Balancing hydrophobicity and sequence pattern to influence self‐assembly of amphipathic peptides

Abstract

Amphipathic peptides with alternating polar and nonpolar amino acid sequences efficiently selfassemble into functional b-sheet fibrils as long as the nonpolar residues have sufficient hydrophobicity. For example, the Ac-(FKFE) 2 -NH 2 peptide rapidly self-assembles into b-sheet bilayer nanoribbons, while Ac-(AKAE) 2 -NH 2 fails to self-assemble under similar conditions due to the significantly reduced hydrophobicity and b-sheet propensity of Ala relative to Phe. Herein, we systematically explore the effect of substituting only two of the four Ala residues at various positions in the Ac-(AKAE) 2 -NH 2 peptide with amino acids of increasing hydrophobicity, b-sheet potential, and surface area (including Phe, 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), cyclohexylalanine (Cha), and pentafluorophenylalanine (F 5 -Phe)) on the self-assembly propensity of the resulting sequences. It was found that double Phe variants, regardless of the position of substitution, failed to self-assemble under the conditions used in this study. In contrast, all double 1-Nal and 2-Nal variants readily self-assembled, albeit at differing rates depending on the substitution patterns. To determine whether this was due to hydrophobicity or side chain surface area, we also prepared double Cha and F 5 -Phe variant peptides (both side chain groups are more hydrophobic than Phe). Each of these variants also underwent effective self-assembly, with the aromatic F 5 -Phe peptides doing so with greater efficiency. These findings provide insight into the role of amino acid hydrophobicity and sequence pattern on self-assembly proclivity of amphipathic peptides and on how targeted substitutions of nonpolar residues in these sequences can be exploited to tune the characteristics of the resulting self-assembled materials.hydrophobicity, peptide, self-assembly | I N TR ODU C TI ONThe development of biomaterials derived from self-assembled peptides is of great current interest due to biomedical applications including controlled release drug delivery, vaccine development, tissue engineering, and wound healing. Amphipathic peptides that consist of alternating hydrophobic and hydrophilic amino acids are a privileged class of peptide that readily self-assembles into b-sheet bilayer nanoribbons that share the basic characteristics of cross-b amyloid assemblies (Figure 1). [23][24][25][26][27][28][29][30] These bilayer nanoribbons effectively sequester all hydrophobic functionality to the bilayer interior, leaving hydrophilic groups exposed to solvent on the exterior face. [24,[31][32][33][34] As a result, these nanoribbons maintain high solubility in aqueous solvents, making them ideal materials for biological applications. Because of the high utility of this class of amphipathic peptide, they have been widely adopted as models to study the fundamental physicochemical basis of peptide self-assembly processes in order to facilitate the rational design of next-generation materials derived from self-assembled b-sheet peptides.[ [35][36][37][38][39]...

Multicomponent peptide assemblies

“…184 Systematic replacement of amino acids in this sequence led to the development of other amphipathic self-assembling peptides that readily self-assemble into fibrils that entangle to form hydrogel networks, including KFE8 185,186 and RADA16, 187,188 Schneider’s MAX hairpin peptides, 189–191 Collier’s Q11 peptide, 192,193 and others (Figure 4). 80,194–198 These self-assembling amphipathic β -sheet systems have been widely exploited as functional biomaterials for applications ranging from wound-healing to tissue regeneration. 26,36,42,48,63,116,199,200…”

Enzyme-responsive progelator cyclic peptides for minimally invasive delivery to the heart post-myocardial infarction

“…SAPs undergo spontaneous assembly through electrostatic and amphiphilic interactions into ordered nanostructures 34,35 . In many instances, variation of sequence and charge distribution in SAPs can influence properties such as secondary structure 36 , fiber diameter 37 , and bulk viscoelasticity 38 . In our design, we began with a gellable core based on a model SAP consisting of the repeat sequence (KLDL) 3 (referred to in this study as KLDL), which has been studied as a non-immunogenic, non-hemolytic, and antimicrobial scaffold for tissue engineering applications 39–41 .…”

Spontaneous Nanobelt Formation by Self‐Assembly of β‐Benzyl GABA

“…Thus, various functional materials using the (FKFE) n peptide have been reported as they readily self‐assemble into well‐defined superstructures. This is realized in the bilayer structure, which is the representative structure formed spontaneously via self‐assembly of amphipathic peptides …”