In this article, cyclic peptide (CP) with lipid substitutions were theoretically designed. Dynamical behavior of the CP dimers and cyclic peptide nanotube (CPNT) without lipid substitutions in the solution (water and chloroform) during the 50 ns molecular dynamic (MD) simulations has been investigated. As a result, the CP dimers and CPNT in non-polar solvent are more stable than polar solvent and CPNT is a good container for non-polar small molecules such as chloroform. The effect of the lipid substitutions on the CP dimers and CPNT has been investigated in the next stage of our studies. Accordingly, these substitutions increase the stability of the CP dimers and CPNT, significantly, in polar solvents. MM-PBSA and MM-GBSA calculations confirm that substitution has an important effect on the stability of the CP dimers and CPNT. Finally, dynamical behavior of CPNT with lipid substitutions in fully hydrated DMPC bilayer shows a high ability of this structure, for molecule transmission across the lipid membrane. This structure is enough stable to be used as a molecular channel. DFT calculations on the CP dimers in the gas phase, water and chloroform, indicate that H-bond formation is the driving force for dimerization. CP dimers are more stable in the gas phase in comparison to solution. HOMO-LUMO orbital analysis indicate that the interaction of the CP units in the dimer structures is due to the molecular orbital interactions between the NH and CO groups.

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