Enzymatic Control of the Conformational Landscape of Self‐Assembling Peptides

Abstract

Post-translational modification is a common mechanism to affect conformational change in proteins, which in turn, regulates function. Herein, this principle is expanded to instruct the formation of supramolecular assemblies by controlling the conformational bias of self-assembling peptides. Biophysical and mechanical studies show that an engineered phosphorylation/dephosphorylation couple can affectively modulate the folding of amphiphilic peptides into a conformation necessary for the formation of well-defined fibrillar networks. Negative design principles based on the incompatibility of hosting residue side-chain point charge within hydrophobic environments proved key to inhibiting the peptide's ability to adopt its low energy fold in the assembled state. Dephosphorylation relieves this restriction, lowers the energy barrier between unfolded and folded peptide, and allows the formation of self-assembled fibrils that contain the folded conformer, thus ultimately enabling the formation of a cytocompatible hydrogel material.

Injectable peptide hydrogel as intraperitoneal triptolide depot for the treatment of orthotopic hepatocellular carcinoma

“…Regardless of their difference in composition and secondary structure, most of these peptide hydrogelators self-assembled into one-dimensional fibrils, which further entangled with each other through salt bridge, hydrogen bond, and electrostatic attraction to form three-dimensional networks and therefore hydrogels40, 45, 46, 47. Additional functional groups such as targeting ligands 48 , enzyme-responsive groups49, 50, 51, drugs52, 53, fatty acids54, 55, DNA 56 , chelator 57 , fluorophores 58 can be integrated into peptide gelators without disturbing their capability in hydrogel formation. These peptide-based hydrogels have found broad biomedical applications in areas, such as tissue engineering 59 , drug delivery 60 and imaging58, 61.…”

Aldolase Cascade Facilitated by Self‐Assembled Nanotubes from Short Peptide Amphiphiles

“…We also found that the morphology of the assembled peptide had a remarkable role on the activity. Fiber‐like morphology accessed after about 15 days of assembly showed about 50 % lower activity compared to the activity seen in case of the matured nanotubes assembled for 30 days (see Table S1) . To probe this difference, the binding capabilities of C10‐FFVK , based on their states of assembly, were investigated.…”

De novo Design of Selective Membrane‐Active Peptides by Enzymatic Control of Their Conformational Bias on the Cell Surface

“…At high concentration, the peptide grossly disrupts the membrane causing lysis and at concentrations below its lytic IC 50 , DVD‐1P acts as a cell‐selective penetrating peptide. We previously showed that dephosphorylation can control the self‐assembly and subsequent gelation of hairpin peptides . Although the exact molecular mechanisms of the cell penetrating and lytic activities of DVD‐1P are not known, they could involve self‐assembly at the cell surface given the high propensity of β‐hairpin amphiphiles towards self‐association.…”