Molecular Modeling of Self-Assembly of Anticancer Drug Amphiphiles

Abstract

Recently, Drug amphiphiles (DAs) have been shown to form discrete and stable supramolecular nanostructures with high and quantitative drug loading1. A drug amphiphile consists of a hydrogen-bonding peptide sequence attached to a hydrophobic drug. Similar to peptide amphiphiles2, DAs 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 (> 200 ns). We also examine the structure of pre-assembled cylindrical supramolecular assembly, comparing the cylindrical radii with reported experimental measurements. We also characterize the distribution of hydrogen bonds, Cl- ions, as well as the secondary structure formation in the peptide over time. Our findings can help add further insight into the rational design of supramolecular assemblies.1.Cheetham, A. G.; Zhang, P. C.; Lin, Y. A.; Lock, L. L.; Cui, H. G., Supramolecular Nanostructures Formed by Anticancer Drug Assembly. Journal of the American Chemical Society 2013, 135 (8), 2907-2910.2.Cui, H. G.; Pashuck, E. T.; Velichko, Y. S.; Weigand, S. J.; Cheetham, A. G.; Newcomb, C. J.; Stupp, S. I., Spontaneous and X-ray-Triggered Crystallization at Long Range in Self-Assembling Filament Networks. Science 2010, 327 (5965), 555-559.