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Spontaneous Aminolytic Cyclization and Self‐Assembly of Dipeptide Methyl Esters in Water

ChemSystemsChem

March 2020
2(5)

DOI:10.1002/syst.202000013

Authors:

Charalampos Pappas

University of Freiburg

Nadeesha K Wijerathne

The Graduate Center, CUNY

Jugal Kishore Sahoo

Tufts University

Show all 9 authorsHide

Dipeptides are known to spontaneously cyclize to diketopiperazines, and in some cases these cyclic dipeptides have been shown to self‐assemble to form supramolecular nanostructures. Herein, we demonstrate the in situ cyclization of dipeptide methyl esters in aqueous buffer by intramolecular aminolysis, leading to the formation of diverse supramolecular nanostructures. The chemical nature of the amino acid side chains dictates the supramolecular arrangement and resulting nanoscale architectures. For c[LF], supramolecular gels are formed, and the concentration of starting materials influences the mechanical properties of these hydrogels. Moreover, by adding metalloporphyrins to the starting dipeptide starting solution, these become incorporated through cooperative assembly, resulting in the formation of nanofibers able to catalyse the oxidation of organic phenol in water. The approach taken here, which combines chemically activated assembly with the versatility of short peptides, demonstrates a new and easy method to achieving spontaneous formation of a variety of functional supramolecular materials using simple building blocks.

(a) Top panel: Chemical structure of different cyclic dipeptides; Bottom panel: Digital micrographs of various cyclic dipeptides showing sequence specific macroscopic behavior (images captured 72 h after reaction). (b) Time‐dependent conversion (%) determined by HPLC (monitored at 225 nm) of the formation of cyclic dipeptides catalyzed from corresponding dipeptide methyl esters in 100 mM sodium phosphate buffer pH 8.0 at room temperature. (c) FT‐IR and (d) CD spectra of cyclic dipeptides after 72 h of reaction. FT‐IR was performed in D2O phosphate buffer.

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(a) Time‐dependent AFM images of the cyclization reaction after 10 min, 6 and 72 hours for c[DF], c[LF], c[DLDF], c[LL] and c[FF]. (b) TEM images after 72 hours, Scale bar: 500 nm.

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(a) Plot comparing the stiffness of different concentrations (10, 20 and 40 mmol kg⁻¹) of c[LF] gels in 100 mM sodium phosphate buffer pH 8.0 after 72 hours of the reaction (b) Temperature sweep measurements and (c) self‐healing measurements of 20 mmol kg⁻¹ of c[LF].

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(a) Schematic representation of the co‐assembly propensity of dipeptide hydrogel c[LF] and metalloporphyrin (FeIII‐TMPyP) and the catalytic activity of c[LF]‐FeIII‐TMPyP nanostructures on oxidation of pyrogallol. (b) Lineweaver burk plot for peroxidase‐like activity of 5 mmol kg⁻¹ c[LF]‐[FeIII‐TMPyP] for the oxidation of pyrogallol. (c) AFM images of different concentrations of c[LF] i. 0 (control) ii. 1 iii. 2 and iv. 5 mmol kg⁻¹ co‐assembled with 1 μM FeIII‐TMPyP, scale bar 500 nm. Inset in (c): Images of the solution or gels formed for the system c[LF]‐[FeIII‐TMPyP].

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(a) Spontaneous aminolysis of dipeptide methyl esters to form cyclic self‐assembling moieties through intermolecular cyclisation in aqueous phosphate buffer (100 mM sodium phosphate buffer pH 8.0) at room temperature. Chemical structures of the dipeptide methyl ester and cyclic building blocks with different amino acid side chains depicted by single letter code, with their self‐assembly propensity to form supramolecular stacks through hydrogen‐ bonding. (b) Schematic representation of the supramolecular organization of different cyclic dipeptides showing sequence‐specific morphologies. D‐amino acids (for c[LF]) are represented with open circles.

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Spontaneous Aminolytic Cyclization and Self-Assembly of

Dipeptide Methyl Esters in Water**

Charalampos G. Pappas+,*[a, b] Nadeesha Wijerathne+,[b, c, d] Jugal Kishore Sahoo+,[a]

Ankit Jain,[b] Daniela Kroiss,[b, e] Ivan R. Sasselli,[a] Ana Sofia Pina,[b] Ayala Lampel,[b] and

Rein V. Ulijn*[b, c, d, e]

Dipeptides are known to spontaneously cyclize to diketopiper-

azines, and in some cases these cyclic dipeptides have been

shown to self-assemble to form supramolecular nanostructures.

Herein, we demonstrate the in situ cyclization of dipeptide

methyl esters in aqueous buffer by intramolecular aminolysis,

leading to the formation of diverse supramolecular nano-

structures. The chemical nature of the amino acid side chains

dictates the supramolecular arrangement and resulting nano-

scale architectures. For c[LF], supramolecular gels are formed,

and the concentration of starting materials influences the

mechanical properties of these hydrogels. Moreover, by adding

metalloporphyrins to the starting dipeptide starting solution,

these become incorporated through cooperative assembly,

resulting in the formation of nanofibers able to catalyse the

oxidation of organic phenol in water. The approach taken here,

which combines chemically activated assembly with the

versatility of short peptides, demonstrates a new and easy

method to achieving spontaneous formation of a variety of

functional supramolecular materials using simple building

blocks.

Chemically triggered formation of supramolecular assemblies,[1]

i. e. the chemical conversion of non-associating precursors to

self-assembling architectures, has gained significant interest as

a means to control structural, spatial and dynamic features of

supramolecular nanomaterials. Using chemical conversions to

trigger self-assembly has been extensively studied by Van

Esch,[2] Boekhoven,[3] Hermans,[4] Xu,[5] and us[6] amongst others,

usually with the objective to trigger and manipulate the

assembly of supramolecular hydrogelators. This approach

provides a level of control over both kinetics (through

modulating reaction rates) and thermodynamics (modulating

chemical structure of building blocks), giving access to

equilibrium,[6] kinetically trapped[7] or dynamically unstable

supramolecular nanostructures.[8–14] A number of

supramolecular functionalities[15] have been reported by using

in-situ formation of self-assembly building blocks that are

difficult to achieve by using conventional self-assembly ap-

proaches, including localized nanostructure formation to selec-

tively kill cancer cells,[16] transient electronic wires,[17] and

negatively charged biological membranes which act as catalysts

for hydrogel formation.[18]

Peptides and peptide derivatives are attractive building

blocks for the fabrication of artificial nanostructures with

tremendous biological and nanotechnology applications, arising

from their combinatorial diversity and biocompatibility.[19–26]

Peptide sequences as short as two or three amino acids have

been utilized for nanostructure formation in a sequence

dependent manner using linear[27–32] or cyclic peptides.[33–36]

Cyclic dipeptides (or diketopiperazines) involve the presentation

of amino acid side chain functionality at the exterior of the

nanostructure, thus rendering it accessible for interactions and/

or functionalization. Govindaraju’s group has extensively inves-

tigated their assembly, highlighting interesting properties of

these systems, including the increased stability towards

proteolysis.[37–39] Both supramolecular organogels[40] and

hydrogels[41] have been reported based on these structures.

Gazit and Reches demonstrated the spontaneous formation and

self-assembly of surface-bound arrays of cyclic diphenylalanine

peptide nanotubes using chemical vapor deposition.[42] Tunable

nanostructures with photoluminescence properties have also

been reported for cyclic dipeptides after dimerization into

quantum dots.[43] More generally, cyclic dipeptides are well-

known byproducts resulting from chemical degradation,

through aminolysis of dipeptide esters (including aspartame),

suggesting that they form spontaneously under much milder,

[a] Dr. C. G. Pappas,+Dr. J. K. Sahoo,+Dr. I. R. Sasselli

Department of Pure and Applied Chemistry, Technology and Innovative

Centre

University of Strathclyde, Glasgow, G1 1RD (UK)

E-mail: c.pappas@rug.nl

[b] Dr. C. G. Pappas,+Dr. N. Wijerathne,+Dr. A. Jain, Dr. D. Kroiss, Dr. A. S. Pina,

Dr. A. Lampel, Prof. R. V. Ulijn

Advanced Science Research Center (ASRC) at the City University of New York

(CUNY)

85 St Nicholas Terrace, New York, 10031 (USA)

E-mail: rein.ulijn@asrc.cuny.edu

[c] Dr. N. Wijerathne,+Prof. R. V. Ulijn

Hunter College, Department of Chemistry

CUNY, 695 Park Avenue, New York, 10065 (USA)

[d] Dr. N. Wijerathne,+Prof. R. V. Ulijn

Ph.D. Program in Chemistry, The Graduate Center of the City University of

New York

New York, NY, 10016 (USA)

[e] Dr. D. Kroiss, Prof. R. V. Ulijn

Ph.D. Program in Biochemistry, The Graduate Center of the City University

of New York

New York, NY, 10016 (USA)

[+]These authors contributed equally to this work.

[**] A previous version of this manuscript has been deposited on a preprint

server (DOI: 10.26434/chemrxiv.11637312.v1)

Supporting information for this article is available on the WWW under

https://doi.org/10.1002/syst.202000013

An invited contribution to a Special Collection on Systems Chemistry Applied

to Materials Science

ChemSystemsChem

Communications

doi.org/10.1002/syst.202000013

Wiley VCH Donnerstag, 27.08.2020

2005 / 161906 [S. 18/23] 1

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Self-assembled peptide nanostructures have been increasingly exploited as functional materials for applications in biomedicine and energy. The emergent properties of these nanomaterials determine the applications for which they can be exploited. It has recently been appreciated that nanomaterials composed of multicomponent coassembled peptides often display unique emergent properties that have the potential to dramatically expand the functional utility of peptide-based materials. This review presents recent efforts in the development of multicomponent peptide assemblies. The discussion includes multicomponent assemblies derived from short low molecular weight peptides, peptide amphiphiles, coiled coil peptides, collagen, and β-sheet peptides. The design, structure, emergent properties, and applications for these multicomponent assemblies are presented in order to illustrate the potential of these formulations as sophisticated next-generation bio-inspired materials.

Spontaneous Aminolytic Cyclization and Self‐Assembly of Dipeptide Methyl Esters in Water

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