Complementary Peptide Interactions Support the Ultra-Rigidity of Polymers of De Novo Designed Click-Functionalized Bundlemers

Computationally designed 29-residue peptides yield tetra-α-helical bundles with <i>D</i>₂ symmetry. The "bundlemers" can be bifunctionally linked via thiol-maleimide cross-links at their N-termini, yielding supramolecular polymers with unusually large, micrometer-scale persistence lengths. To provide a molecularly resolved understanding of these systems, all-atom molecular modeling and simulations of linked bundlemers in explicit solvent are presented. A search over relative orientations of the bundlemers identifies a structure, wherein at the bundlemer-bundlemer interface, interior hydrophobic residues are in contact, and α-helices are aligned with a pseudocontiguous α-helix that spans the interface. Calculation of a potential of mean force confirms that the structure in which the bundlemers are in contact and colinearly aligned is a stable minimum. Analyses of hydrogen bonds and hydrophobic complementarity highlight the complementary interactions at the interface. The molecular insight provided reveals the molecular origins of bundlemer alignment within the supramolecular polymers.