Glucose derivatives substitution and cyclic peptide diameter effects on the stability of the self-assembled cyclic peptide nanotubes; a joint QM/MD study.

Dynamical behavior and the stability of eighteen nanostructures composed of cyclic peptide (CP) with the general structure of the cyclo(CO(CH2 )n=4, 6, 10 COCyst), in the gas phase, water and chloroform were investigated during 50ns molecular dynamic (MD) simulations. CP dimers and cyclic peptide nanotubes (CPNTs) are more stable in chloroform than water and this stability is reversely correlated with the ring size of the CP units. Also the effect of glucose derivatives substitution, d-glucose (S1) and N-methyl-d-glucamine (S2), on the stability and other physicochemical properties of the CP dimers and CPNTs were evaluated. These substitutions increase the inner-subunits hydrogen bonds (H-bond) which in turn increase the stability of these structures. Moreover, the S2 substitution in comparison to the S1 makes dimers and CPNTs more stable. Gibbs free energy analysis based on the MM-PBSA and MM-GBSA calculations confirmed that substitutions affect the stability of the studied nanostructures, considerably and an increase in the length of the CPNT units reduces their stability. Quantum chemistry calculations on the dimer structures using the density functional theory (DFT) and DFT-D3 methods were performed. Based on the DFT-D3 calculations, it was revealed that the dispersion interactions play a key role in the dimerization process. The ring size increment, elevates the dispersion interaction energy which is accordance with the MD results. H-bond formation between the CO and NH groups of the CP units inside the dimers have been analyzed by using the quantum theory of atoms in molecules and natural bond orbital description. Finally, through these analyses, the electrostatic interaction between the mentioned groups have been evaluated.