Programming peptide assembly

There are many examples of peptides that self-assemble to form long, fibrous structures. Forming closed assemblies is more difficult. This HFSP-funded study shows that two α-helical peptides can be joined by a series of peptide linkers of different lengths to form a range of new peptide assemblies. The structure formed depends on the length of the linker employed, with short linkers favoring fibers and the longer linkers leading to closed nanostructures.

HFSP Program Grant holders Derek Woolfson, Heiner Linker, Nancy Forde, Paul Curmi and colleagues
authored on Tue, 13 November 2012

In recent years, multiple examples of nanostructures formed from DNA have been presented.  This is because we have good rules for constructing objects from DNA.  However, it is envisaged that similar structures formed from peptidic components would have a greater range of potential applications due to the more-varied chemistries of the amino-acid building blocks of peptides.  More specifically, whilst there are good examples of long fibers made from peptides, small, closed, discrete peptide-based nanostructures have generally been difficult to make.  The problem is that we do not have the same level of understanding for such assemblies as we do for DNA-based structures.

One potential peptide building block for constructing nanostructures is the coiled coil.  These are protein-protein-interaction domains composed of two or more α-helices that wrap around each other like strands of a rope.  Many studies over the past twenty years have led to a set of reasonably well-defined rules that describe how these coiled-coil peptides are formed and interact.  In this new study, two complementary α-helical peptides were designed and joined by peptidic linkers of varied length.  The idea was that the helices of these helix-linker-helix constructs would bind together, and that as the linkers were longer there should be more freedom for them to fold back on themselves to make discrete objects, see Figure below.

Consistent with this design concept, constructs with short linkers (two amino acids long) produced long fibers comprising many thousands of assembled peptides; and those with linkers of intermediate length (4 amino acids) resulted in large spherical structures again with multiple copies of peptides.  However, with longer linkers of 6 – 10 amino acids, nanostructures of defined sizes comprising either 4 or 3 helix-linker-helix units were achieved.

The authors rationalize the behavior of this system in terms of a balance between the bulk of the helices, which favors the formation of continuous fibrous structures, and wins out when the linkers are short; and chain flexibility, which favors intramolecular helix-helix interactions, and dominates when the linkers are long.

That the authors can achieve a range of structures from just two building blocks is encouraging for taking a modular or synthetic biology approach to protein and materials design; and their new structures could pave the way to materials with potential applications in tissue engineering (the fibers), drug delivery (the spheres), and MRI-contrast agents (the discrete structures).

Text by Aimee Boyle

Reference

Squaring the circle in peptide assembly: from fibers to discrete nanostructures by de novo design. Aimee L. Boyle, Elizabeth H. C. Bromley, Gail J. Bartlett, Richard B. Sessions, Thomas H. Sharp, Claire L. Williams, Paul M. G. Curmi, Nancy R. Forde, Heiner Linker and Derek N. Woolfson. J. Am. Chem. Soc. 2012, 134 (37):15457-15467.

Pubmed link