Recently, Drug amphiphiles (DAs) have been shown to form discrete and stable supramolecular nanostructures with high and quantitative drug loading. A drug amphiphile consists of a hydrogen-bonding peptide sequence attached to a hydrophobic drug. Similar to peptide amphiphiles, DA’s also self-assemble into discrete and well-defined supramolecular structures. Using molecular dynamics simulations we investigate inter- and intra-molecular interactions driving the self-assembly and formation of the morphology of supramolecular DAs. More specifically, we investigate the self-assembly of camptothecin-based DAs, which have been shown to form cylindrical supramolecular assemblies with a well-defined structure. For each DA, we examine the self-assembly process from random using long-time all-atomistic molecular dynamics simulations (&gt; 200 ns). We also examine the structure of a pre-assembled cylindrical supramolecular assembly, comparing the cylindrical radii with reported experimental measurements.<br/><br/>We find that the chirality of the filament is initially mediated by the π-π stacking between CPTs, not by the well-expected intermolecular hydrogen bonding among the peptide segment. Molecular simulations show that π-π stacking of CPTs governs the early stages of the self-assembly process, while the hydrogen bonding network starts at a relatively later stage to rearrange, acting in concert with the π-π interactions to define the eventual morphology. Our simulations results also show the possible presence of water molecules within the core of the CPT filament, in sharp contrast to the typical core-shell structures formed by peptide amphiphiles containing linear hydrocarbons. We believe these results provide very useful guiding principles for the rational design of supramolecular assemblies of peptide conjugates containing aromatic segments.

Molecular modeling self-assembly of anticancer drug amphiphiles

251st National Meeting (2016)

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