Interplay between intrinsic conformational propensities and intermolecular interactions in the self-assembly of short surfactantlike peptides composed of leucine/isoleucine

To study how the conformational propensities of individual amino acid residues, primary structures (i.e., adjacent residues and molecular lengths), and intermolecular interactions of peptides affect their self-assembly properties, we report the use of replica exchange molecular dynamics (REMD) to investigate the monomers, dimers, and trimers of a series of short surfactant-like peptides (I₃K, L₃K, L₄K, and L₅K). For four-residue peptides X3K (I₃K and L₃K), the results show that their different aggregation behaviors arise from the different intrinsic conformational propensities of isoleucine and leucine. For L_mK peptides (L₃K, L₄K, and L₅K), the molecular length is found to dictate their aggregation via primarily modulating intermolecular interactions. Increasing the number of hydrophobic amino acid residues of L_mK peptides enhances their intermolecular H-bonding and promotes the formation of β-strands in dimer and trimer aggregates, overwhelming the intrinsic preference of Leu for helical structures. Thus, the interplay between the conformational propensities of individual amino acid residues for secondary structures and molecular interactions determines the self-assembly properties of the peptides, and the competition between intramolecular and intermolecular H-bonding interactions determines the probability of β-sheet alignment of peptide molecules. These results are validated by comparing simulated and experimental CD spectra of the peptides. This study will aid the design of short peptide amphiphiles and improve the mechanistic understanding of their self-assembly behavior.