A spirocyclic backbone accesses new conformational space in an extended, dipole-stabilized foldamer

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Abstract

Most aromatic foldamers adopt uniform secondary structures, offering limited potential for the exploration of conformational space and the formation of tertiary structures. Here we report the incorporation of spiro bis-lactams to allow controlled rotation of the backbone of an iteratively synthesised foldamer. This enables precise control of foldamer shape along two orthogonal directions, likened to the aeronautical yaw and roll axes. XRD, NMR and computational data suggest that homo-oligomers adopt an extended right-handed helix with a pitch of over 30 Å, approximately that of B-DNA. Compatibility with extant foldamers to form hetero-oligomers is demonstrated, allowing greater structural complexity and function in future hybrid foldamer designs.

Abstract

Foldamers containing an aromatic linker can adopt a variety of backbone shapes, but exploration of conformational space has been limited to one plane. Here, spiro bis-lactams linkers in dipole-controlled foldamers enable controlled rotation of the backbone and projection of side-chains along two orthogonal directions.

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Optimization of parameters for semiempirical methods VI: more modifications to the NDDO approximations and re-optimization of parameters

James J. P. Stewart (2012)

Modern semiempirical methods are of sufficient accuracy when used in the modeling of molecules of the same type as used as reference data in the parameterization. Outside that subset, however, there is an abundance of evidence that these methods are of very limited utility. In an attempt to expand the range of applicability, a new method called PM7 has been developed. PM7 was parameterized using experimental and high-level ab initio reference data, augmented by a new type of reference data intended to better define the structure of parameter space. The resulting method was tested by modeling crystal structures and heats of formation of solids. Two changes were made to the set of approximations: a modification was made to improve the description of noncovalent interactions, and two minor errors in the NDDO formalism were rectified. Average unsigned errors (AUEs) in geometry and ΔH f for PM7 were reduced relative to PM6; for simple gas-phase organic systems, the AUE in bond lengths decreased by about 5 % and the AUE in ΔH f decreased by about 10 %; for organic solids, the AUE in ΔH f dropped by 60 % and the reduction was 33.3 % for geometries. A two-step process (PM7-TS) for calculating the heights of activation barriers has been developed. Using PM7-TS, the AUE in the barrier heights for simple organic reactions was decreased from values of 12.6 kcal/mol-1 in PM6 and 10.8 kcal/mol-1 in PM7 to 3.8 kcal/mol-1. The origins of the errors in NDDO methods have been examined, and were found to be attributable to inadequate and inaccurate reference data. This conclusion provides insight into how these methods can be improved. Electronic supplementary material The online version of this article (doi:10.1007/s00894-012-1667-x) contains supplementary material, which is available to authorized users.

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Helical polymers: synthesis, structures, and functions.

Eiji Yashima, Katsuhiro Maeda, Hiroki Iida … (2009)

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Foldamers with heterogeneous backbones.

W Horne, Samuel H. Gellman (2008)

The functions performed by proteins and nucleic acids provide the foundation for life. Chemists have recently begun to ask whether it is possible to design synthetic oligomers that approach the structural and functional complexities of these biopolymers. The study of foldamers, non-natural oligomers displaying discrete folding propensities, has demonstrated that there are several synthetic backbones that exhibit biopolymer-like conformational behavior. Early work in this area focused on oligomers comprised of a single type of monomer subunit, but recent efforts have highlighted the potential of mixed or "heterogeneous" backbones to expand the structural and functional repertoire of foldamers. In this Account, we illustrate the promise of heterogeneous backbone foldamers by focusing on examples containing both alpha- and beta-amino acid residues. Some beta-residues bear protein-like side chains, while others have cyclic structures that confer conformational rigidity. The study of heterogeneous backbone foldamers has several advantages over that of their homogeneous backbone counterparts, including access to many new molecular shapes based on variations in the stoichiometries and patterns of the subunit combinations and improved prospects for side chain diversification. Recent efforts to develop alpha/beta-peptide foldamers can be divided into two conceptually distinct classes. The first includes entities prepared using a "block" strategy, in which alpha-peptide segments and beta-peptide segments are combined to form a hybrid oligomer. The second class encompasses designs in which alpha- and beta-amino acid monomers are interspersed in a regular pattern throughout an oligomer sequence. One alpha/beta-peptide helical secondary structure, containing C=O(i)...H-N(i+4) H-bonds analogous to those in the alpha-helix, has been shown via crystallography to form helix bundle quaternary structures. Desirable biological functions have been elicited from alpha/beta-peptide foldamers. Efforts to mimic naturally occurring host-defense alpha-peptides have yielded new antimicrobial agents and have led to a reexamination of the long-held views regarding structure-activity relationships among these alpha-peptides and their analogues. Foldamers offer new platforms for mimicry of the molecular surfaces involved in specific protein-protein recognition events; recent achievements in the preparation of alpha/beta-peptide inhibitors of the protein-protein interactions involved in apoptotic signaling (e.g., between Bcl-xL and pro-apoptotic partners) have revealed the benefits of employing heterogeneous backbones relative to homogeneous backbones for foldamer-based designs. These initial successes in the development of alpha/beta-peptides exhibiting specific biological activities highlight the potential of heterogeneous backbone foldamers for use in biomedical applications and provide guidelines for future studies into new target functions.

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Author and article information

Contributors

Peter Clarke Knipe:

ORCID: http://orcid.org/0000-0001-9728-2339

p.knipe@qub.ac.uk

Journal

Journal ID (nlm-ta): Commun Chem

Journal ID (iso-abbrev): Commun Chem

Title: Communications Chemistry

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2399-3669

Publication date (Electronic): 17 April 2023

Publication date PMC-release: 17 April 2023

Publication date Collection: 2023

Volume: 6

Electronic Location Identifier: 71

Affiliations

GRID grid.4777.3, ISNI 0000 0004 0374 7521, School of Chemistry and Chemical Engineering, , Queen’s University Belfast, ; David Keir Building, Belfast, BT9 5AG UK

Author information

William Edward Roe http://orcid.org/0000-0003-2577-4048

Peter Clarke Knipe http://orcid.org/0000-0001-9728-2339

Article

Publisher ID: 868

DOI: 10.1038/s42004-023-00868-8

PMC ID: 10110530

PubMed ID: 37069245

SO-VID: 71d2c343-6824-4eb5-9ce5-3335a185fb18

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 14 February 2023

Date accepted : 24 March 2023

Funding

Funded by: FundRef https://doi.org/10.13039/501100000873, Queen's University Belfast;

Funded by: Queen's University Belfast

Funded by: FundRef https://doi.org/10.13039/501100000266, RCUK | Engineering and Physical Sciences Research Council (EPSRC);

Award ID: EP/S018077/1

Award Recipient : Peter Clarke Knipe

Funded by: Queen's University Belfast

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Keywords: asymmetric synthesis,nmr spectroscopy,polymer synthesis

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Keywords: asymmetric synthesis, nmr spectroscopy, polymer synthesis

A spirocyclic backbone accesses new conformational space in an extended, dipole-stabilized foldamer

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Most cited references 69

Optimization of parameters for semiempirical methods VI: more modifications to the NDDO approximations and re-optimization of parameters

Helical polymers: synthesis, structures, and functions.

Foldamers with heterogeneous backbones.

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