Mapping the Morphological Landscape of Oligomeric Di‐block Peptide–Polymer Amphiphiles**

Abstract

Peptide-polymer amphiphiles (PPAs) are tunable hybrid materials that achieve complex assembly landscapes by combining the sequence-dependent properties of peptides with the structural diversity of polymers. Despite their promise as biomimetic materials, determining how polymer and peptide properties simultaneously affect PPA self-assembly remains challenging. We herein present a systematic study of PPA structure-assembly relationships. PPAs containing oligo(ethyl acrylate) and random-coil peptides were used to determine the role of oligomer molecular weight, dispersity, peptide length, and charge density on self-assembly. We observed that PPAs predominantly formed spheres rather than anisotropic particles. Oligomer molecular weight and peptide hydrophilicity dictated morphology, while dispersity and peptide charge affected particle size. These key benchmarks will facilitate the rational design of PPAs that expand the scope of biomimetic functionality within assembled soft materials.

Monomer Architecture as a Mechanism to Control the Self-Assembly of Oligomeric Diblock Peptide-Polymer Amphiphiles

“…The maleimide chain end was then deprotected under vacuum and heated to generate a reactive handle for peptide coupling (Figures 1b and S3-S18). 21 To limit the impact of peptide secondary structure and incorporate a hydrophilic block capable of solubilizing the series of hydrophobic oligomers, we chose the charged random coil peptide XTEN2 containing 17 amino acids (Figures 1c and S19). 26,27 XTEN2 was synthesized using solid phase peptide synthesis, incorporating an N-terminal cysteine residue to couple the peptide with the deprotected maleimide terminus of each of the hydrophobic oligomers.…”

“…To evaluate the impact of tail architecture on the accessible assembled morphologies, each amphiphile (1 mM) was assembled in HEPES buffer (50 mM, pH 7) via bath sonication (1 h). 21 The assemblies were visualized via negatively-stained transmission electron microscopy (NS-TEM) (Figures 2a and S25-S28), showing a mixture of spherical particles and supramolecular assemblies of cylinders. Cryogenic electron microscopy (cryo-EM) of the four PPA assemblies confirmed spherical particles to be mixtures of micelles and larger nanostructures with an empty cavity, which we describe as vesicle-like (Figure 2b).…”

“…To determine the average diameters of the micelle and vesicle-like particles for each PPA assembly, the full spherical particle population was fit to the sum of a Gaussian fit for the micelle population and lognormal fit for the vesicle-like population (Figure 2d). 21,[34][35][36][37] The peak centers of both fits were used to calculate the average micelle and vesicle-like particle diameters respectively. Average nanoparticle diameters were similar across the amphiphile assemblies, as anticipated due to the uniform PPA length (Figure 1d); however, differences were observed in the micelle and vesicle-like diameters within the series.…”

“…[18][19][20] We have previously demonstrated that oligomeric diblock PPAs composed of oligo(ethyl acrylate) tails and random-coil peptides exhibit similarities to block copolymers, assembling into nanoparticles with diverse morphological distributions influenced by the average molecular weight and dispersity of the hydrophobic oligomer. 21 Efforts with amphiphilic block copolymers have demonstrated that the chemical composition of pendent moieties can impact both the packing density 8,22 and exchange dynamics 8,23,24 of multi-chain assemblies. However, the impact of monomer architecture within the hydrophobic tails of PPAs on morphology and assembly dynamics has remained unexplored.…”

Data-Driven Design of Protein-Like Single-Chain Polymer Nanoparticles

“…86,87 Another challenge with complex copolymer conjugates involves deconvoluting physical contributions between polymer and peptide which would require other techniques such as NMR or small-angle neutron scattering (SANS). 88 In addition to all of these factors, it is likely difficult to synthesize structures with the same level of order and folding as proteins mainly because of the lack of sequence-level control. 6,18,67,87,89,90 Until advances are made to achieve this level of control with synthetic ease, polymer chemists may need to rely on quantifying reactivity ratios, [91][92][93] illustrating compositional drift, 94 and potentially designing for molecular weight distribution.…”