Collagen connection: The sticky ends

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  • Published: Nov 1, 2014
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Collagen connection: The sticky ends

Tissue engineering

Discovering the secrets of collagen, a major component of connective tissue in mammals could lead to improved tissue engineering and cosmetic and reconstructive medicine. Researchers at Rice University have now used NMR spectroscopy to demonstrate how model collagen fibres self-assemble via their sticky ends. Credit: Hartgerink et al/Rice/JACS/American Chemical Society)

Discovering the secrets of collagen, a major component of connective tissue in mammals could lead to improved tissue engineering and cosmetic and reconstructive medicine. Researchers at Rice University have now used NMR spectroscopy to demonstrate how model collagen fibres self-assemble via their sticky ends.

Jeffrey Hartgerink and his team at Rice have been studying synthetic collagen for a decade, they hope to unravel its behaviour in which it starts out as three distinct peptides that twist into the typical triple helices. Such synthetic collagens have been developed and investigated by the group for use as blood clotting agents and as scaffolding materials for regenerative medicine. Now, the team has published two papers in the Journal of the American Chemical Society, one in May and the second in October that provide an explanation for precisely how these mimetic peptides become aligned with each other to twist into helices with sticky ends that allow them to subsequently aggregate into fibres or gels.

"We proposed in a Nature Chemistry paper (in 2011) that peptides self-assemble in an offset fashion that creates sticky ends," Hartgerink explains. "And those sticky ends can then propagate. But even in the review of that paper, the mechanism took a fair amount of flak because there had been no reports in the literature that a collagen system could, in fact, create this offset." It has taken the team several years to reach the point at which they can, through these two papers, show that their critics were in fact wrong.

Blunt or sticky

Natural collagen is the most abundant protein in mammals representing between a quarter and a third of protein mass. It forms from helical arrangements of three peptide chains containing a large number of glycine and proline amino acid residues. These helices allow collagen to form elongated fibrils, which are then constituents of fibrous tissues such as tendons, ligaments and skin. Collage is, however, also present in the cornea of the eye, in cartilage, bone, blood vessels, the gut, intervertebral discs and even the dentin in teeth.

Scientists, including Hartgerink, have made custom nanoscale peptide chains by carefully arranging the amino acids and their positive and negative charges to design in properties that mimic natural collagen. Such biomimetic materials could have applications not only in improving our understanding of natural collagen but in replacing damaged tissues or in engineering applications where the natural properties might outstrip conventional materials.

With the appropriate order of charged amino acids, cross links form through axial salt bridges, non-covalent bonds that hold the helices together with the help of stabilizing hydrogen bonds. "Most of the work we've done on collagen has been to define those axial charged pairs and then utilize them to do different things," Hartgerink explains. He points out that the ends of these helices can be "blunt" or "sticky". It depends on the offset, or staggering, between chains. Chains offset by just one amino acid are blunt and have no "stickiness" at all. The greater the offset, the stickier the bundle becomes.

Collagen central

In the earlier JACS paper, Hartgerink and graduate students Abihishek Jalan and Katherine Jochim demonstrated how standalone, sticky-ended triple helices with offsets of four amino acids undergo self-assembly using nuclear magnetic resonance (NMR) spectroscopy. "We chose to use a really short offset because as soon as we make it a little bit bigger, it becomes stickier and fibres start forming," Hartgerink explains. "As soon as you have a fibre, NMR doesn't work any more. But NMR is the go-to analytical tool, and in this case we were able to show at a molecular level that the offset takes place."

In the second paper graduate student Biplab Sarkar and former graduate student Lesley O'Leary, did the reverse in that they synthesized a series of peptides with large sticky ends that drive fibre assembly. They made two classes of synthetic collagen peptides with the same chemical components but different arrangements and showed those with extensive sticky ends quickly self-assembled into fibres. Those with misaligned sequences either formed amorphous aggregates or remained separated in solution.

"We chose to satisfy the critics by breaking our work into two studies," Hartgerink says. "One was to demonstrate at the molecular level that these charged pairs are powerful and can drive this kind of offset, which hadn't been demonstrated before, and that the resulting helices are potentially sticky," he adds. "Then, in the second study, we made them actually sticky and showed that when you use charged pairs properly, you get fibres. And when you don't, you don’t get fibres."

The potential for designer synthetic collagens is obvious. "A number of biomaterials use natural collagen, and there are advantages to replacing them with synthetic collagens," Hartgerink says. "One of the main advantages is that we move away from health and regulatory problems associated with using animal sources." Additionally, synthetic collagen may also help answer important questions about natural collage. "Collagen is an incredibly important central player in tissue behaviour, but even some of the very basic ideas about collagen structure have eluded scientists for decades," Hartgerink says. "One of the things we're pursuing now is generating libraries of collagen mimetic peptides to test them against known collagen-binding proteins and proteases, proteins that cut up collagen. These mechanistic studies will allow us to push the science forward and do more practical things."

Related Links

J Am Chem Soc
, 2014, 136, 7535-7538
: "Rational Design of a Non-canonical “ Sticky-Ended ” Collagen Triple Helix"

J Am Chem Soc, 2014, 136, 14417-14424: "Self-Assembly of Fiber-Forming Collagen Mimetic Peptides Controlled by Triple-Helical Nucleation"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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