7UBE

Solution NMR structure of 8-residue Rosetta-designed cyclic peptide D8.21 in d6-DMSO with cis/trans switching

Summary for 7UBE

• Entry DOI: 10.2210/pdb7ube/pdb
• NMR Information: BMRB: 30999
• Descriptor: Cyclic peptide D8.21 DVA-MLE-DPR-LEU-DVA-MLE-DPR-LEU (1 entity in total)
• Functional Keywords: cyclic peptide, non natural amino acids, cis/trans, switch peptides, de novo design, membrane permeability, de novo protein
• Biological source: synthetic construct
• Total number of polymer chains: 1
• Total formula weight: 891.19

Authors

Ramelot, T.A.,Tejero, R.,Montelione, G.T. (deposition date: 2022-03-14, release date: 2022-09-14, Last modification date: 2022-09-28)

Primary citation

Bhardwaj, G.,O'Connor, J.,Rettie, S.,Huang, Y.H.,Ramelot, T.A.,Mulligan, V.K.,Alpkilic, G.G.,Palmer, J.,Bera, A.K.,Bick, M.J.,Di Piazza, M.,Li, X.,Hosseinzadeh, P.,Craven, T.W.,Tejero, R.,Lauko, A.,Choi, R.,Glynn, C.,Dong, L.,Griffin, R.,van Voorhis, W.C.,Rodriguez, J.,Stewart, L.,Montelione, G.T.,Craik, D.,Baker, D.
Accurate de novo design of membrane-traversing macrocycles.
Cell, 185:3520-3532.e26, 2022

PubMed Abstract: We use computational design coupled with experimental characterization to systematically investigate the design principles for macrocycle membrane permeability and oral bioavailability. We designed 184 6-12 residue macrocycles with a wide range of predicted structures containing noncanonical backbone modifications and experimentally determined structures of 35; 29 are very close to the computational models. With such control, we show that membrane permeability can be systematically achieved by ensuring all amide (NH) groups are engaged in internal hydrogen bonding interactions. 84 designs over the 6-12 residue size range cross membranes with an apparent permeability greater than 1 × 10 cm/s. Designs with exposed NH groups can be made membrane permeable through the design of an alternative isoenergetic fully hydrogen-bonded state favored in the lipid membrane. The ability to robustly design membrane-permeable and orally bioavailable peptides with high structural accuracy should contribute to the next generation of designed macrocycle therapeutics.

PubMed: 36041435
DOI: 10.1016/j.cell.2022.07.019

Experimental method

SOLUTION NMR