Molecular Insights on the Cyclic Peptide Nanotube-Mediated Transportation of Antitumor Drug 5-Fluorouracil

Abstract

Self-assembled cyclic peptide nanotubes (CPNs) show a potential use in drug delivery. In this study, the CPN composed of (Trp-d-Leu)4-Gln-d-Leu was synthesized and tested for the transport of the antitumor drug 5-fluorouracil (5-FU). CPN-mediated release of 5-FU from liposomes experimentally tested the transportation function of the synthetic CPNs. To explore the transportation mechanism of CPNs, computational studies have been performed on the CPN models stacked by 8 subuints, including conventional molecular dynamics (CMD) simulations, and steered molecular dynamics (SMD) simulations in the environment of hydrated dimyristoylphosphatidylcholine (DMPC) lipid bilayer. Our CMD simulations demonstrated that the ortho-CPN is the most stable nanotube, in which the Gln residue is in the ortho-position relative to other residues. The calculated diffusion coefficient value for inner water molecules was 1.068 × 10−5 cm2·s−1, almost half that of the bulky water and 24 times faster than that of the typical gramicidin A channel. The CPN conserved its hollow structure along the 10 ns CMD simulations, with a tile angle of 50° relative to the normal of DMPC membrane. Results from SMD simulations showed that the 5-FU molecule was transported by hopping through different potential energy minima distributed along subunits, and finally exited the nanotube by escaping from the kink region at the last two subunits. The hopping of 5-FU was driven by switching from hydrophobic interactions between 5-FU and the interior wall of the nanotube to hydrogen bonding interactions of 5-FU with the backbone carbonyl group and amide group of ortho-CPN. The calculated binding free energy profile of 5-FU interacting with the CPN indicated that there was an energy well near the outer end of the nanotube.

Theoretical studies on the transport mechanism of 5-fluorouracil through cyclic peptide based nanotubes

“…[11][12][13]27,70 The earlier MD study shows that the tendency for the backbone amide group to interact with water molecules is relatively small. 27 On the other hand, the carbonyl group clearly interact in a significant manner with the water molecules.…”

“…[4][5][6][7][8][9][10] It has been demonstrated using experimental and theoretical studies that a CPNT embedded in a lipid bilayer can act as an active transporter for various molecules. [4][5][6][7][8][11][12][13] Granja et al showed that 3 is characterized as the alternating Cα and mid-Cα regions. The plane formed by the Cα atoms in a CP is called the Cα plane.…”

Recent advances in self-assembled peptides: Implications for targeted drug delivery and vaccine engineering

“…Additionally, cyclic peptide nanotubes composed of (W-D -L)4-Q-D -L and applied to the delivery of the antitumor drug 5-fluorouracil (5-FU) rapidly reached a high level of penetration into tumor cells where the drug effect was strengthened as the dosage of the cyclic peptide increased. This increase was associated with the cyclic peptide improving the transport of the drug into the target cell [108]. …”

Structure and stability of cyclic peptide based nanotubes: a molecular dynamics study of the influence of amino acid composition

“…In the design of CPs, the selection of the amino acid composition is occasionally based on the feasibility of experimental synthesis or to make strong polar/non-polar side chain-side chain interactions. 29 However, extensive studies on the propensity of various amino acids on the structure and stability of CPNTs are scarce. In our previous classical molecular dynamics study, we have investigated the critical steps involved in the self-assembly of CPs based on 4 ]} n , where n represents the number of CPs ranging from 1 to 8.…”