The Self-Assembly Mechanism of Cyclopeptide-Dendrimer Hybrid Molecules

The self-assembly of cyclopeptide-dendrimer hybrid molecules is a complex synergistic process. Its essence is a process in which molecules spontaneously form ordered supramolecular structures through various non-covalent interactions driven by thermodynamics. The core driving forces include hydrogen bonding, hydrophobic interaction, π-π stacking interaction and electrostatic interaction. The synergistic coordination of these interactions determines the morphology, size and stability of the self-assembled structures.

Hydrogen bonding is the core driving force for the self-assembly of cyclopeptide-dendrimer hybrid molecules, mainly derived from the amide bonds (―CO―NH―) of the cyclopeptide segments. The amide bonds in cyclopeptide molecules can act as hydrogen bond donors (NH) and hydrogen bond acceptors (CO). Multiple cyclopeptide molecules interact with each other through intermolecular hydrogen bonds to form regular stacked structures, which further construct ordered structures such as nanotubes and nanofibers. For example, various cyclopeptides such as cyclic α-alternating (D,L)-peptides, cyclic β-peptides, and cyclic α,γ-peptides can be assembled into nanotubes through intermolecular hydrogen bonds. Among them, the cavity of α,γ-cyclopeptide nanotubes is partially hydrophobic, which can be used to encapsulate non-polar solvents, showing potential application value in drug delivery.

The terminal functional groups of dendrimers (such as hydroxyl and carboxyl groups) can also participate in the formation of hydrogen bonds, forming intramolecular or intermolecular hydrogen bonds with the amide bonds of cyclopeptides, which further stabilizes the conformation of hybrid molecules and regulates the self-assembly process. The strength and direction of hydrogen bonding can be regulated by adjusting the amino acid sequence of cyclopeptides and the terminal functional groups of dendrimers, thereby realizing the precise construction of self-assembled structures.

Hydrophobic interaction is a key factor affecting the self-assembly morphology of hybrid molecules. Its essence is the repulsive interaction between water molecules and the hydrophobic part of hybrid molecules, which promotes the aggregation of hydrophobic groups and the exposure of hydrophilic groups in the aqueous environment, thereby forming different amphiphilic assembly structures. The hydrophobic part of cyclopeptide-dendrimer hybrid molecules is mainly derived from the hydrophobic amino acid residues of cyclopeptides (such as leucine and phenylalanine) and the hydrophobic terminals of dendrimers (such as alkyl chains), while the hydrophilic part is derived from the hydrophilic terminals of dendrimers (such as hydroxyl, carboxyl and amino groups).

When hybrid molecules are in aqueous solution, hydrophobic groups spontaneously aggregate to form a hydrophobic core, and hydrophilic groups form a hydrophilic shell, thereby forming assembly structures such as nanospheres and micelles; if the amphiphilicity of hybrid molecules is in a balanced state, one-dimensional ordered structures such as nanofibers and nanotubes can be formed. For example, cystine-bridged γ-cyclopeptide-dendrimer hybrid molecules have amphiphilicity. Their hydrophobic cyclopeptide parts form nanotubes through intermolecular hydrogen bonds, and the hydrophilic dendrimer parts are located outside the nanotubes, which can form uniform filamentous structures through hydrophobic interaction in water and aqueous solutions.

In addition to hydrogen bonding and hydrophobic interaction, π-π stacking interaction and electrostatic interaction also play important roles in the self-assembly process of hybrid molecules, cooperating with the previous two interactions to ensure the stability and regularity of self-assembled structures. π-π stacking interaction is mainly derived from the aromatic amino acid residues in cyclopeptide segments (such as phenylalanine and tryptophan). These aromatic groups form regular stacked structures through the interaction of π electron clouds, further stabilizing the self-assembly system. For example, cyclodipeptides containing aromatic groups can achieve efficient self-assembly through the synergistic effect of π-π stacking and hydrogen bonding, forming structures such as nanofibers.

Electrostatic interaction is mainly derived from the charges of the terminal functional groups of hybrid molecules (such as the negative charge of carboxyl groups and the positive charge of amino groups). When hybrid molecules carry charges, the electrostatic attraction or repulsion between molecules will affect the size and morphology of self-assembled structures. By adjusting the pH value of the solution, the charge state of hybrid molecules can be changed, thereby regulating the strength of electrostatic interaction and realizing the reversible regulation of self-assembled structures.

Lijinjie, Email: lijinjie@dilunbio.com