Polymorphism in Self-Assembly of Peptide-Based β-Hairpin Contributes to Network Morphology and Hydrogel Mechanical Rigidity

Abstract

Hydrogels are proving to be an excellent class of materials for biomedical applications. The molecular self-assembly of designed MAX1 β-hairpin peptides into fibrillar networks has emerged as a novel route to form responsive hydrogels. Herein, computational modeling techniques are used to investigate the relative arrangements of individual hairpins within the fibrils that constitute the gel. The modeling provides insight into the morphology of the fibril network, which defines the gel’s mechanical properties. Our study suggests polymorphic arrangements of the hairpins within the fibrils; however, the relative populations and the relative conformational energies of the polymorphic arrangements show a preference toward an arrangement of hairpins where their turn regions are not capable of forming intermolecular interaction. Repulsive intramolecular electrostatic interactions appear to dictate the formation of fibrils with shorter, rather than longer, persistent lengths. These repulsive intramolecular interactions also disfavor the formation of fibril entanglements. Taken together, the modeling predicts that MAX1 forms a network containing a large number of branch points, a network morphology supported by the formation of short fibril segments. We posit that, under static conditions, the preferred branched structures of the MAX1 peptide assembly result in a cross-linked hydrogel organization. At the same time, the shear stress leads to short fibrillar structures, thus fluidic hydrogel states.

Designer Self‐Assembling Peptide Hydrogels to Engineer 3D Cell Microenvironments for Cell Constructs Formation and Precise Oncology Remodeling in Ovarian Cancer

“…[ 109 ] Both MAX1 and MAX8 form hydrogel matrix network containing a large number of branch points to keep fluidic hydrogel state. [ 110 ] It is supposed that this very low viscous kind of hydrogel is a good candidate of 3D cell culture scaffolds in vitro for circulating tumor cells in various cancer types, [ 111 ] although there are few study reports involved in 3D cell culture models in MAX1 or MAX8 peptide hydrogel.…”

Switchable Hydrolase Based on Reversible Formation of Supramolecular Catalytic Site Using a Self‐Assembling Peptide

“…The alternation of the valine and lysine in the backbone results in one face of the sheet being hydrophobic and the other one being hydrophilic. A second layer of hairpins causes formation of a bilayer with the hydrophobic faces of the two layers facing and buried into each other to separate the hydrophobic moieties from water . Once the hairpin folds, VK2H self assembles laterally through hydrogen binding of the strands of adjoining hairpins to form fibrils.…”

“…The conformational transition of VK2H from random coil to fibrils induced by an increase in pH involves the formation of extended β‐sheet structures. As characteristic circular dichroism (CD) spectra for β‐sheets exhibit a minimum around 216 nm, we measured the CD spectra as a function of pH of aqueous solutions (50 μ m ) of VK2H to confirm the conformational transition. As shown in Figure A, with an increase in pH from acidic to alkaline, the 216 minima became more pronounced, providing strong evidence for the transition from random coil to β‐sheet, indicative of β‐sheet formation.…”

Structural and Spectroscopic Properties of Assemblies of Self-Replicating Peptide Macrocycles

“… 30 Because of the many identical molecules in a self-assembled nanostructure, these systems typically represent a well-averaged ensemble and should thus form an ideal case for the frequency mapping algorithms originally developed for proteins. In addition, the structural heterogeneity of supramolecular systems (and sometimes polymorphism 16 , 31 , 32 ) is intrinsically sampled when multiple snapshots from the MD are considered in higher level calculations.…”