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Title: Comprehensive computational design of ordered peptide macrocycles

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.

Authors:
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Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1436810
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Published Article
Journal Name:
Science
Additional Journal Information:
Journal Name: Science Journal Volume: 358 Journal Issue: 6369; Journal ID: ISSN 0036-8075
Publisher:
American Association for the Advancement of Science (AAAS)
Country of Publication:
United States
Language:
English

Citation Formats

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, and Baker, David. Comprehensive computational design of ordered peptide macrocycles. United States: N. p., 2017. Web. doi:10.1126/science.aap7577.
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. Comprehensive computational design of ordered peptide macrocycles. United States. doi:10.1126/science.aap7577.
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, and Baker, David. Thu . "Comprehensive computational design of ordered peptide macrocycles". United States. doi:10.1126/science.aap7577.
@article{osti_1436810,
title = {Comprehensive computational design of ordered peptide macrocycles},
author = {Hosseinzadeh, Parisa and Bhardwaj, Gaurav and Mulligan, Vikram Khipple and Shortridge, Matthew D. and Craven, Timothy W. and Pardo-Avila, Fátima and Rettie, Stephen A. and Kim, David E. and Silva, Daniel-Adriano and Ibrahim, Yehia M. and Webb, Ian K. and Cort, John R. and Adkins, Joshua N. and Varani, Gabriele and Baker, David},
abstractNote = {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.},
doi = {10.1126/science.aap7577},
journal = {Science},
number = 6369,
volume = 358,
place = {United States},
year = {2017},
month = {12}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1126/science.aap7577

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