Modeling Interactions within and between Peptide Amphiphile Supramolecular Filaments

Abstract

Many peptides are able to self-assemble into one-dimensional (1D) nanostructures, such as cylindrical fibers or ribbons of variable widths, but the relationship between the morphology of 1D objects and their molecular structure is not well understood. Here, we use coarse-grained molecular dynamics (CG-MD) simulations to study the nanostructures formed by self-assembly of different peptide amphiphiles (PAs). The results show that ribbons are hierarchical superstructures formed by laterally assembled cylindrical fibers. Simulations starting from bilayer structures demonstrate the formation of filaments, whereas other simulations starting from filaments indicate varying degrees of interaction among them depending on chemical structure. These interactions are verified by observations using atomic force microscopy of the various systems. The interfilament interactions are predicted to be strongest in supramolecular assemblies that display hydrophilic groups on their surfaces, while those with hydrophobic ones are predicted to interact more weakly as confirmed by viscosity measurements. The simulations also suggest that peptide amphiphiles with hydrophobic termini bend to reduce their interfacial energy with water, which may explain why these systems do not collapse into superstructures of bundled filaments. The simulations suggest that future experiments will need to address mechanistic questions about the self-assembly of these systems into hierarchical structures, namely, the preformation of interactive filaments vs equilibration of large assemblies into superstructures.

Peptide Sequence Determines Structural Sensitivity to Supramolecular Polymerization Pathways and Bioactivity

“…When PA1 monomers were exposed to screening by salt without thermal annealing (Pathway 1), we only observed short ribbon-like structures that were unable to polymerize into high-aspect-ratio fibers. With thermal annealing (Pathways 2–5), PA1 nanostructures exhibited a peak at approximately q = 2.6, 5.3, and 8.0 nm –1 , indicating a one-dimensional lattice with characteristic repeat distance of d = 2.4 nm, possibly due to either the stacking of the ribbon-like nanostructures into multilamellar lyotropic liquid crystals or the periodic arrangement of internal structures within the ribbon-like structures . This again showed the distinct roles of screening versus annealing in the supramolecular polymerization of PA1 .…”

“…With thermal annealing (Pathways 2−5), PA1 nanostructures exhibited a peak at approximately q = 2.6, 5.3, and 8.0 nm −1 , indicating a one-dimensional lattice with characteristic repeat distance of d = 2.4 nm, possibly due to either the stacking of the ribbon-like nanostructures into multilamellar lyotropic liquid crystals or the periodic arrangement of internal structures within the ribbon-like structures. 38 This again showed the distinct roles of screening versus annealing in the supramolecular polymerization of PA1. On the other hand, we observed negligible change in PA2 scattering patterns depending on the pathway.…”

“…We designed and synthesized two PA monomers, each comprising a tetrapeptide conjugated to palmitic acid at the N-terminus: C 16 - AAEE -OH ( PA1 ) and C 16 - AEAE -OH ( PA2 ), shown in Figures a and S1. Our design was based on our previous work demonstrating that PA monomers containing palmitoylated tetrapeptide sequences VVEE and VEVE polymerized into cylindrical nanofibers and flat nanobelts, respectively. − Here, we substituted the valine residues of earlier work for alanine to investigate if weaker β-sheet forming propensity would modify the effect of peptide sequence on morphological changes . In our previous work, self-assembly of C 16 -VVEE into highly one-dimensional nanofibers was attributed to the dominant noncovalent polymerization of monomers associated with internal β-sheet secondary structure.…”

Tractable molecular adaptation patterns in a designed complex peptide system

“…To test this possibility, we selected V-X in anticipation that its oligomers would have the tendency to self-aggregate. 15 To measure the relative contributions of electrostatics and aggregation, we studied these systems in the absence and presence of ATP and by varying the reaction temperature.…”

Biomimetic Extracellular Scaffolds by Microfluidic Superstructuring of Nanofibers

“…Our laboratory has developed a class of PAs that utilize β-sheet-forming peptide regions to promote the aqueous assembly of one-dimensional nanostructures with an inner aliphatic core and an outer peptide shell. After initial formation of the nanofibers in aqueous media, thermal annealing brings these supramolecular nanostructures closer to equilibrium, enhancing their internal β-sheet secondary structure, increasing their length, and generating a more uniform morphology. − These nanofibers have diameters between 7 and 10 nanometers and are several microns in length. − By design, these nanofibers can activate receptors to trigger signaling pathways, as natural ECMs do, through the addition of protein-derived or mimetic epitopes to their outer surface. ,, Specifically, previous work has demonstrated efficacy in cardiovascular applications such as hemorrhage and atherosclerosis, osteogenic applications, , and CNS applications, − among other targets. Arranging these nanoscopic structures into microscopic and macroscopic constructs that resemble ECM superstructure is an ongoing challenge, though significant strides toward macrostructural control have been made. − …”