Proteins are one of the most fundamental groups of biopolymers. Although they are primarily built up from only twenty different amino acid residues, they exhibit remarkable variety both in structure and function, and their properties can be further tuned by the presence of other co-factors such as metal ions.
Our research is focused on the reactivity of metalloenzymes, especially of heme enzymes. To address questions related to protein structure and function, we combine classical force field-based molecular dynamics simulations with QM/MM calculations. Notable contributions include the mechanisms of gas binding to myoglobin and reactivity of cytochrome P450 enzymes.
Strikingly, as much as 2% of global energy consumption can be attributed to a single chemical reaction: the Haber-Bosch ammonia (NH₃) synthesis. Even more than a century after its invention, this process remains the only economically feasible way of utilizing atmospheric nitrogen (N₂) as a raw material. The high energy demand of ammonia production can be traced back to the harsh conditions required (400–500 °C, 150–250 bar). Consequently, developing a novel, environmentally friendly alternative process requires working under ambient conditions, or at least close to atmospheric pressure and room temperature.
In recent decades, numerous research groups have attempted to tackle this problem by studying nitrogenase enzymes. Microorganisms synthesizing nitrogenases are capable of converting N₂ into biologically usable NH₃ at the pressure and temperature of their environment. Based on the active site of this enzyme family, "artificial nitrogenases" have been developed—among them, triphosphino-borate, -carbonyl, or -silyl ligated iron complexes are currently viewed as the most promising candidates for biomimetic catalyst development. Although these structures are suitable for catalyzing the reduction of N₂ at atmospheric pressure in the presence of proton and electron source molecules (acid, reductant), they are far from being industrially applicable due to their limited lifetime and selectivity. The reasons for this low catalytic performance remain unclear.
The aim of our current research is to explore the mechanism of the main reaction (dinitrogen reduction) and side reactions (hydrogen evolution, catalyst deactivation) that occur concurrently in the reaction mixture. We aim to develop a rational design strategy to facilitate the discovery of more efficient biomimetic catalysts.
This research is conducted in collaboration with Dr. Tibor Szilvási (The University of Alabama).
This research project was supported by the New National Excellence Program of the Ministry of Human Capacities of Hungary.
Breast cancer is the leading type of cancer in women, accounting for approximately 25% of all cases. The disease is most common among 45–65-year-old postmenopausal women. According to recent studies, hormone replacement therapy (HRT), which is gaining increasing popularity in this age group, raises the probability of breast cancer development. However, the biochemical mechanism behind this statistical observation remains uncertain.
Typical HRT drugs contain conjugated estrogens, consisting of a mixture of the human hormone estrone and the non-human hormones equilin and equilenin. These three compounds are highly similar in structure, differing only in the degree of unsaturation of ring “B” of the sterane skeleton (1, 2, and 3 double bonds for estrone, equilin, and equilenin, respectively). As a result, highly similar activity is observed in estrogen receptors. Nevertheless, several in vivo and in vitro experiments suggest that equine estrogens might be significantly more mutagenic than estrone. To perform an accurate risk analysis of HRT, it is necessary to explore structure-activity relationships. Experimentally, however, such examinations cannot be performed as the different DNA-damaging pathways cannot be investigated separately; only macroscopic observations (e.g., the number of DNA mutations) can be made. In such cases, theoretical chemistry offers a deeper insight into the process of carcinogenesis at the molecular level.
In this research, we utilize quantum chemical calculations and microkinetic modeling to explore the possible estrogen-initiated reaction sequences leading to DNA mutations. We focus on the hydroxylation of estrogens resulting in catechols, the formation of reactive oxygen species (ROS) during catechol-to-quinone oxidation, and the interaction of quinone metabolites with DNA bases. Through theoretical calculations, we aim to determine whether the intracellular reactivity of equine estrogen significantly differs from that of human estrone.
The examination of potentially carcinogenic mechanisms might—in the long term—contribute to the development of a novel HRT protocol with considerably lower risk.
This research is supported by the New National Excellence Program of the Ministry for Innovation and Technology of Hungary.
Publications - Mechanism of Estrogen Mediated Carcinogenesis
Hydrogen bond is the most profound intermolecular interaction that primarily influences the properties of various condensed phase systems: e.g. of water and other molecules capable of hydrogen-bonding, and also biomolecules including proteins, nucleic acids and carbohydrates.
The unique properties of water arise due to the presence of a complex, fastly changing three dimensional network of hydrogen bonds. Together with Prof. Imre Bakó (Research Centre for Natural Sciences of the Hungarian Academy of Sciences), we have been interested in the topological properties of the hydrogen bond network in various systems (around proteins, in water-methanol and water-formamide mixtures). In order to gain a deeper insight into the nature of intermolecular interactions, we used topological descriptors such as average hydrogen bond number, cycle size distribution and characteristics of the Laplacian matrices of the H-bond network.
Silicon and germanium are commonly considered four-valent elements. In recent decades, however, it has become clear that numerous compounds can be synthesized containing a divalent Si or Ge atom (i.e., the central Si/Ge atom of the molecule, which has a lone electron pair, is connected to two ligands—rather than the usual four in Group 14). Nowadays, the chemistry of low-valent silicon and germanium compounds is developing rapidly. Earlier, the stable and durable forms of such structures were widely viewed as synthetically inaccessible; however, hundreds of silylenes and germylenes have now been isolated.
Nevertheless, the existence of these exotic compounds remains a mere chemical curiosity as long as no practical applications are found. Thus, intensive research is being conducted by experimental groups in the following fields:
1. Silylene and germylene complexes of transition metals: These can be used as catalysts in organic syntheses, primarily in cross-coupling reactions. It is suspected that the efficacy (e.g., reaction rate, lifetime) of currently applied catalysts containing phosphine or carbene ligands can be enhanced by introducing properly designed Si- or Ge-based ligand moieties.
2. Molecule trapping: Silylenes and germylenes are suitable for “trapping” small molecules—such as phosphinidene (:PH)—which are highly unstable and therefore unsuitable for synthetic purposes. This trapping makes new synthons accessible and opens novel synthetic pathways in organic and element-organic chemistry.
Our subgroup examines the factors that contribute to the stability of low-valent silicon and germanium compounds using computational chemistry. This approach facilitates the discovery of novel silylenes and germylenes. Furthermore, we develop theoretical methods to determine whether the molecular (electronic, steric) properties of recently synthesized compounds meet the requirements of the aforementioned potential applications.
An additional area of our research is the investigation of unsaturated silicon compounds. These structures are analogous to well-known unsaturated carbon compounds; however, much less is known about their properties. For instance, the silicon analogue of benzene—hexasilabenzene—has yet to be isolated. Theoretical chemistry can uncover suitable synthetic pathways towards this “holy grail.”
The research is conducted in collaboration with Dr. Tamás Veszprémi (Department of Inorganic and Analytical Chemistry) and Dr. Tibor Szilvási (The University of Alabama).
Publications - Low-valent Silicon and Germanium Compounds
