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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 through the structural space spanned by such compounds for new drug candidates. Natural proteins do not provide a useful guide: peptide macrocycles lack regular secondary structures and hydrophobic cores and have different backbone torsional constraints. Hence the development of new peptide macrocycles has been approached by modifying natural products or using library selection methods; the former is limited by the small number of known structures, and the latter by the limited size and diversity accessible through library-based methods. To overcome these limitations, here we enumerate the stable structures that can be adopted by macrocyclic peptides composed of L and D amino acids. 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. We synthesize and characterize by NMR twelve 7-10 residue macrocycles, 9 of which have structures very close to the design models in solution. NMR structures of three 11-14 residue bicyclic designs are also very close to the computational models. Our results provide a nearly complete coverage of themore » rich space of structures possible for short peptide based macrocycles unparalleled for other molecular systems, and vastly increase the available starting scaffolds for both rational drug design and library selection methods.« less

Authors:
ORCiD logo; ORCiD logo; ORCiD logo; ORCiD logo; ; ; ORCiD logo; ORCiD logo; ORCiD logo; ORCiD logo; ORCiD logo; ; ORCiD logo; ; ORCiD logo
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1414526
Report Number(s):
PNNL-SA-128820
Journal ID: ISSN 0036-8075
DOE Contract Number:
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: Science; Journal Volume: 358; Journal Issue: 6369
Country of Publication:
United States
Language:
English
Subject:
NMR; SLIM; protein folding; protein structure

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. 2017. "Comprehensive computational design of ordered peptide macrocycles". United States. doi:10.1126/science.aap7577.
@article{osti_1414526,
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 through the structural space spanned by such compounds for new drug candidates. Natural proteins do not provide a useful guide: peptide macrocycles lack regular secondary structures and hydrophobic cores and have different backbone torsional constraints. Hence the development of new peptide macrocycles has been approached by modifying natural products or using library selection methods; the former is limited by the small number of known structures, and the latter by the limited size and diversity accessible through library-based methods. To overcome these limitations, here we enumerate the stable structures that can be adopted by macrocyclic peptides composed of L and D amino acids. 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. We synthesize and characterize by NMR twelve 7-10 residue macrocycles, 9 of which have structures very close to the design models in solution. NMR structures of three 11-14 residue bicyclic designs are also very close to the computational models. Our results provide a nearly complete coverage of the rich space of structures possible for short peptide based macrocycles unparalleled for other molecular systems, 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 =
}
  • The de novo design of protein-binding peptides is challenging because it requires the identification of both a sequence and a backbone conformation favorable for binding. We used a computational strategy that iterates between structure and sequence optimization to redesign the C-terminal portion of the RGS14 GoLoco motif peptide so that it adopts a new conformation when bound to G{alpha}{sub i1}. An X-ray crystal structure of the redesigned complex closely matches the computational model, with a backbone root-mean-square deviation of 1.1 {angstrom}.
  • Herein we describe the synthesis and characterization of two novel organometallic nanodimensional macrocycles. In contrast to our previously reported macrocycles, these new complexes display two trans-platinum linear linkages along the sides of the square, as well as platinum or iodonium centers with roughly 90{degree} geometries at the corners of the macrocycle. We propose that these new organometallic macrocycles, and other similar complexes currently under investigation, will be potentially useful devices, particularly in the area of organic synthesis and organometallic catalysis. Furthermore, complex 7 is of significant interest in regard to its potential nonlinear optical and electronic properties, given the presencemore » of metal-alkynyl units and possible {pi}-conjugation within the macrocycle frame. 18 refs.« less
  • Phosphoryl (P=O), urea (N/sub 2/C=O), pyridine, and pyridine oxide (N ..-->.. O) groups have been incorporated into the ring systems of macrocyclic polyethers. The association constants of the resulting eight new ligand systems toward Li/sup +/, Na/sup +/, K/sup +/, Rb/sup +/, Cs/sup +/, and NH/sub 4//sup +/ picrates in CHCl/sub 3/ were surveyed, and the free energies of association were estimated. The P=O complexing sites were covalently bonded through two attached o-tolyl groups as in the unit RP(O)(C/sub 6/H/sub 4/CH/sub 2/-o)/sub 2/, in which different R groups were attached to phosphorus. The resulting unit, written as RPOD, was attachedmore » to two ether oxygens (0), which in turn were connected through CH/sub 2/CH/sub 2/ or E units to form macrocycles. Ligand systems C/sub 6/H/sub 5/POD(OEOE)/sub 2/O (9), C/sub 6/H/sub 5/POD(OEOEO)/sub 2/E (10), o-HO/sub 2/CC/sub 6/H/sub 4/POD(OEOE)/sub 2/O (11), o-CH/sub 3/O/sub 2/CC/sub 6/H/sub 4/POD(OEOE)/sub 2/O (12), CH/sub 3/OPOD(OEOE)/sub 2/O (13), and C/sub 6/H/sub 5/POD(OEO)/sub 2/PODC/sub 6/H/sub 5/ (14 and 15, the syn and anti isomers) were synthesized and examined. The urea complexing site was cyclic, CH/sub 2/(CH/sub 2/N)/sub 2/C = O (abbreviated to UON), and was bonded through its two nitrogens to E units. The cycle prepared and examined was UON(EOEOE)/sub 2/O (16). The pyridine and pyridine oxide complexing sites were bonded through CH/sub 2/ groups in their ..cap alpha..,..cap alpha..' positions to comprise the units ..cap alpha..-CH/sub 2/(C/sub 5/H/sub 3/N)CH/sub 2/-..cap alpha.. and ..cap alpha..-CH/sub 2/(C/sub 5/H/sub 3/NO)CH/sub 2/-..cap alpha.., respectively, the latter of which was abbreviated as POM. The new cycle prepared and examined was POM(OEOE)/sub 2/O (18). The patterns of ..delta..G/sup 0/ values of complexation of these ligand systems were compared to those of 2,3-naphtho 18-crown-6 (19), 2,6-pyrido-18-crown-6 (20), and 1,3-benzo-18-crown-5 (21). The results suggest that those ligand systems whose organization of binding sites before and after complexation are the most similar show the highest structural recognition toward the anions.« less
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  • Combining monodisperse building blocks that have distinct folding properties serves as a modular strategy for controlling structural complexity in hierarchically organized materials. We combine an α-helical bundle-forming peptide with self-assembling dendrons to better control the arrangement of functional groups within cylindrical nanostructures. Site-specific grafting of dendrons to amino acid residues on the exterior of the α-helical bundle yields monodisperse macromolecules with programmable folding and self-assembly properties. The resulting hybrid biomaterials form thermotropic columnar hexagonal mesophases in which the peptides adopt an α-helical conformation. Bundling of the α-helical peptides accompanies self-assembly of the peptide-dendron hybrids into cylindrical nanostructures. The bundle stoichiometrymore » in the mesophase agrees well with the size found in solution for α-helical bundles of peptides with a similar amino acid sequence.« less