Peptide-based drug amphiphiles (DAs) have been shown to be promising new candidates as drug delivery vehicles [1]. A DA contains a drug, a reducible linker, and a short peptide sequence. However, the molecular level interaction between these DAs and model cell membranes in unknown. Furthermore, the Cui laboratory has found that the number of conjugated drugs can also affect the IC50 of drug conjugates, which may be correlated to the effective cellular uptake. Long-time molecular dynamics can assess if the DA structure affects the translocation across and interaction with the cellular membrane. Long-time simulation on Anton 2 indicate that the interaction of a DA with a single hydrophobic drug attached with model cellular membranes is repulsive, and that small aggregates of the DAs do not interact with or disturb the membrane, even after 18 microsecond simulation time. Further investigation was next performed to investigate if the interaction between the DAs and the membrane will change, with the attachment of additional drugs to the DAs. The results for a slightly different structure of the DA, with four hydrophobic drugs attached per peptide, instead of only one, are strikingly different. After 25 microseconds we see that the drug builds up in a stacking configuration in the outer hydrophobic core of the membrane, starting to form a pore, pulling the positively charged peptide groups towards the membrane. The results of these simulations should inform the future rational design of peptide-based drug delivery vehicles.

Molecular level insight into the interactions between drug amphiphiles and model cell membranes

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.