Order from Disorder with Intrinsically Disordered Peptide Amphiphiles

Abstract

Amphiphilic molecules and their self-assembled structures have long been the target of extensive research due to their potential applications in fields ranging from materials design to biomedical and cosmetic applications. Increasing demands for functional complexity have been met with challenges in biochemical engineering, driving researchers to innovate in the design of new amphiphiles. An emerging class of molecules, namely, peptide amphiphiles, combines key advantages and circumvents some of the disadvantages of conventional phospholipids and block-copolymers. Herein, we present new peptide amphiphiles comprised of an intrinsically disordered peptide conjugated to two variants of hydrophobic dendritic domains. These molecules termed intrinsically disordered peptide amphiphiles (IDPA), exhibit a sharp pH-induced micellar phase-transition from low-dispersity spheres to extremely elongated worm-like micelles. We present an experimental characterization of the transition and propose a theoretical model to describe the pH-response. We also present the potential of the shape transition to serve as a mechanism for the design of a cargo hold-and-release application. Such amphiphilic systems demonstrate the power of tailoring the interactions between disordered peptides for various stimuli-responsive biomedical applications.

3D printed SAXS chamber for controlled in-situ dialysis and optical characterization

“…To show reversibility, we used a pH-responsive system of intrinsically disordered peptide amphiphiles (IDPAs (Jacoby et al ., 2021)). Specific amino acids in the used sequence can get protonated and become uncharged with decreasing pH.…”

Self-Assembly of Tunable Intrinsically Disordered Peptide Amphiphiles

“…trinsically disordered carboxy tail-domain of neurofilament-light (NF-L) protein found in the cytoskeleton of nerve cells. [35][36][37]54 In previous research, 47 we introduced this IDP sequence to create IDPAs where aromatic branchings units were used to cap the N-terminus of the IDP sequence and allow the branching into two different types of architectures containing either two or four hydrocarbon tails (2×12, 4×7). We showed that these IDPAs undergo a sharp phase transition from low-dispersity micellar spheres to extremely elongated wormlike micelles.…”

“…To investigate the role of single amino acid mutation, we designed IDPA we found that the hydrophilic domain (i.e., the disordered peptide) and its interactions controlled the complex aggregations at low pH and served to strengthen the interaction between worm-like micelles. 47 Here, we focus on the intermediate pH region where a single mutation can potentially fine-tune the phase transition point.…”

“…14 Previously, we showed that hydrophobic dendritic domains conjugated to the peptide sequence of IDP 1 could slightly alter the pH-induced phase transition from sphere to rod-like micelles. 47 Here, we studied how the phase transition depends on the hydrocarbon length. Using SAXS, we find that double-chained IDPA Significantly, the sharpness of the transition depends on the length of the tails: longer tails result in a phase transition at higher pHs with a much broader range (2×16: pH 4.7-7.8, 2×14: pH 4.7-7.5) between the two mesophases (Fig.…”

“…In this context, intrinsically disordered peptide amphiphiles (IDPAs) are of great interest as they combine building blocks from natural lipids and proteins. [47][48][49] IDPAs are composed of intrinsically disordered peptides conjugated to hydrocarbon chains, creating amphiphiles with polymeric headgroups and hydrophobic anchors that remain compatible with natural 5 lipid membranes. Though IDPAs hold promise for fine-tuned nanoscopic self-assembly, the sequence space of even a 20 amino-acid short polypeptide is extremely large and hardly explored.…”