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Self-assembly of peptide nano-structures

Introduction

Recent technological advances allow us to build nanoscale structures using advanced lithographic processes, but these processes are complex, expensive, and have restricted functionality. In nature there already exists an extensive toolbox of techniques for assembling structures from the nanoscale up to the macroscopic, and scientists at the University of Leeds are working to understand these processes.

Proteins are one of the most important building blocks of living organisms. These display controlled structure and function at a range of scales. In biochemical terminology, molecular level structure - the order of amino acids within a protein - is referred to as primary structure:

Peptide primary structure

Polypepeptides are short chain polymers of amino acids, bi-functional monomers that can be combined in a controlled manner to create a macromolecule with a defined structure, as shown in the animation below. Only α-Amino acids are commonly found in nature, these are simple molecules in which a single, central carbon is attached to four groups - a carboxylic acid, an amine, a 'side chain', and a hydrogen atom. All but the simplest amino acid (glycine, in which the side chain is also a hydrogen atom) are, therefore, chiral, existing as two optical isomers, only one of which is ever formed by living organisms. The variability in the side chain gives rise to an infinite number of possible amino acids - but again only 20 are common in nature (the 'standard' amino acids).

The growth mechanism of the peptide results in one end being terminated by a carboxyl group, while the other has a free amine group. This allows us to readily distinguish between the two ends of a peptide chain (or, indeed, a larger protein molecule).

Peptide secondary structure

The primary structure results in an alternating motif of amine (NH) and carbonyl (CO) chemical groups along the spine of the peptide. These groups are highly polar, and readily form hydrogen bonds with each other N-H ---- O=C. This tendency gives rise to two important secondary structures, the α-helix, and the β-pleated sheet. Given amino-acid sequences have been found to exhibit a preference for one or other of these structures, depending in part upon the nature of the side chain groups.

Here we will focus on synthetic peptides that have a strong preference for the beta-sheet morphology. The β-sheet is formed when hydrogen bonds are established between adjacent peptide strands. In very large peptide molecules (or proteins), the adjacent strands can be parts of the same molecule that has folded back on itself. In shorter peptides, these interactions are intermolecular, between two or more separate molecules.

At Leeds, researchers have been looking at the finer detail of the structures that can be formed by β-sheet forming peptides. They have found that a hierarchy of self-assembling structures are attainable, depending upon the concentration of peptide in solution. Thus, control over the nano-scale architectures can be achieved simply by adjusting the peptide concentration in solution, solution conditions and peptide design.

Self-assembling structures formed at low concentration

At low concentrations in solution peptide strands sit side-by-side to form a tape.1 Adjacent peptides in the tape are oriented head-to-tail. The tape curls up to form a simple helical structure.

If a dilute solution is dripped onto a mica surface, however, the tapes uncoil as the solution dries, and lie out flat on the surface, with any hydrophilic groups on the peptide chain pointed towards the silica surface. Sequential drips increase the density of tapes on the surface, until near 100% coverage is attained. The tapes can be orientated to lie parallel to each other by application of a shear stress. This results in what is effectively a protein layer which hides the mica surface completely, and may be functionalised as desired simply by changing the original peptide synthesis.1

Structures formed at higher peptide concentrations

At higher peptide concentrations the tapes form a double thickness ribbon this in-turn adopts a twisted conformation, rather than the simple helix seen at low concentrations.

At high peptide concentrations the ribbons stack up, and the stack twists to form fibrils - as shown in the animation below right. Thicker fibres can be formed through the interaction of fibrils...

Applications

The ability to self-assemble into well-defined structures make these synthetic peptides interesting to nano-engineering projects. The fibrillar structures have been used as templates for silica nano-tubes.2

While peptides may play a role as a template for engineering of hard materials at the nano-scale, they are also interesting in biological applications, where their chemical nature is often an asset, making them compatible with living tissues.

The fibrillar structure of some of the peptides designed at Leeds is similar in properties to the extracellular matrix laid down prior to mineralisation to form hard tissues such as bones and teeth. In in-vitro tests, it has been found that peptide fibrils enhance re-mineralisation of teeth, and may lead to an improved treatment for dental caries, repairing damaged dentine and enamel, rather than replacing it with plastics or amalgam; this is called "filling without drilling".3, 4

References

1. "Hierarchical self-assembly of chiral units as a model for peptide beta-sheet tapes, ribbons, fibrils and fibres" Aggeli A, Nyrkova IA, Bell M, Harding R, Carrick L, McLeish TCB, Semenov AN and Boden N Proc. Natl. Ac. Sci. USA, 98 (2001), 11857-11862

2. "Designed self-assembled beta-sheet peptide fibrils as templates for silica nanotubes" Meegan, J, Aggeli, A, Boden, N, Brydson, R, Brown, A, Carrick, L, Brough, A, Hussain, A, Ansell, R, Advanced Functional Materials, 14 (2004), 31-37.

3. "Self-assembling Peptide Scaffolds Promote Enamel Remineralization" J. Kirkham1, A. Firth, D. Vernals, N. Boden, C. Robinson, R.C. Shore, S.J. Brookes, and A. Aggeli J Dent Res, 86 (2007), 426-430.

4. "Biomimetic self-assembling peptides as injectable scaffolds for hard tissue engineering" Firth A, Aggeli A, Burke JL, Yang XB and Kirkham J Nanomedicine, 1 (2006), 189-199.

Web links for more information

Find out more about self assembling peptides on the Centre for Molecular Nanoscience website: website link.

Wikipedia article on glycine, the simplest amino acid

Wikipedia article on an introduction to amino acids, with structures and properties of the 20 'standard types' found in nature.

 
Link to the University of Leeds. Link to the University of Sheffield.

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