Comprehensive computational design of ordered peptide macrocycles

Hosseinzadeh, Parisa; Bhardwaj, Gaurav; Mulligan, Vikram Khipple; Shortridge, Matthew D.; Craven, Timothy W.; Pardo-Avila, Fátima; Rettie, Stephen A.; Kim, David E.; Silva, Daniel-Adriano; Ibrahim, Yehia M.; Webb, Ian K.; Cort, John R.; Adkins, Joshua N.; Varani, Gabriele; Baker, David

doi:10.1126/science.aap7577

Comprehensive computational design of ordered peptide macrocycles

Journal Article · Thu Dec 14 00:00:00 EST 2017 · Science

DOI:https://doi.org/10.1126/science.aap7577· OSTI ID:1436810

; ; ; ; Craven, Timothy W.; Pardo-Avila, Fátima; ; ; ; ; ; Cort, John R.; ; Varani, Gabriele;

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.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1436810

Alternate ID(s):: OSTI ID: 1414526

Journal Information:: Science, Journal Name: Science Journal Issue: 6369 Vol. 358; ISSN 0036-8075

Publisher:: American Association for the Advancement of Science (AAAS)Copyright Statement

Country of Publication:: United States

Language:: English

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