Modulating peptide co-assembly <i>via</i> macromolecular crowding: Recipes for co-assembled structures

Peptide-based biomaterials are commonly found in applications such as tissue engineering, wound healing, and drug delivery. Control over the size and morphology of the peptide supramolecular structure remains a challenge. One way to influence peptide assembly is through macromolecular crowding. Here we use discontinuous molecular dynamics simulation combined with the PRIME20 force field to investigate the effect of hydrophobic crowders on the architecture of co-assembled peptide aggregates. The peptide system used in this work is a mixture of oppositely-charged synthetic peptides: "CATCH(6K+)" (KQKFKFKFKQK) and "CATCH(6E-)" (EQEFEFEFEQE). The systems explored contained a mixture of 50 CATCH(6K+) and 50 CATCH (6E-) peptides at peptide concentrations of 5 mM and 20 mM, and crowders with diameters of 10, 20, 40 and 80 Å. Crowders were modeled as spheres with either hard-sphere or square-well/square-shoulder interactions. At low concentrations where CATCH co-assembly typically does not occur, the crowders were effective chaperones to trigger co-assembly. Small hard-sphere crowders promoted formation of multilayer fibrils. Large highly hydrophobic crowders promoted the formation of monolayer β-sheet structures and suppressed the formation of fibril structures. Overall, the simulations demonstrate that the crowder size and crowder-sidechain interaction strength govern the supramolecular architecture of peptide co-assemblies.