Investigation of the encapsulation of metal cations (Cu2+, Zn2+, Ca2+ and Ba2+) by the dipeptide Phe-Phe using natural bond orbital theory and molecular dynamics simulation.

Complexes of the dipeptide phenylalanine-phenylalanine (Phe-Phe) with divalent metal cations (Cu2+, Zn2+, Ca2+ and Ba2+) were studied at the B3LYP and MP2 levels of theory with the basis sets 6-311++G(d,p) and 6-31 + G(d) in the gas phase. The relative energies of these complexes indicated that cation-π bidentate/tridentate conformations are more favourable than other conformations with uncoordinated rings. These findings were confirmed by the calculated values of thermodynamic parameters such as the Gibbs free energy. Natural bond orbital (NBO) analysis was carried out to explore the metal-ligand coordination in Phe-Phe-Cu2+/Zn2+ complexes. Possible orbital transitions, types of orbitals and their occupancies were determined for a range of Phe-Phe-Cu2+/Zn2+ complexes. The charge transfer involved in various orbital transitions was explored by considering the second-order perturbation energy. NBO analysis revealed that the change transfer is stronger when the metal cation uses both the 4s + 4p subshells rather than just its 4p subshell. We also performed molecular dynamics (MD) simulations to check the stability and consistency of the most favourable binding motifs of Cu2+, Zn2+, Ca2+ and Ba2+ with Phe-Phe over time. The structures of the Phe-Phe-Cu2+/Zn2+/Ca2+/Ba2+ complexes obtained using MD simulation were found to be in good agreement with those obtained in the DFT-based calculations. Graphical Abstract Conformational search on encapsulation of divalent metal cations (Ca2+, Zn2+, Ca2+, Ba2+) by the Phe-Phe dipeptide.