Self-Assembled Nanostructures of Peptide Amphiphiles: Charge Regulation by Size Regulation

Abstract

Self-assembled nanostructures of peptide amphiphiles (PAs) with molecular structures C 16 K 2 and C 16 K 3 (where C indicates the number of carbon atoms in the alkyl chain and K is the lysine in the head group) were studied by a combination of theoretical modeling, transmission electron and atomic force microscopes, and acid−base titration experiments. The supramolecular morphology of the PAs (micelles, fibers, or lamellas) was dependent on the pH and ionic strength of the solution. Theoretical modeling was performed using a molecular theory that allows determining the equilibrium morphology, the size, and the charge of the soft nanoassemblies as a function of the molecular structure of the PA, and the pH and salt concentration of the solution. Theoretical predictions showed good agreement with experimental data for the pH-dependent morphology and size of the nanoassemblies and their apparent pK a s. Two interesting effects associated with charge regulation mechanisms were found: first, ionic strength plays a dual role in the modulation of the electrostatic interactions in the system, which leads to complex dependencies of the aggregation numbers with salt concentration; second, the aggregation number of the nanostructures decreases upon increasing the charge per PA. The second mechanism, charge regulation by size regulation, tunes the net charge of the assemblies to decrease the electrostatic repulsions. A remarkable consequence of this behavior is that adding an extra lysine residue to the charged region of the PAs can lead to an unexpected decrease in the total charge of the micelles. 59 Antimicrobial properties are also highly dependent on the 60 charge of the PAs: a recent study has shown that cationic PAs 61 can inhibit the formation of bacterial films, while anionic ones 62 show no antimicrobial activity at all. 25 In a related biomedical 63 application, the performance of vaccines prepared from PA 64 nanostructures was found to be strongly dependent on their 65 morphology, size, and charge. 26 The importance of nanostruc-66 ture morphology and charge transcends the biological uses of 67 PAs and spans nanotechnology applications as well. For 68 example, Stupp's group has developed a biomineralization 69 strategy for PA nanofibers that requires a negative surface

Hydrophobized Short Peptide Amphiphile Functionalized Gold Nanoparticles as Antibacterial Biomaterials

“…Short peptide amphiphiles (sPAs) or Lipid‐peptide conjugates exhibits a wide range of tightly packed self‐assembling nanostructures such as spherical micelles, vesicles, fibers and ribbons, etc [3,4,34–36] . These nanostructures demonstrate delicate balance between hydrophobicity from lipid alkyl chain and hydrophilicity from a group of peptide side chains [4,21–24,34] .…”

“…[31][32][33] Short peptide amphiphiles (sPAs) or Lipid-peptide conjugates exhibits a wide range of tightly packed self-assembling nanostructures such as spherical micelles, vesicles, fibers and ribbons, etc. [3,4,[34][35][36] These nanostructures demonstrate delicate balance between hydrophobicity from lipid alkyl chain and hydrophilicity from a group of peptide side chains. [4,[21][22][23][24]34] Such peptide coated gold nanoparticles can easily adopt amphiphilic nature of used sPA, hence facilitates stabilization and transportation of AuNPs through cell membranes.…”

Ultrashort Peptide Self-Assembly: Front-Runners to Transport Drug and Gene Cargos

“…A selfassembly model of PAs produced by a C 16 alkyl tail linked to a chain of two lysines (C 16 K 2 ) or three lysines (C 16 K 3 ) stand reasonably accurate on the predicted behavior in terms of morphology, size and the state of protonation of the aggregates. The work by Zaldivar et al revealed that the system followed a charge regulation mechanism and found to decrease electrostatic repulsions between charged lysines (Zaldivar et al, 2019). An atomic level study by Rad-Malekshahi et al (2015a) analyzed the vesicle surface structure and dynamics of self-assembled nanovesicles along with the intermolecular forces between amphiphilic peptides to improve and tune the biophysical properties of the nanocarrier.…”

Mapping the Morphological Landscape of Oligomeric Di-block Peptide Polymer Amphiphiles

“…[1,4] As peptide sequences can be borrowed directly from natural proteins to create synthetic peptide amphiphiles, biomimetic functionality can be introduced into self-assembled nanostructures with defined morphologies facilitating the study of effects of local environment on peptide activity. [9,10] For example, peptide-lipid conjugates have generated assemblies capable of catalysis, [10,11] metal-binding, [12][13][14] stimuli-response, [15,16] and cell adhesion [17] while demonstrating the complimentary ways that electrostatics, polarity, hydrogen bonding, and sterics contribute to self-assembly. [18][19][20] Moving forward, building on this established knowledge base by adding new layers of complexity to the assembly landscape provides opportunities to bring peptide amphiphiles closer to the versatility and functionality of natural proteins.…”

“…[9,10] For example, peptide-lipid conjugates have generated assemblies capable of catalysis, [10,11] metal-binding, [12][13][14] stimuli-response, [15,16] and cell adhesion [17] while demonstrating the complimentary ways that electrostatics, polarity, hydrogen bonding, and sterics contribute to self-assembly. [18][19][20] Moving forward, building on this established knowledge base by adding new layers of complexity to the assembly landscape provides opportunities to bring peptide amphiphiles closer to the versatility and functionality of natural proteins.…”