Review
Designing supramolecular protein assemblies

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Abstract

Many natural proteins self-assemble, either to fulfill their biological function or as part of a pathogenic process. Biological assembly phenomena such as amyloidogenesis, domain swapping and symmetric oligomerization are inspiring new strategies for designing proteins that self-assemble to form supramolecular complexes. Recent advances include the design of novel proteins that assemble into filaments, symmetric cages and regular arrays.

Introduction

Our knowledge of the three-dimensional structures of proteins has proven to be extraordinarily valuable from both scientific and engineering perspectives. Whereas the structures as a whole have taught us about physical principles, the individual structures are serving as starting points for a variety of engineering studies whose goals are to duplicate, modify or expand upon what Nature has achieved on its own.

Considerable efforts in protein engineering have been devoted to introducing variation into otherwise natural protein sequences to achieve new or altered functions, or to introduce particular properties, such as enhanced stability (reviewed in 1., 2., 3., 4., 5., 6., 7.). Others have designed sequences more or less de novo to fold into relatively simple structures (reviewed in 8., 9., 10.). Several recent studies have begun to take protein design to the next level of organization by designing self-assembling systems. Most of these studies have focused on particularly simple protein folding patterns, especially α helices in bundles or coiled-coil arrangements. For this type of fold, several groups have succeeded in recent years in designing small proteins that self-assemble a few at a time to form helical bundles composed of between two and four helices (11., 12., reviewed in 8., 10., 13.). Several groups are developing new strategies for designing more complex protein assemblies, such as filaments, cages and extended ordered arrays. In this review, we discuss these strategies and touch on potential applications for emerging protein-based nanomaterials.

Section snippets

Linear assemblies

A variety of linear assemblies have been designed using peptide-based systems. Nearly ten years ago, Ghadiri et al. [14] synthesized cyclic polypeptides (containing alternating d- and l-amino acids) that self-assembled to form filaments. Several variations on this theme have been explored as well 15., 16., 17., 18., 19•., 20.. Here, we review recent work on linear assemblies built from proteins or polypeptides containing the natural l-amino acids.

Ordered architectures by polyvalent design

In the filament designs discussed above, each protein subunit is tailored to make interactions with two others. In the case of polar filaments, these are two identical head-to-tail interactions, whereas in the case of bipolar filaments, these are two distinct symmetric interactions. In either case, the bivalent nature of the subunit gives rise to simple linear assemblies. By contrast, when each molecule tends to interact with three or more other molecules — a situation we refer to here as

Applications

The various types of designed assemblies discussed here could all lead to useful nanomaterials. Good examples can be found for several types. Linear nanofibers of alkylated peptides have been used to direct the mineralization of hydroxyapatite in a way that mimics the lowest structural organization of bone [43•]. Self-assembling cyclic poly-peptides have shown promise as bactericidal agents [19•]. Cage-like assemblies might someday be useful as molecular delivery vehicles or as catalysts active

Future directions

Specificity and control are two problems that require further work. At the present time, designing self-assembling proteins involves some amount of uncertainty about whether a particular design will be successful and whether it will self-assemble precisely as intended. The occurrence of filaments when individual β sheets were intended (discussed in 21., 22•.) and the frequent occurrence of filament bundles when individual filaments are designed 29••., 31••., 34••. both illustrate this point.

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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