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 D2 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.