Coarse-grained molecular dynamics studies of the structure and stability of peptide-based drug amphiphile filaments

Abstract

Peptide-based supramolecular filaments, in particular filaments self-assembled by drug amphiphiles (DAs), possess great potential in the field of drug delivery. These filaments possess one hundred percent drug loading, with a release mechanism that can be tuned based on the dissociation of the supramolecular filaments and the degradation of the DAs [Cheetham et al., J. Am. Chem. Soc. 135 (8), 2907 (2013)]. Recently, much attention has been drawn to the competing intermolecular interactions that drive the self-assembly of peptide-based amphiphiles into supramolecular filaments. Recently, we reported on long-time atomistic molecular dynamics simulations to characterize the structure and growth of chiral filaments by the self-assembly of a DA containing the aromatic anti-cancer drug camptothecin [Kang et al., Macromolecules 49 (3), 994 (2016)]. We found that the π–π stacking of the aromatic drug governs the early stages of the self-assembly process, while also contributing towards the chirality of the self-assembled filament. Based on these all-atomistic simulations, we now build a chemically accurate coarse-grained model that can capture the structure and stability of these supramolecular filaments at long time-scales (microseconds). These coarse-grained models successfully recapitulate the growth of the molecular clusters (and their elongation trends) compared with previously reported atomistic simulations. Furthermore, the interfacial structure and the helicity of the filaments are conserved. Next, we focus on characterization of the disassembly process of a 0.675 μm DA filament at microsecond time-scales. These results provide very useful tools for the rational design of functional supramolecular filaments, in particular supramolecular filaments for drug delivery applications.

Molecular simulations of peptide amphiphiles

“…In a subsequent simulation study, CG models are built based on AA simulation results, providing access to the µs-timescale molecular view on the assembly and disassembly processes. 95 These CG models successfully reproduce the growth of the molecular clusters and their elongation trends, compared with previously reported AA simulations. Furthermore the structure and the helicity of the ‘mCPT-buSS-Tau’ filaments are conserved in these CG simulations as shown in Figure 6.…”

Self-assembling prodrugs

“…This differing arrangement of CPT molecules is a result of increased π–π interactions among individual CPT segments, as evidenced by excitonic coupling in the circular dichroism (CD) spectrum and molecular simulations. 193, 194 A later study by the same group, however, also suggests that the peptide segment could have an influence in nanotube formation as nanotubes were observed for a number of dCPT-based DAs. 195 By mixing of oppositely charged CPT drug amphiphiles (catanionic mixing), the Cui Lab reported on the formation of multiwalled nanotubes containing a fixed and high drug loading.…”

Development of transferable coarse-grained models of amino acids

“…The Shinoda-Devane-Klein (SDK) model 23 is another CG force field that can be used for protein and peptide simulations, yet only non-bonded parameters were developed for the model and not bonded parameters (only generic bonded parameters were used in the parameterization of the model). Those who wish to use the SDK model thus may need to develop their own bonded parameters as in reference 46 . Regarding the non-bonded interactions, the softer LJ (9-6) potential form was used rather than the LJ (12-6) form shown in equation 1.…”

“…23 However, there is also an SDK CG water model that can be used in conjunction with the SDK protein model, in which parameters were developed for a CG water bead comprised of three water molecules. 46 43 The Martini model has a higher resolution for the side chains with up to four beads for a given amino acid. However, the backbone is modeled with just one bead per residue, and when using the Martini model, it is required that one specify the type of backbone bead-whether it is in an alpha helix or beta sheet or free in solution, for example.…”