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

Cyclic peptide nanotubes (CPNTs) formed by the self-assembly of cyclic peptides (CPs) with an even number of alternate l/d amino acids are typically used in the field of the transport of ions and drug molecules across the lipid bilayer. This study investigates the transport mechanism of the antitumor drug molecule, 5-fluorouracil (5FU), through the CPNT using classical and steered molecular dynamics simulations combined with umbrella sampling. During the transport of 5FU through the CPNT, 5FU is partially desolvated because the lumen of the CPNT is too small to allow for water molecules solvating it. 5FU forms H-bonding interactions with the backbones of the CPNT and at the same time, also forms hydrophobic contacts with the backbone Cα and C atoms of the CPNT. The cooperative breaking of the H-bond and hydrophobic interactions between the CPNT and 5FU increases the pulling force to transport the 5FU from the mid-Cα region to the Cα one. The calculated free energies of binding reveal that the energy barriers for the transport of 5FU are ∼-6.0 and ∼-2.0 kcal mol(-1) in the mid-Cα and Cα plane regions, respectively.