationally-designed models with backbone heavy-atom RMSD values of 1 å or better. Crystal structures of an S4-symmetric macrocycle (consisting of a sequence and structure segment mirrored at each of three successive repeats) designed to bind zinc reveal a large-scale zinc-driven conformational change from an S4-symmetric apo-state to a nearly inverted S4-symmetric holo-state almost identical to the design model. This work demonstrates the power of computational design for exploring symmetries and structures not found in nature, and for creating synthetic switchable systems. This article is protected by copyright. All rights reserved.</p>

peptide C2-1: PDB IDs 6UFU and 6UG2; peptide C3-1: PDB IDs 6UG3 and 6UG6; peptide C3-2: PDB ID 6UGB; peptide C3-3: PDB ID 6UGC; peptide S2-1: PDB ID 6UCX; peptide S2-2: PDB ID 6UD9; peptide S2-3: PDB IDs 6UDR and 6UDW; peptide S2-4: PDB IDs 6UDZ and 6UF4; peptide S2-5: PDB ID 6UF7; peptide S2-6: PDB ID 6UF8; peptide S4-1(holo): PDB ID 6UFA; peptide S4-1(apo): PDB ID 6UF9