Effect of glycine substitution on Fmoc-diphenylalanine self-assembly and gelation properties.

We have investigated the self-assembly behavior of fluorenyl-9-methoxycarbonyl (Fmoc)-FG, Fmoc-GG, and Fmoc-GF and compared it to that of Fmoc-FF using potentiometry, fluorescence and infrared spectroscopy, transmission electron microscopy, wide-angle X-ray scattering, and oscillatory rheometry. Titration experiments revealed a substantially shifted apparent pK(a) transition for Fmoc-FG, Fmoc-GG, and Fmoc-GF. The apparent pK(a) values observed correlated with the hydrophobicity (log P) of the Fmoc-dipeptide molecules. Fmoc-GG and Fmoc-GF were found to self-assemble only in their protonated form (below their apparent pK(a)), while Fmoc-FG formed self-assembled structures above and below its apparent pK(a). Fmoc-GG and Fmoc-FG were found to form hydrogels below their apparent pK(a) transitions in agreement with the entangled fibers morphologies revealed by TEM. Unlike Fmoc-FF and Fmoc-GG, Fmoc-FG showed unusual gelation behavior as gels were found to form upon heating. Fmoc-GF formed precipitates instead of a hydrogel below its apparent pK(a) in agreement with the formation of micrometer scale sheetlike structures observed by TEM. The fact that all four Fmoc-dipeptides were found to self-assemble suggests that the main driving force behind the self-assembly process is a combination of the hydrophobic and π-π interactions of the fluorenyl moieties with a secondary role for hydrogen bonding of the peptidic components. The nature of the peptidic tail was found to have a pronounced effect on the type of self-assembled structure formed. This work indicates that the substitution of phenylalanine by glycine significantly impacts on the mode of assembly and illustrates the versatility of aromatic peptide amphiphiles in the formation of structurally diverse nanostructures.

[1]  R. Youngman,et al.  Self-assembly and hydrogelation promoted by F5-phenylalanine , 2010 .

[2]  Jindrich Kopecek,et al.  Peptide-directed self-assembly of hydrogels. , 2009, Acta biomaterialia.

[3]  F. Avilés,et al.  Ile-phe dipeptide self-assembly: clues to amyloid formation. , 2007, Biophysical journal.

[4]  J. Lakowicz.  Principles of fluorescence spectroscopy , 1983 .

[5]  Meital Reches,et al.  Casting Metal Nanowires Within Discrete Self-Assembled Peptide Nanotubes , 2003, Science.

[6]  A. Miller,et al.  Self-assembly and gelation properties of α-helix versus β-sheet forming peptides , 2009 .

[7]  Andrew M. Smith,et al.  Fmoc-diphenylalanine self-assembly mechanism induces apparent pKa shifts. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[8]  Kyle L. Morris,et al.  Effect of molecular structure on the properties of naphthalene-dipeptide hydrogelators. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[9]  Bing Xu,et al.  Small molecule hydrogels based on a class of antiinflammatory agents. , 2004, Chemical communications.

[10]  C. Ratcliffe,et al.  Interfacing Supramolecular Gels and Quantum Dots with Ultrasound: Smart Photoluminescent Dipeptide Gels , 2008 .

[11]  Bing Xu,et al.  Supramolecular hydrogels respond to ligand-receptor interaction. , 2003, Journal of the American Chemical Society.

[12]  T. M. Parker,et al.  Nanometric design of extraordinary hydrophobic‐induced pKa shifts for aspartic acid: Relevance to protein mechanisms , 1994, Biopolymers.

[13]  P. Janmey,et al.  Use of a gel‐forming dipeptide derivative as a carrier for antigen presentation , 1995, Journal of peptide science : an official publication of the European Peptide Society.

[14]  Jason J. Han,et al.  Dynamic π−π Stacked Molecular Assemblies Emit from Green to Red Colors , 2003 .

[15]  A. Kros,et al.  Power struggles in peptide-amphiphile nanostructures. , 2010, Chemical Society reviews.

[16]  Bing Xu,et al.  Aromatic-aromatic interactions induce the self-assembly of pentapeptidic derivatives in water to form nanofibers and supramolecular hydrogels. , 2010, Journal of the American Chemical Society.

[17]  Paul Sanderson,et al.  A new method for maintaining homogeneity during liquid–hydrogel transitions using low molecular weight hydrogelators , 2009 .

[18]  Rein V Ulijn,et al.  Enzyme-triggered self-assembly of peptide hydrogels via reversed hydrolysis. , 2006, Journal of the American Chemical Society.

[19]  D. Shah,et al.  Effect of Premicellar Aggregation on the pKa of Fatty Acid Soap Solutions , 2003 .

[20]  D. Adams.  Dipeptide and tripeptide conjugates as low-molecular-weight hydrogelators. , 2011, Macromolecular bioscience.

[21]  Jangwook P. Jung,et al.  Multi-component extracellular matrices based on peptide self-assembly. , 2010, Chemical Society reviews.

[22]  I. Hamley,et al.  Hydrogelation and self-assembly of Fmoc-tripeptides: unexpected influence of sequence on self-assembled fibril structure, and hydrogel modulus and anisotropy. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[23]  Peptide directed synthesis of silica coated gold nanocables. , 2010, Chemical communications.

[24]  Andrew M. Smith,et al.  Designing peptide based nanomaterials. , 2008, Chemical Society reviews.

[25]  C. Pace,et al.  Hydrogen bonding markedly reduces the pK of buried carboxyl groups in proteins. , 2006, Journal of molecular biology.

[26]  Hjalmar Brismar,et al.  Self-assembling Fmoc dipeptide hydrogel for in situ 3D cell culturing , 2007, BMC biotechnology.

[27]  Honggang Cui,et al.  Self‐assembly of peptide amphiphiles: From molecules to nanostructures to biomaterials , 2010, Biopolymers.

[28]  Katsuhiko Ariga,et al.  Tunable pK of amino acid residues at the air-water interface gives an L-zyme (langmuir enzyme). , 2005, Journal of the American Chemical Society.

[29]  W. Frith,et al.  Relationship between molecular structure, gelation behaviour and gel properties of Fmoc-dipeptides , 2010 .

[30]  A. Banerjee,et al.  Self-assembling tripeptide based hydrogels and their use in removal of dyes from waste-water , 2009 .

[31]  Chan Beum Park,et al.  Photoluminescent Peptide Nanotubes , 2009 .

[32]  J. Parquette,et al.  A pi-conjugated hydrogel based on an Fmoc-dipeptide naphthalene diimide semiconductor. , 2010, Chemical communications.

[33]  B. Cousins,et al.  A study of the dynamic interaction of surfactants with graphite and carbon nanotubes using Fmoc-amino acids as a model system. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[34]  P. Y. Chou,et al.  Secondary structural prediction of proteins from their amino acid sequence , 1977 .

[35]  M. Turner,et al.  An investigation of the conductivity of peptide nanotube networks prepared by enzyme-triggered self-assembly. , 2010, Nanoscale.

[36]  D. W. Fink,et al.  pH Effects on fluorescence of umbelliferone , 1970 .

[37]  R. Ulijn,et al.  Micelle to fibre biocatalytic supramolecular transformation of an aromatic peptide amphiphile. , 2011, Chemical communications.

[38]  K. Hausser,et al.  Transanular interaction in [2.2]phanes: [2.2](4,4')diphenylophane and [2.2](2,7) fluorenophane , 1978 .

[39]  E. Gazit,et al.  Self-assembly of peptide nanotubes and amyloid-like structures by charged-termini-capped diphenylalanine peptide analogues , 2005 .

[40]  Rein V Ulijn,et al.  Enzyme-assisted self-assembly under thermodynamic control. , 2009, Nature nanotechnology.

[41]  Rein V. Ulijn,et al.  Fmoc‐Diphenylalanine Self Assembles to a Hydrogel via a Novel Architecture Based on π–π Interlocked β‐Sheets , 2008 .

[42]  D. Seliktar,et al.  Self-assembled Fmoc-peptides as a platform for the formation of nanostructures and hydrogels. , 2009, Biomacromolecules.

[43]  Bing Xu,et al.  Enzyme‐instructed self‐assembly of peptide derivatives to form nanofibers and hydrogels , 2010, Biopolymers.

[44]  D. Gowda,et al.  Relative Significance of Electrostatic- and Hydrophobic-Induced pKa Shifts in a Model Protein: The Aspartic Acid Residue , 1993 .

[45]  Meital Reches,et al.  Rigid, Self‐Assembled Hydrogel Composed of a Modified Aromatic Dipeptide , 2006 .

[46]  S. Richardson,et al.  Introducing chemical functionality in Fmoc-peptide gels for cell culture. , 2009, Acta biomaterialia.

[47]  A. Miller,et al.  Nanostructured Hydrogels for Three‐Dimensional Cell Culture Through Self‐Assembly of Fluorenylmethoxycarbonyl–Dipeptides , 2006 .

[48]  R. Ulijn,et al.  Exploiting biocatalysis in peptide self‐assembly , 2010, Biopolymers.

[49]  D. Shah,et al.  Cooperativity among Molecules at Interfaces in Relation to Various Technological Processes: Effect of Chain Length on the pKa of Fatty Acid Salt Solutions† , 2000 .