PDBsum entry 6bf5

De novo protein

PDB id: 6bf5

Contents

Ligands

GLN-ASP-PRO-DPR-LYS-DTH-DAS

PDB id:

6bf5

Name:

De novo protein

Title:

Solution structure of de novo macrocycle design7.3a

Structure:

Qdp(dpr)k(dth)(das). Chain: a. Engineered: yes

Source:

Synthetic: yes. Homo sapiens. Organism_taxid: 9606

NMR struc:

20 models

Authors:

M.D.Shortridge,P.Hosseinzadeh,F.Pardo-Avila,G.Varani,D.Baker

Key ref:

P.Hosseinzadeh et al. (2017). Comprehensive computational design of ordered peptide macrocycles. Science, 358, 1461-1466. PubMed id: 29242347 DOI: 10.1126/science.aap7577

Date:

25-Oct-17 Release date: 10-Jan-18

DOI no: 10.1126/science.aap7577

Science 358:1461-1466 (2017)

PubMed id: 29242347

Comprehensive computational design of ordered peptide macrocycles.

P.Hosseinzadeh, G.Bhardwaj, V.K.Mulligan, M.D.Shortridge, T.W.Craven, F.Pardo-Avila, S.A.Rettie, D.E.Kim, D.A.Silva, Y.M.Ibrahim, I.K.Webb, J.R.Cort, J.N.Adkins, G.Varani, D.Baker.

ABSTRACT

Mixed-chirality peptide macrocycles such as cyclosporine are among the most potent therapeutics identified to date, but there is currently no way to systematically search the structural space spanned by such compounds. Natural proteins do not provide a useful guide: Peptide macrocycles lack regular secondary structures and hydrophobic cores, and can contain local structures not accessible with l-amino acids. Here, we enumerate the stable structures that can be adopted by macrocyclic peptides composed of l- and d-amino acids by near-exhaustive backbone sampling followed by sequence design and energy landscape calculations. We identify more than 200 designs predicted to fold into single stable structures, many times more than the number of currently available unbound peptide macrocycle structures. Nuclear magnetic resonance structures of 9 of 12 designed 7- to 10-residue macrocycles, and three 11- to 14-residue bicyclic designs, are close to the computational models. Our results provide a nearly complete coverage of the rich space of structures possible for short peptide macrocycles and vastly increase the available starting scaffolds for both rational drug design and library selection methods.