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 years old postmenopausal women. According to recent studies, hormone replacement therapy (HRT), which is gaining more and more popularity in the latter age group, increases the probability of breast cancer development. However, the biochemical mechanism behind this statistical observation is uncertain.
Typical HRT drugs contain conjugated estrogens, which consist of a mixture of the human hormone estrone, and the non-human hormones equilin and equilenin. These three compounds are highly similar in structure, as they only differ 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 equin estrogens might be significantly more mutagenic than estrone. In order 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. number of DNA mutations) can be made. In this kind of situation, 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, on the formation of reactive oxygen species (ROS) formed during catechol-to-quinone oxidation and on the interaction of quinone metabolites with DNA bases. By means of theoretical calculations, it can be decided whether the intracellular reactivity of equin estrogen significantly differs from that of human estrone.
The examination of potentially carcinogenic mechanisms might – in long term- contribute to the development of a novel HRT protocol of considerably lower risk.
This research is supported by the New National Excellence Program of the Ministry for Innovation and Technology of Hungary.
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 remarkabley variety both in stucture 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, although we are happy to collaborate with other groups on other systems as well. In order to address questions related to protein structure and function we always try to use the most suitable combination of methods. In most cases we use classical force field based molecular dynamics simulations to get a representative set of protein conformations among physiological conditions, and afterwards apply combined quantum mechanics molecular mechanics (QM/MM) calculations to study the reactivity of the system. Recently, we developed a simple combined approach to investigate the mechanism of small molecules gas binding to myoglobin. We have also addressed various aspects of the reactivity of cytochrome P450 enzmyes, peroxiredoxins, isopropyl-malate dehydrogenase and the biosynthesis and metabolism of estrogens.
Strikingly, as many as 2% of global energy consumption can be attributed to a sole chemical reaction: the Haber-Bosch ammonia (NH3) synthesis. Even more than a century after its invention, this process is 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 applied (400-500 °C, 150-250 bar). Consequently, if we are to develop a novel, environmental-friendly alternative process, the primary aim is to work under ambient conditions, or at least close to atmospheric pressure and room temperature.
In the recent decades, numerous research groups attempted to tackle this problem by studying nitrogenase enzymes. Namely, microorganisms synthesizing nitrogenases are able to convert N2 to biologically usable NH3 at the pressure and temperature of their environment. Based on the active site of this enzyme family, “artificial nitrogenases” can be developed – among them, the triphosphino-borate, -carbonyl or –silyl ligated iron complexes are currently viewed as the most promising candidates of 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 the limited lifetime and selectivity observed. The reasons for the low catalytic performance is currently unclear.
The aim of our present research is to explore the mechanism of main reaction (dinitrogen reduction) and side reactions (hydrogen evolution, catalyst deactivation) occurring concurrently in a reaction mixture. We attempt to develop a rational design strategy, which can facilitate the discovery of more efficient biomimetic catalysts.
The research is conducted in collaboration with Dr. Tibor Szilvási (University of Wisconsin-Madison).
This research project was supported by the New National Excellence Program of the Ministry of Human Capacities of Hungary.
Silicon and germanium are commonly considered as four-valent elements. In the recent decades, however, it has become clear that numerous compounds can be synthesized which contain 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 four as usual in Group 14). Nowadays, the chemistry of low-valent silicon and germanium compounds is developing rapidly: even though, earlier, the stable, durable forms of such structures were widely viewed to be synthetically inaccessible, hundreds of silylenes and germylenes have been isolated to date.
Nevertheless, the existence of these exotic compounds remains a mere chemical curiosity as long as no practical application can be found. Thus, intensive research is conducted by experimental research groups on the following fields:
1. Silylene and germylene complexes of transition metals can be used as catalysts in organic syntheses, primarily in cross coupling reactions. It is suspected that the efficacy (reaction rate, lifetime, etc.) of the currently applied catalysts containing phoshphine or carbene ligands can be increased by introducing properly designed Si or Ge based ligand moieties.
2. Silylenes and germylens are suitable for „trapping” small molecules – e. g. phosphinidene (:PH) - which are highly unstable (thus, useless for synthetic proposes) in themselves. In this way, new synthons become accessible and novel synthetic pathways can be opened in organic and element-organic chemistry.
Our subgroup examines the factors that contribute to the stability of low-valent silicon and germanium compounds by means of computational chemistry, which facilitates the discovery of novel silylenes and germylenes. Furthermore, we develop theoretical methods to determine whether the molecular (electronic, steric) properties of the 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 the well-known unsaturated carbon compounds; still, remarkably less is known about their properties. For instance, the silicon analogue of benzene – hexasilabenze – has even escaped isolation to date. Theoretical chemistry, however, can discover the suitable synthetic pathway towards this “holy grail”.
The research is conducted in collaboration with Dr. Tamás Veszprémi (Department of Inorganic and Analytical Chemistry) and Dr. Tibor Szilvási (University of Wisconsin-Madison).
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.