Hierarchical self-assembly of chiral rod-like molecules as a model for peptide β-sheet tapes, ribbons, fibrils, and fibers

Abstract

A generic statistical mechanical model is presented for the selfassembly of chiral rod-like units, such as ␤-sheet-forming peptides, into helical tapes, which with increasing concentration associate into twisted ribbons (double tapes), fibrils (twisted stacks of ribbons), and fibers (entwined fibrils). The finite fibril width and helicity is shown to stem from a competition between the free energy gain from attraction between ribbons and the penalty because of elastic distortion of the intrinsically twisted ribbons on incorporation into a growing fibril. Fibers are stabilized similarly. The behavior of two rationally designed 11-aa residue peptides, P 11-I and P11-II, is illustrative of the proposed scheme. P11-I and P11-II are designed to adopt the ␤-strand conformation and to selfassemble in one dimension to form antiparallel ␤-sheet tapes, ribbons, fibrils, and fibers in well-defined solution conditions. The energetic parameters governing self-assembly have been estimated from the experimental data using the model. The 8-nm-wide fibrils consist of eight tapes, are extremely robust (scission energy Ϸ200 kBT), and sufficiently rigid (persistence length lfibril Ϸ 20 -70 m) to form nematic solutions at peptide concentration c Ϸ 0.9 mM (volume fraction Ϸ0.0009 vol͞vol), which convert to self-supporting nematic gels at c > 4 mM. More generally, these observations provide a new insight into the generic self-assembling properties of ␤-sheet-forming peptides and shed new light on the factors governing the structures and stability of pathological amyloid fibrils in vivo. The model also provides a prescription of routes to novel macromolecules based on a variety of self-assembling chiral units, and protocols for extraction of the associated energy changes.P rospects for the large-scale production of low-cost peptides by genetic engineering (1) open up new opportunities for exploiting protein-like self-assembly as a route to novel biomolecular materials (2-5). In this context, the small-oligopeptide route has distinct processing advantages over the use of longer polypeptides. Previously, we have demonstrated that oligopeptides can be designed to self-assemble into micrometer-long ␤-sheet tapes (6). We now wish to show that, as a consequence of the amino acid chirality, an entire hierarchy of twisted self-assembling macromolecular structures is accessible, with tapes as the most primitive form: ribbons, fibrils, and fibers. These polymers are shown to give rise to nematic fluids and gels at concentrations determined by the characteristic flexibility and length of each type of polymer.The type of molecular assembly we discuss and exemplify here arises not only in the context of desirable engineered biomaterials, but also in pathological self-assembly of mis-folded proteins, when the aggregated assemblies are referred-to as ''amyloids.'' A very wide class of proteins may be induced into producing the tapefibril-fiber sequence of structures (7) We present a theoretical model that enables the morphology and properties of thes...

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