De Novo Designed Peptide and Protein Hairpins Self-assemble into Sheets and Nanoparticles

Johanna M Galloway; Harriet E V Bray; Deborah K Shoemark; Lorna R Hodgson; Jen Coombs; Judith M Mantell; Ruth S Rose; James F Ross; Caroline Morris; Robert L Harniman; Christopher W Wood; Chris Arthur; Paul Verkade; Derek N Woolfson

doi:10.1002/smll.202100472

De Novo Designed Peptide and Protein Hairpins Self-assemble into Sheets and Nanoparticles

Johanna M Galloway, Harriet E V Bray, Deborah K Shoemark, Lorna R Hodgson, Jen Coombs, Judith M Mantell, Ruth S Rose, James F Ross, Caroline Morris, Robert L Harniman, Christopher W Wood, Chris Arthur, Paul Verkade, Derek N Woolfson

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Abstract

The design and assembly of peptide‐based materials has advanced considerably, leading to a variety of fibrous, sheet, and nanoparticle structures. A remaining challenge is to account for and control different possible supramolecular outcomes accessible to the same or similar peptide building blocks. Here a de novo peptide system is presented that forms nanoparticles or sheets depending on the strategic placement of a “disulfide pin” between two elements of secondary structure that drive self‐assembly. Specifically, homodimerizing and homotrimerizing de novo coiled‐coil α‐helices are joined with a flexible linker to generate a series of linear peptides. The helices are pinned back‐to‐back, constraining them as hairpins by a disulfide bond placed either proximal or distal to the linker. Computational modeling indicates, and advanced microscopy shows, that the proximally pinned hairpins self‐assemble into nanoparticles, whereas the distally pinned constructs form sheets. These peptides can be made synthetically or recombinantly to allow both chemical modifications and the introduction of whole protein cargoes as required.

Original language	English
Article number	2100472
Number of pages	11
Journal	Small
Volume	17
Issue number	10
Early online date	15 Feb 2021
DOIs	https://doi.org/10.1002/smll.202100472
Publication status	Published - 11 Mar 2021

Bibliographical note

Funding Information:
This research was supported by funding from a SLoLa (Strategic Longer and Larger) grant from the BBSRC “Development of supramolecular assemblies for enhancing cellular productivity and the synthesis of chemicals and biotherapeutics,” (BB/M002969/1). Dan Mulvihill and Martin Warren, who are based at the University of Kent, and Richard Pickersgill based at Queen Mary's University of London, contributed to discussion and development of this work as part of this consortium. The authors also thank Evelyne Deery and Maria Stanley for supplying the pET3a and TBAD plasmids, (University of Kent) and Richard Sessions for support with the computational modeling (University of Bristol). The authors thank the EPSRC for awarding HECBiosym and an Archer Leadership Award for providing computer time on the U.K. Supercomputer Archer. The authors thank the BBSRC/EPSRC funded Synthetic Biology Research Centre (BrisSynBio, BB/L01386X/1) for providing funding for researchers and Bluegem. The authors thank the EPSRC for funding the Chemical Imaging Facility (PF‐AFM, EP/K035746/1), the mass spectrometry equipment (EP/K03927X/1), and the Wolfson Bioimaging Facility (fluorescence and electron microscopy, BB/L014181/1) at the University of Bristol.

Funding Information:
This research was supported by funding from a SLoLa (Strategic Longer and Larger) grant from the BBSRC ?Development of supramolecular assemblies for enhancing cellular productivity and the synthesis of chemicals and biotherapeutics,? (BB/M002969/1). Dan Mulvihill and Martin Warren, who are based at the University of Kent, and Richard Pickersgill based at Queen Mary's University of London, contributed to discussion and development of this work as part of this consortium. The authors also thank Evelyne Deery and Maria Stanley for supplying the pET3a and TBAD plasmids, (University of Kent) and Richard Sessions for support with the computational modeling (University of Bristol). The authors thank the EPSRC for awarding HECBiosym and an Archer Leadership Award for providing computer time on the U.K. Supercomputer Archer. The authors thank the BBSRC/EPSRC funded Synthetic Biology Research Centre (BrisSynBio, BB/L01386X/1) for providing funding for researchers and Bluegem. The authors thank the EPSRC for funding the Chemical Imaging Facility (PF-AFM, EP/K035746/1), the mass spectrometry equipment (EP/K03927X/1), and the Wolfson Bioimaging Facility (fluorescence and electron microscopy, BB/L014181/1) at the University of Bristol.

Publisher Copyright:
© 2021 The Authors. Small published by Wiley-VCH GmbH

Research Groups and Themes

BrisSynBio
Bristol BioDesign Institute

Keywords

coiled coil
computational modeling
peptide design
protein design
self-assembly

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10.1002/smll.202100472

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Galloway, J. M., Bray, H. E. V., Shoemark, D. K., Hodgson, L. R., Coombs, J., Mantell, J. M., Rose, R. S., Ross, J. F., Morris, C., Harniman, R. L., Wood, C. W., Arthur, C., Verkade, P., & Woolfson, D. N. (2021). De Novo Designed Peptide and Protein Hairpins Self-assemble into Sheets and Nanoparticles. Small, 17(10), Article 2100472. https://doi.org/10.1002/smll.202100472

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abstract = "The design and assembly of peptide‐based materials has advanced considerably, leading to a variety of fibrous, sheet, and nanoparticle structures. A remaining challenge is to account for and control different possible supramolecular outcomes accessible to the same or similar peptide building blocks. Here a de novo peptide system is presented that forms nanoparticles or sheets depending on the strategic placement of a “disulfide pin” between two elements of secondary structure that drive self‐assembly. Specifically, homodimerizing and homotrimerizing de novo coiled‐coil α‐helices are joined with a flexible linker to generate a series of linear peptides. The helices are pinned back‐to‐back, constraining them as hairpins by a disulfide bond placed either proximal or distal to the linker. Computational modeling indicates, and advanced microscopy shows, that the proximally pinned hairpins self‐assemble into nanoparticles, whereas the distally pinned constructs form sheets. These peptides can be made synthetically or recombinantly to allow both chemical modifications and the introduction of whole protein cargoes as required.",

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note = "Funding Information: This research was supported by funding from a SLoLa (Strategic Longer and Larger) grant from the BBSRC “Development of supramolecular assemblies for enhancing cellular productivity and the synthesis of chemicals and biotherapeutics,” (BB/M002969/1). Dan Mulvihill and Martin Warren, who are based at the University of Kent, and Richard Pickersgill based at Queen Mary's University of London, contributed to discussion and development of this work as part of this consortium. The authors also thank Evelyne Deery and Maria Stanley for supplying the pET3a and TBAD plasmids, (University of Kent) and Richard Sessions for support with the computational modeling (University of Bristol). The authors thank the EPSRC for awarding HECBiosym and an Archer Leadership Award for providing computer time on the U.K. Supercomputer Archer. The authors thank the BBSRC/EPSRC funded Synthetic Biology Research Centre (BrisSynBio, BB/L01386X/1) for providing funding for researchers and Bluegem. The authors thank the EPSRC for funding the Chemical Imaging Facility (PF‐AFM, EP/K035746/1), the mass spectrometry equipment (EP/K03927X/1), and the Wolfson Bioimaging Facility (fluorescence and electron microscopy, BB/L014181/1) at the University of Bristol. Funding Information: This research was supported by funding from a SLoLa (Strategic Longer and Larger) grant from the BBSRC ?Development of supramolecular assemblies for enhancing cellular productivity and the synthesis of chemicals and biotherapeutics,? (BB/M002969/1). Dan Mulvihill and Martin Warren, who are based at the University of Kent, and Richard Pickersgill based at Queen Mary's University of London, contributed to discussion and development of this work as part of this consortium. The authors also thank Evelyne Deery and Maria Stanley for supplying the pET3a and TBAD plasmids, (University of Kent) and Richard Sessions for support with the computational modeling (University of Bristol). The authors thank the EPSRC for awarding HECBiosym and an Archer Leadership Award for providing computer time on the U.K. Supercomputer Archer. The authors thank the BBSRC/EPSRC funded Synthetic Biology Research Centre (BrisSynBio, BB/L01386X/1) for providing funding for researchers and Bluegem. The authors thank the EPSRC for funding the Chemical Imaging Facility (PF-AFM, EP/K035746/1), the mass spectrometry equipment (EP/K03927X/1), and the Wolfson Bioimaging Facility (fluorescence and electron microscopy, BB/L014181/1) at the University of Bristol. Publisher Copyright: {\textcopyright} 2021 The Authors. Small published by Wiley-VCH GmbH",

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AU - Bray, Harriet E V

AU - Shoemark, Deborah K

AU - Hodgson, Lorna R

AU - Coombs, Jen

AU - Mantell, Judith M

AU - Rose, Ruth S

AU - Ross, James F

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AU - Harniman, Robert L

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AU - Arthur, Chris

AU - Verkade, Paul

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N1 - Funding Information: This research was supported by funding from a SLoLa (Strategic Longer and Larger) grant from the BBSRC “Development of supramolecular assemblies for enhancing cellular productivity and the synthesis of chemicals and biotherapeutics,” (BB/M002969/1). Dan Mulvihill and Martin Warren, who are based at the University of Kent, and Richard Pickersgill based at Queen Mary's University of London, contributed to discussion and development of this work as part of this consortium. The authors also thank Evelyne Deery and Maria Stanley for supplying the pET3a and TBAD plasmids, (University of Kent) and Richard Sessions for support with the computational modeling (University of Bristol). The authors thank the EPSRC for awarding HECBiosym and an Archer Leadership Award for providing computer time on the U.K. Supercomputer Archer. The authors thank the BBSRC/EPSRC funded Synthetic Biology Research Centre (BrisSynBio, BB/L01386X/1) for providing funding for researchers and Bluegem. The authors thank the EPSRC for funding the Chemical Imaging Facility (PF‐AFM, EP/K035746/1), the mass spectrometry equipment (EP/K03927X/1), and the Wolfson Bioimaging Facility (fluorescence and electron microscopy, BB/L014181/1) at the University of Bristol. Funding Information: This research was supported by funding from a SLoLa (Strategic Longer and Larger) grant from the BBSRC ?Development of supramolecular assemblies for enhancing cellular productivity and the synthesis of chemicals and biotherapeutics,? (BB/M002969/1). Dan Mulvihill and Martin Warren, who are based at the University of Kent, and Richard Pickersgill based at Queen Mary's University of London, contributed to discussion and development of this work as part of this consortium. The authors also thank Evelyne Deery and Maria Stanley for supplying the pET3a and TBAD plasmids, (University of Kent) and Richard Sessions for support with the computational modeling (University of Bristol). The authors thank the EPSRC for awarding HECBiosym and an Archer Leadership Award for providing computer time on the U.K. Supercomputer Archer. The authors thank the BBSRC/EPSRC funded Synthetic Biology Research Centre (BrisSynBio, BB/L01386X/1) for providing funding for researchers and Bluegem. The authors thank the EPSRC for funding the Chemical Imaging Facility (PF-AFM, EP/K035746/1), the mass spectrometry equipment (EP/K03927X/1), and the Wolfson Bioimaging Facility (fluorescence and electron microscopy, BB/L014181/1) at the University of Bristol. Publisher Copyright: © 2021 The Authors. Small published by Wiley-VCH GmbH

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AB - The design and assembly of peptide‐based materials has advanced considerably, leading to a variety of fibrous, sheet, and nanoparticle structures. A remaining challenge is to account for and control different possible supramolecular outcomes accessible to the same or similar peptide building blocks. Here a de novo peptide system is presented that forms nanoparticles or sheets depending on the strategic placement of a “disulfide pin” between two elements of secondary structure that drive self‐assembly. Specifically, homodimerizing and homotrimerizing de novo coiled‐coil α‐helices are joined with a flexible linker to generate a series of linear peptides. The helices are pinned back‐to‐back, constraining them as hairpins by a disulfide bond placed either proximal or distal to the linker. Computational modeling indicates, and advanced microscopy shows, that the proximally pinned hairpins self‐assemble into nanoparticles, whereas the distally pinned constructs form sheets. These peptides can be made synthetically or recombinantly to allow both chemical modifications and the introduction of whole protein cargoes as required.

KW - coiled coil

KW - computational modeling

KW - peptide design

KW - protein design

KW - self-assembly

U2 - 10.1002/smll.202100472

DO - 10.1002/smll.202100472

M3 - Article (Academic Journal)

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SN - 1613-6810

VL - 17

JO - Small

JF - Small

IS - 10

M1 - 2100472

ER -

De Novo Designed Peptide and Protein Hairpins Self-assemble into Sheets and Nanoparticles

Abstract

Bibliographical note

Research Groups and Themes

Keywords

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