Crafting of functional biomaterials by directed molecular self-assembly of triple helical peptide building blocks

Abstract

Collagen is the most abundant extracellular matrix protein in the body and has widespread use in biomedical research, as well as in clinics. In addition to difficulties in the production of recombinant collagen due to its high non-natural imino acid content, animal-derived collagen imposes several major drawbacks-variability in composition, immunogenicity, pathogenicity and difficulty in sequence modification-that may limit its use in the practical scenario. However, in recent years, scientists have shifted their attention towards developing synthetic collagen-like materials from simple collagen model triple helical peptides to eliminate the potential drawbacks. For this purpose, it is highly desirable to develop programmable self-assembling strategies that will initiate the hierarchical self-assembly of short peptides into large-scale macromolecular assemblies with recommendable bioactivity. Herein, we tried to elaborate our understanding related to the strategies that have been adopted by few research groups to trigger self-assembly in the triple helical peptide system producing fascinating supramolecular structures. We have also touched upon the major epitopes within collagen that can be incorporated into collagen mimetic peptides for promoting bioactivity.

Keywords: collagen; hierarchical self-assembly; supramolecular structures; synthetic collagen; triple helical peptides.

Figure 1.

Illustration of each distinct step towards the hierarchical self-assembly of fibril-forming collagen type I. Adapted from [1].

Figure 2.

TEM images of triple helical peptides polymerized using NCL methodology (b–d). Image (a) represents TEM of (POG)₁₀ polymerized by self-condensation. The primary peptide sequence corresponding to picture (b) COG(POG)₉ COSØ, (c) COG(POG)₄EOG(POG)₄ COSØ and (d) COG(POG)₃PRGDOG(POG)₄ COSØ^, where COSØ represents C-terminal thioester derivative of para-acetamidophenyl. Reprinted with permission from Paramonov et al. [35]. (Copyright © 2005 American Chemical Society).

Figure 3.

AFM topographical images of peptides (a–d) corresponding to peptide structures 1a, 1b, 1c and 1d; The scale bar in each image is 1 µm. Reprinted with permission from Cejas et al. [38]. (Copyright © 2008 National Academy of Sciences.) (Online version in colour.)

Figure 4.

(a) Synergistic packing model of peptide FT4Y with aromatic residues at both terminal ends showing head-to-tail interactions as well as π–CH interactions. (b) In peptide T4Y, this effect is less pronounced as the number of interactions are less due to the absence of N-terminal aromatic group. The model clearly shows that the aromatic groups are capable of mediating π–CH interactions, which are non-specific. Reprinted with permission from Kar et al. [41]. (Copyright © 2010 American Chemical Society.)

Figure 5.

The left panel shows the chemical structure of peptides used for metal mediated self-assembly. The right panel corresponding to each peptide shows cartoon of triple helical folded structure, ordered assembled structure for linear and cross-link designs and the electron microscopic images—TEM/SEM of the self-assembled higher-order structures. (a) Reprinted with permission from Przybyla & Chmielewski [44] (copyright © 2008 American Chemical Society); (b) reprinted with permission from Przybyla & Chmielewski [45] (copyright © 2010 from American Chemical Society); (c) reprinted with permission from Przybyla et al. [46] (copyright © 2013 from American Chemical Society); (d) reprinted with permission from Pires & Chmielewski [48] (copyright © 2009 from American Chemical Society); (e) reprinted with permission from Pires et al. [49] (copyright © 2011 from American Chemical Society); (f) reprinted with permission from Hernandez-Gordillo & Chmielewski [50] (copyright © 2016 from MDPI AG). (g) Reprinted with permission and adapted from Hernandez-Gordillo & Chmielewski [52] (copyright © 2014 from Elsevier).

Figure 5.

The left panel shows the chemical structure of peptides used for metal mediated self-assembly. The right panel corresponding to each peptide shows cartoon of triple helical folded structure, ordered assembled structure for linear and cross-link designs and the electron microscopic images—TEM/SEM of the self-assembled higher-order structures. (a) Reprinted with permission from Przybyla & Chmielewski [44] (copyright © 2008 American Chemical Society); (b) reprinted with permission from Przybyla & Chmielewski [45] (copyright © 2010 from American Chemical Society); (c) reprinted with permission from Przybyla et al. [46] (copyright © 2013 from American Chemical Society); (d) reprinted with permission from Pires & Chmielewski [48] (copyright © 2009 from American Chemical Society); (e) reprinted with permission from Pires et al. [49] (copyright © 2011 from American Chemical Society); (f) reprinted with permission from Hernandez-Gordillo & Chmielewski [50] (copyright © 2016 from MDPI AG). (g) Reprinted with permission and adapted from Hernandez-Gordillo & Chmielewski [52] (copyright © 2014 from Elsevier).

Figure 6.

Schematic of self-assembly in three discrete steps: triple helix–nanofibres–hydrogel. The fibrous morphology of the hydrogel is captured by cryo TEM, AFM and SEM (from left to right). Reprinted with permission from O'Leary et al. [58]. (Copyright © 2011 Macmillan Publishers Ltd.)

Figure 7.

Scheme showing the self-assembly mechanism of elongated triple helical fibres using cysteine knot strategy to drive the self-assembly process. The chemical structure shows the exact location of disulfide bonds between Cys (indicated in black) that helps to create three specific strand registers—α1 (blue), α2 (red) and α1′ (blue) in each individual triple helix. The (Pro-Yaa-Gly)₅ shown within rectangular boxes are the overhanging sticky-ends. The overhanging sticky-ends further drives the self-assembly through intermolecular triple helix formation eventually yielding extended fibrils of unprecedented length. Adapted with permission from Kotch & Raines [63]. (Copyright © 2006 National Academy of Sciences.)