The aromatic amino acid phenylalanine: a versatile tool for binding transition metal ions

The human body contains many different types of transition metal ions, such as Zn²⁺, Cu²⁺, which are involved in many physiological processes. An excess or deficiency of these ions can cause diseases, such as Alzheimer's disease, which is closely related to the levels of these ions in the body. In-depth understanding of various physiological and pathological mechanisms related to metal ions requires understanding the interaction between metal ions and nearby amino acids at the atomic level. This article selected four transition metal ions: Zn²⁺, Cu²⁺, Fe²⁺, and Mn²⁺ and the aromatic amino acid Phe, known for its strong coordination capability, as study subjects, comprehensively examining their binding situations. The results show that there are multiple binding modes between them and Phe, and most of the binding modes involve benzene ring coordination. The coordination strength order of the four metal ions with benzene ring, carbonyl O, hydroxyl O and amino N is different. For the lowest energy structure formed by each ion with Phe, all four ions are bound to N, carbonyl O, and benzene ring. Zn²⁺ is combined with two C's of the benzene ring, Cu²⁺ with four C's of the benzene ring, and Fe²⁺ and Mn²⁺ with the benzene ring as a whole. Part of the reason for this phenomenon may be derived from the tendency of transition metal ions to reach 18e stable structures when bound to ligands. There is a strong binding force between the four ions and Phe, and the binding trend is Cu²⁺(-294.9 kcal/mol) > Zn²⁺(-261.3 kcal/mol) > Fe²⁺(-247.5 kcal/mol) > Mn²⁺(-220.2 kcal/mol). Mayer bond order analysis and molecular orbital localization analysis found that there are very strong chemical interactions between transition metal ions and surrounding atoms, especially with N and carbonyl O.

Several initial structures with different coordination modes to Phe were created according to chemical intuition for each divalent cation. Then semiempirical MD simulations at GFN2 level were run on these structures. The numerous generated structures were classified according to some criteria, then representative geometries were preliminarily optimized by TPSSh/6-31G*/LanL2DZ. To get more accurate electronic energies, high-precision quantum chemistry calculations at the level of TPSSh/def2TZVPP//TPSSh/def2QZVPP were carried out on the selected low-lying structures. All the optimized structures were confirmed to be minima without imaginary frequency by performing frequency analyses. Further electronic structure analyses such as IRI, Mayer bond order, IBSI etc. were performed to get more insights into the binding between the transition metal ions and Phe.