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Crystal structure and NMR of an α,δ-peptide foldamer helix shows side-chains are well placed for bifunctional catalysis: application as a minimalist aldolase mimic**

Crystal structure and NMR of an α,δ-peptide foldamer helix shows side-chains are well placed for bifunctional catalysis: application as a minimalist aldolase mimic**
Crystal structure and NMR of an α,δ-peptide foldamer helix shows side-chains are well placed for bifunctional catalysis: application as a minimalist aldolase mimic**

We report the first NMR and X-ray diffraction (XRD) structures of an unusual 13/11-helix (alternating i, i+1 {NH−O=C} and i, i+3 {C=O−H−N} H-bonds) formed by a heteromeric 1 : 1 sequence of α- and δ-amino acids, and demonstrate the application of this framework towards catalysis. Whilst intramolecular hydrogen bonds (IMHBs) are the clear driver of helix formation in this system, we also observe an apolar interaction between the ethyl residue of one δ-amino acid and the cyclohexyl group of the next δ-residue in the sequence that seems to stabilize one type of helix over another. To the best of our knowledge this type of additional stabilization leading to a specific helical preference has not been observed before. Critically, the helix type realized places the α-residue functionalities in positions proximal enough to engage in bifunctional catalysis as demonstrated in the application of our system as a minimalist aldolase mimic.

aldolase, catalysis, helical conformation, peptides, peptidic foldamers
1433-7851
Lin, Qi
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Lan, Hao
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Ma, Chunmiao
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Stendall, Ryan T.
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Shankland, Kenneth
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Musgrave, Rebecca A.
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Horton, Peter N.
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Baldauf, Carsten
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Hofmann, Hans Jörg
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Butts, Craig P.
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Müller, Manuel M.
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Cobb, Alexander J.A.
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Lin, Qi
adeed24a-22fd-4875-8e89-44a80b24858d
Lan, Hao
fe18a4f2-21cb-479e-9760-d2997609f19f
Ma, Chunmiao
5d0cd349-2216-4543-9942-b3c841347fae
Stendall, Ryan T.
3352b709-1725-431e-b201-59ce866ebcc4
Shankland, Kenneth
79757288-ed6a-46b9-9efb-895febd9d8a3
Musgrave, Rebecca A.
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Horton, Peter N.
154c8930-bfc3-495b-ad4a-8a278d5da3a5
Baldauf, Carsten
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Hofmann, Hans Jörg
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Butts, Craig P.
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Müller, Manuel M.
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Cobb, Alexander J.A.
3f94e39a-9294-4d26-a3bf-094b78cfbaab

Lin, Qi, Lan, Hao, Ma, Chunmiao, Stendall, Ryan T., Shankland, Kenneth, Musgrave, Rebecca A., Horton, Peter N., Baldauf, Carsten, Hofmann, Hans Jörg, Butts, Craig P., Müller, Manuel M. and Cobb, Alexander J.A. (2023) Crystal structure and NMR of an α,δ-peptide foldamer helix shows side-chains are well placed for bifunctional catalysis: application as a minimalist aldolase mimic**. Angewandte Chemie - International Edition, 62 (36), [e202305326]. (doi:10.1002/anie.202305326).

Record type: Article

Abstract

We report the first NMR and X-ray diffraction (XRD) structures of an unusual 13/11-helix (alternating i, i+1 {NH−O=C} and i, i+3 {C=O−H−N} H-bonds) formed by a heteromeric 1 : 1 sequence of α- and δ-amino acids, and demonstrate the application of this framework towards catalysis. Whilst intramolecular hydrogen bonds (IMHBs) are the clear driver of helix formation in this system, we also observe an apolar interaction between the ethyl residue of one δ-amino acid and the cyclohexyl group of the next δ-residue in the sequence that seems to stabilize one type of helix over another. To the best of our knowledge this type of additional stabilization leading to a specific helical preference has not been observed before. Critically, the helix type realized places the α-residue functionalities in positions proximal enough to engage in bifunctional catalysis as demonstrated in the application of our system as a minimalist aldolase mimic.

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Accepted/In Press date: 23 May 2023
e-pub ahead of print date: 23 May 2023
Published date: 4 September 2023
Additional Information: Funding Information: We thank The Leverhulme Trust for funding from a Research Project Grant (RPG‐2019‐283), in addition to King's College London and the China Scholarship Council (Studentship to QL) as well as the Wellcome Trust and the Royal Society (Sir Henry Dale Fellowship to MM, 202250/Z/16/Z). In respect of periodic DFT calculations, we are grateful to the UK Materials and Molecular Modelling Hub for computational resources, which is partially funded by EPSRC (EP/T022213/1, EP/W032260/1 and EP/P020194/1). We also thank the EPSRC UK National Crystallography Service at the University of Southampton, and the University of Reading's Chemical Analysis Facility, for the collection of the crystallographic data. Hao Lan would like to thank the Bristol Chemical Synthesis CDT, funded by EPSRC (EP/L015366/1), for a PhD studentship. Finally, we thank Prof. Christina Redfield, the University of Oxford, for the help with using 950 MHz ultra‐high resolution NMR spectrometer. Funding Information: We thank The Leverhulme Trust for funding from a Research Project Grant (RPG-2019-283), in addition to King's College London and the China Scholarship Council (Studentship to QL) as well as the Wellcome Trust and the Royal Society (Sir Henry Dale Fellowship to MM, 202250/Z/16/Z). In respect of periodic DFT calculations, we are grateful to the UK Materials and Molecular Modelling Hub for computational resources, which is partially funded by EPSRC (EP/T022213/1, EP/W032260/1 and EP/P020194/1). We also thank the EPSRC UK National Crystallography Service at the University of Southampton, and the University of Reading's Chemical Analysis Facility, for the collection of the crystallographic data. Hao Lan would like to thank the Bristol Chemical Synthesis CDT, funded by EPSRC (EP/L015366/1), for a PhD studentship. Finally, we thank Prof. Christina Redfield, the University of Oxford, for the help with using 950 MHz ultra-high resolution NMR spectrometer. Publisher Copyright: © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
Keywords: aldolase, catalysis, helical conformation, peptides, peptidic foldamers

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Local EPrints ID: 480951
URI: http://eprints.soton.ac.uk/id/eprint/480951
ISSN: 1433-7851
PURE UUID: fc3f9ea1-c2d4-4eca-9628-07c5b70ad598
ORCID for Peter N. Horton: ORCID iD orcid.org/0000-0001-8886-2016

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Date deposited: 11 Aug 2023 16:56
Last modified: 18 Mar 2024 02:51

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Contributors

Author: Qi Lin
Author: Hao Lan
Author: Chunmiao Ma
Author: Ryan T. Stendall
Author: Kenneth Shankland
Author: Rebecca A. Musgrave
Author: Peter N. Horton ORCID iD
Author: Carsten Baldauf
Author: Hans Jörg Hofmann
Author: Craig P. Butts
Author: Manuel M. Müller
Author: Alexander J.A. Cobb

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