Sequence-Directed Hierarchy of Supramolecular Peptide Bilayers and Heme Cofactor Insertion

Peptide-based materials have enormous potential for applications including therapeutics, sensing, catalysis, and flexible electronics. Recent material discovery screenings through peptide sequence space have identified a class of amphiphilic heme-containing peptides that self-assemble at the nanoscale while efficiently sequestering heme as a prerequisite for electron transfer. However, the assemblies are remarkably sensitive to changes in peptide sequence, even at the single-residue level, impacting heme uptake, aggregate characteristics, and stability. In a combined experimental and molecular simulation study, we examine the interplay between hydrophobicity and charge-charge repulsion on the heme uptake performance and physicochemical characteristics of the assemblies of representative peptides, ExL4-xL5HL6 for x = 2, 3, 4. We find that membrane permeability and compressibility are beneficial for heme uptake, while striking a balance with the overall stability of the assembly. This work highlights the sensitivity of material performance within peptide design space while providing insight into the compromise that must be struck between competing characteristics.