International Scientific Journals
of Scientific Technical Union of Mechanical Engineering "Industry 4.0"

Metal ions are essential for the structural stability and catalytic activity of numerous metalloproteins involved in cellular regulation and signaling. Protein phosphatases such as PHLPP2 and PPM1A play a key role in phosphorylation-dependent pathways with direct biomedical relevance, including cancer-related signaling mechanisms. Still, the factors governing metal selectivity in their active sites remain insufficiently understood. In the present study, Density Functional Theory (DFT) calculations are employed to investigate the metal preferences of two structurally distinct phosphatases: PHLPP2, characterized by a mononuclear Zn²⁺ binding site, and PPM1A, containing a binuclear Mn²⁺ catalytic center. The calculations are performed at the B3LYP/6-31+G(3d,p) level of theory to assess the thermodynamics of metal substitution in biologically relevant coordination environments. The results indicate pronounced differences in structural protection and solvent accessibility between the two metal-binding sites, with the Zn²⁺ site in PHLPP2 exhibiting high thermodynamic stability and well-pronounced protection against competing divalent metal ions. In contrast, the binuclear Mn²⁺ center in PPM1A demonstrates greater flexibility and increased susceptibility to metal exchange, particularly in the presence of biologically abundant cations. Overall, the study demonstrates the applicability of DFT calculations as a predictive tool for investigating metal selectivity in metalloproteins and provides further insight into the possible prospects of innovative cancer-treatment strategies in biologically relevant systems.

Recently, supramolecular complexes based on synthetic macrocyclic host molecules have received much attention due to their broad applications as drug delivery carriers, biological and chemical sensors, light-emitting materials, bioimaging agents, etc. Cucurbit[n]urils are cavitands known for their high affinity for various guest molecules, although some aspects of their coordination chemistry remain enigmatic. They are still not tested as metalloenzyme models and not much is known about their metal-binding properties. Furthermore, there is no systematic study on the key factors controlling the processes of metal coordination to these systems. In the
computational study herein, DFT molecular modeling has been employed in order to investigate the interactions of biologically essential mono- (Na+), di- (Mg2+) and some trivalent (La3+, Lu3+) metal cations to cucurbit[n]urils and evaluate the major determinants shaping the process of recognition. The thermodynamic descriptors (Gibbs energies in the gas phase and in a water medium) of the corresponding complexation reactions have been estimated. The results obtained shed light on the mechanism of host–guest recognition and disclose which factors more specifically affect the metal binding process.

Almost half of all known to date proteins contain metal co-factors. Over the course of 3–4 billion years of organism evolution, several metal species of different oxidation state (Na+, K+, Mg2+, Ca2+, Zn2+, Mn2+, Fe2+/3+, Co2+/3+, Ni2+ and Cu+/2+) have been chosen to participate in key biological processes. They are known as “native”, or “biogenic” metals. On the other end stand toxins like mercury and lead, which poison the recipient by competing with the natural co-factors for binding the essential proteins. As a third example, however, should be outlined some abiogenic metal species, which exert a curative effect on the host organism, and are, therefore, applied in medicine as novel drugs. Such are silver (Ag+), strontium (Sr2+), and gallium (Ga3+). The current study investigates their ability to compete with the native cuprous (Cu+), calcium (Ca2+), and ferric (Fe3+) cations, respectively, by exploiting the methods of the computational chemistry. Nowadays, silver finds broad application in many areas of medicinal use, e.g. being added to dressings of burn wounds as a concomitant therapy of skin ulcers, as a potential water disinfectant, or even in ophthalmology as an active component in eye drops. Strontium prevents the destruction of bones and contributes to their restoration. Sr2+ salt of ranelic acid is a medication (under the names Protelos, Protos, Strontium ranelate Aristo) used for treatment of osteoporosis in postmenopausal women and very elderly patients. Gallium, in its cationic form (Ga3+), is well known for its anticancer activity. Nonetheless, recent experimental studies have considered the employment of gallium as a promising “Trojan horse” strategy against pathogenic microorganisms. Herewith, we set on a quest for deciphering the most acclaimed mechanisms of therapeutic action of the aforementioned metal cations at atomic level. The obtained results shed light on the intimate echanisms of metal recognition, thus revealing key factors governing the processes of native/abiogenic metal rivalry. This approach serves not only for explaining already existing experimental findings, but also as a first step in designing/engineering novel drug molecules of potential therapeutic value.