A comparative study between phenylglycine and phenylalanine derived peptide hydrogels: Towards atomic elucidation

Jolien Bertouille; Ruben Van Lommel; Roy Aerts; Luka Dockx; Jessica Mangialetto; Niko Van den Brande; Ronnie G. Willaert; Frank De Proft; Ulrich Hennecke; Charlotte Martin; Wouter Herrebout; Thomas L.C. Jansen; Ana V. Cunha; Steven Ballet

doi:10.1016/j.mtchem.2025.102593

A comparative study between phenylglycine and phenylalanine derived peptide hydrogels: Towards atomic elucidation

Jolien Bertouille
, Ruben Van Lommel
, Roy Aerts
, Luka Dockx
, Jessica Mangialetto
, Niko Van den Brande
, Ronnie G. Willaert
, Frank De Proft
, Ulrich Hennecke
, Charlotte Martin
, Wouter Herrebout
, Thomas L.C. Jansen
, Ana V. Cunha
, Steven Ballet

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Peptide hydrogels are naturally inspired soft materials which, due to their biocompatibility, are potential candidates for controlled drug delivery matrices and wound healing applications. The properties of the gel materials are directly linked to the peptide sequence as minor alterations in the sequence are known to create substantial differences in the assembly mode. The majority of hydrogelators self-assemble by a combination of different non-covalent interactions, including hydrophobic effects, π-π stacking, ionic interactions and hydrogen bonding. Consequently, the impact and tunability of each separate interaction towards the self-assembly process is difficult to unravel. In this study, the role of aromatic interactions towards the self-assembly process of a hydrogelator is investigated by interchanging the more flexible phenylalanine amino acids with the more rigid phenylglycines in a short amphipathic hexamer peptide hydrogelator. This substitution resulted in four new effective hydrogelators that show different configurations around the aryl rings. The phenylglycine-rich hydrogel SBL-HG-085 showed an increased gel strength by almost threefold, fast recovery after injection and improved stability under physiological conditions. The soft materials were further characterized at different levels and atomic models of their stacking modes were obtained by all-atom molecular dynamics simulations. A strong correlation has been achieved upon combining the theoretical and experimental results. Altogether, reducing the aromatic side chain flexibility stabilized the assemblies by modified π-π stacking interactions.

Original language	English
Article number	102593
Journal	Materials Today Chemistry
Volume	44
DOIs	https://doi.org/10.1016/j.mtchem.2025.102593
State	Published - Mar 2025
Externally published	Yes

Funding

This work was supported by the Research Foundation Flanders (FWO, PhD grant J.B. 1SD7321N and research grant G024019N) and the Strategic Research Programme (SRP9, SRP50, SRP73 and SRP95) of the Vrije Universiteit Brussel (VUB). A.V.C. acknowledges the Dutch National e-Infrastructure (DNI)- SURF cooperative (NWO-2022.004/L1 and EINF-3817). Support was also provided via the Wetenschappelijke Onderzoeksgemeenschap (WOG) “Supramolecular Chemistry and Materials” of FWO. AFM equipment has been funded by FWO grant number I002620. J.M. received an FWO junior postdoctoral fellowship (1203524N). R.V.L. thanks the FWO for the PhD fellowship received (1185221N). SB, CM and UH also thank the Research Council of VUB for the infrastructure support (OZR3584 and OZR3939). Steven Ballet reports financial support was provided by Vrije Universiteit Brussel Faculty of Sciences and Bio-Engineering Sciences. This work was supported by the Research Foundation Flanders (FWO, PhD grant J.B., 1SD7321N and research grant G024019N) and the Strategic Research Programme (SRP9, SRP50, SRP73 and SRP95) of the Vrije Universiteit Brussel (VUB). A.V.C. acknowledges the Dutch National e-Infrastructure (DNI)- SURF cooperative (NWO-2022.004/L1 and EINF-3817). Support was also provided via the Wetenschappelijke Onderzoeksgemeenschap (WOG) “Supramolecular Chemistry and Materials” of FWO. AFM equipment has been funded by FWO grant number I002620. J.M. received an FWO junior postdoctoral fellowship (1203524N). R.V.L. thanks the FWO for the PhD fellowship received (1185221N). SB, CM and UH also thank the Research Council of VUB for the infrastructure support (OZR3584 and OZR3939).

Keywords

Aromatic interactions
Molecular dynamics simulations
Peptide hydrogels
Peptide self-assembly
Phenylglycine

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10.1016/j.mtchem.2025.102593

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Bertouille, J., Van Lommel, R., Aerts, R., Dockx, L., Mangialetto, J., Van den Brande, N., Willaert, R. G., De Proft, F., Hennecke, U., Martin, C., Herrebout, W., Jansen, T. L. C., Cunha, A. V., & Ballet, S. (2025). A comparative study between phenylglycine and phenylalanine derived peptide hydrogels: Towards atomic elucidation. Materials Today Chemistry, 44, Article 102593. https://doi.org/10.1016/j.mtchem.2025.102593

@article{f0676d658fd74d89ab94f1e642e077e7,

title = "A comparative study between phenylglycine and phenylalanine derived peptide hydrogels: Towards atomic elucidation",

abstract = "Peptide hydrogels are naturally inspired soft materials which, due to their biocompatibility, are potential candidates for controlled drug delivery matrices and wound healing applications. The properties of the gel materials are directly linked to the peptide sequence as minor alterations in the sequence are known to create substantial differences in the assembly mode. The majority of hydrogelators self-assemble by a combination of different non-covalent interactions, including hydrophobic effects, π-π stacking, ionic interactions and hydrogen bonding. Consequently, the impact and tunability of each separate interaction towards the self-assembly process is difficult to unravel. In this study, the role of aromatic interactions towards the self-assembly process of a hydrogelator is investigated by interchanging the more flexible phenylalanine amino acids with the more rigid phenylglycines in a short amphipathic hexamer peptide hydrogelator. This substitution resulted in four new effective hydrogelators that show different configurations around the aryl rings. The phenylglycine-rich hydrogel SBL-HG-085 showed an increased gel strength by almost threefold, fast recovery after injection and improved stability under physiological conditions. The soft materials were further characterized at different levels and atomic models of their stacking modes were obtained by all-atom molecular dynamics simulations. A strong correlation has been achieved upon combining the theoretical and experimental results. Altogether, reducing the aromatic side chain flexibility stabilized the assemblies by modified π-π stacking interactions.",

keywords = "Aromatic interactions, Molecular dynamics simulations, Peptide hydrogels, Peptide self-assembly, Phenylglycine",

author = "Jolien Bertouille and \{Van Lommel\}, Ruben and Roy Aerts and Luka Dockx and Jessica Mangialetto and \{Van den Brande\}, Niko and Willaert, \{Ronnie G.\} and \{De Proft\}, Frank and Ulrich Hennecke and Charlotte Martin and Wouter Herrebout and Jansen, \{Thomas L.C.\} and Cunha, \{Ana V.\} and Steven Ballet",

note = "Publisher Copyright: {\textcopyright} 2025 Elsevier Ltd",

year = "2025",

month = mar,

doi = "10.1016/j.mtchem.2025.102593",

language = "English",

volume = "44",

journal = "Materials Today Chemistry",

issn = "2468-5194",

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Bertouille, J, Van Lommel, R, Aerts, R, Dockx, L, Mangialetto, J, Van den Brande, N, Willaert, RG, De Proft, F, Hennecke, U, Martin, C, Herrebout, W, Jansen, TLC, Cunha, AV & Ballet, S 2025, 'A comparative study between phenylglycine and phenylalanine derived peptide hydrogels: Towards atomic elucidation', Materials Today Chemistry, vol. 44, 102593. https://doi.org/10.1016/j.mtchem.2025.102593

TY - JOUR

T1 - A comparative study between phenylglycine and phenylalanine derived peptide hydrogels

T2 - Towards atomic elucidation

AU - Bertouille, Jolien

AU - Van Lommel, Ruben

AU - Aerts, Roy

AU - Dockx, Luka

AU - Mangialetto, Jessica

AU - Van den Brande, Niko

AU - Willaert, Ronnie G.

AU - De Proft, Frank

AU - Hennecke, Ulrich

AU - Martin, Charlotte

AU - Herrebout, Wouter

AU - Jansen, Thomas L.C.

AU - Cunha, Ana V.

AU - Ballet, Steven

PY - 2025/3

Y1 - 2025/3

N2 - Peptide hydrogels are naturally inspired soft materials which, due to their biocompatibility, are potential candidates for controlled drug delivery matrices and wound healing applications. The properties of the gel materials are directly linked to the peptide sequence as minor alterations in the sequence are known to create substantial differences in the assembly mode. The majority of hydrogelators self-assemble by a combination of different non-covalent interactions, including hydrophobic effects, π-π stacking, ionic interactions and hydrogen bonding. Consequently, the impact and tunability of each separate interaction towards the self-assembly process is difficult to unravel. In this study, the role of aromatic interactions towards the self-assembly process of a hydrogelator is investigated by interchanging the more flexible phenylalanine amino acids with the more rigid phenylglycines in a short amphipathic hexamer peptide hydrogelator. This substitution resulted in four new effective hydrogelators that show different configurations around the aryl rings. The phenylglycine-rich hydrogel SBL-HG-085 showed an increased gel strength by almost threefold, fast recovery after injection and improved stability under physiological conditions. The soft materials were further characterized at different levels and atomic models of their stacking modes were obtained by all-atom molecular dynamics simulations. A strong correlation has been achieved upon combining the theoretical and experimental results. Altogether, reducing the aromatic side chain flexibility stabilized the assemblies by modified π-π stacking interactions.

AB - Peptide hydrogels are naturally inspired soft materials which, due to their biocompatibility, are potential candidates for controlled drug delivery matrices and wound healing applications. The properties of the gel materials are directly linked to the peptide sequence as minor alterations in the sequence are known to create substantial differences in the assembly mode. The majority of hydrogelators self-assemble by a combination of different non-covalent interactions, including hydrophobic effects, π-π stacking, ionic interactions and hydrogen bonding. Consequently, the impact and tunability of each separate interaction towards the self-assembly process is difficult to unravel. In this study, the role of aromatic interactions towards the self-assembly process of a hydrogelator is investigated by interchanging the more flexible phenylalanine amino acids with the more rigid phenylglycines in a short amphipathic hexamer peptide hydrogelator. This substitution resulted in four new effective hydrogelators that show different configurations around the aryl rings. The phenylglycine-rich hydrogel SBL-HG-085 showed an increased gel strength by almost threefold, fast recovery after injection and improved stability under physiological conditions. The soft materials were further characterized at different levels and atomic models of their stacking modes were obtained by all-atom molecular dynamics simulations. A strong correlation has been achieved upon combining the theoretical and experimental results. Altogether, reducing the aromatic side chain flexibility stabilized the assemblies by modified π-π stacking interactions.

KW - Aromatic interactions

KW - Molecular dynamics simulations

KW - Peptide hydrogels

KW - Peptide self-assembly

KW - Phenylglycine

UR - https://www.scopus.com/pages/publications/85218633486

U2 - 10.1016/j.mtchem.2025.102593

DO - 10.1016/j.mtchem.2025.102593

M3 - Article

AN - SCOPUS:85218633486

SN - 2468-5194

VL - 44

JO - Materials Today Chemistry

JF - Materials Today Chemistry

M1 - 102593

ER -

A comparative study between phenylglycine and phenylalanine derived peptide hydrogels: Towards atomic elucidation

Abstract

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Keywords

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