Modeling of protein reactivity and stability

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.

Our publications in this topic:

Quantum chemical calculations support pseudouridine synthase reaction through a glycal intermediate and provide details of the mechanism
Kiss, D.J. ; Oláh, J. ; Tóth, G. ; Menyhárd, D.K. ; Ferenczy, G.G. Theor. Chem. Acc., 2018, 137, 162.
DOI WoS Scopus

First Principles Calculation of the Reaction Rates for Ligand Binding to Myoglobin: The Cases of NO and CO /OPEN ACCESS!/
Lábas, A ; Menyhárd, D.K. ; Harvey, J.N. ; Oláh, J. Chem. Eur. J., 2018, 24, 5350-5358.
DOI PubMed REAL WoS

Combined Docking and Quantum Chemical Study on CYP-mediated Metabolism of Estrogens in Man
Lábas, A. ; Krámos, B. ; Oláh, J. Chem. Res. Toxicol., 2017, 30, 583-594.
DOI PubMed REAL WoS Scopus

Dual Role of the Active Site Residues of Thermus thermophilus 3-Isopropylmalate Dehydrogenase: Chemical Catalysis and Domain Closure
Gráczer, É. ; Szimler, T. ; Garamszegi, A. ; Konarev, P.V. ; Lábas, A. ; Oláh, J. ; Palló, A. ; Svergun, D.I. ; Merli, A. ; Závodszky, P.; Weiss, M.S.; Vas, M. Biochemistry, 2016, 55, 560-574.
DOI PubMed REAL WoS Scopus

Glutamate 270 plays an essential role in K+-activation and domain closure of Thermus thermophilus isopropylmalate dehydrogenase /OPEN ACCESS!/
Gráczer, É. ; Palló, A. ; Oláh, J. ; Szimler, T. ; Konarev, P.V. ; Svergun, D.I. ; Merli, A. ; Závodszky, P. ; Weiss, M.S. ; Vas, M. FEBS Letters, 2015, 589, 240-245.
DOI PubMed REAL WoS Scopus

The mechanism of human aromatase (CYP 19A1) revisited: DFT and QM/MM calculations support a compound I-mediated pathway for the aromatization process
Krámos, B.; Oláh, J. Struct. Chem., 2015, 26, 279-300.
DOI REAL WoS Scopus

Accurate modeling of cation–π interactions in enzymes: a case study on the CDPCho:phosphocholine cytidylyltransferase complex
Lábas, A.; Krámos, B.; Bakó, I.; Oláh, J. Struct. Chem., 2015, 26, 1411-1423.
DOI REAL WoS Scopus

Molecular Mechanism for the Thermo-Sensitive Phenotype of CHO-MT58 Cell Line Harbouring a Mutant CTP:Phosphocholine Cytidylyltransferase /OPEN ACCESS!/
Marton, L. ; Nagy, G.N. ; Ozohanics, O. ; Lábas, A. ; Krámos, B. ; Oláh, J. ; Vékey, K. ; Vértessy, B.G. PLOS One, 2015, 10, e0129632.
DOI PubMed REAL WoS Scopus

How does the protein environment optimize the thermodynamics of thiol sulfenylation? Insights from model systems to QM/MM calculations on human 2-Cys peroxiredoxin
Oláh, J. ; van Bergen, L. ; De Proft, F. ; Roos, G. J. Biomol. Struct. Dyn., 2015, 33, 584-596.
DOI PubMed REAL WoS Scopus

Enolization as an Alternative Proton Delivery Pathway in Human Aromatase (P450 19A1)
Krámos, B.; Oláh, J. J. Phys. Chem. B, 2014, 118, 390-405.
DOI WoS Scopus

Structural and energetic basis of isopropylmalate dehydrogenase enzyme catalysis /OPEN ACCESS!/
Palló, A. ; Oláh, J. ; Gráczer, É. ; Merli, A. ; Závodszky, P. ; Weiss, M.S. ; Vas, M. FEBS Journal, 2014, 281, 5063-5076.
DOI PubMed REAL WoS Scopus

Evolutionary and mechanistic insights into substrate and product accommodation of CTP:phosphocholine cytidylyltransferase from Plasmodium falciparum /OPEN ACCESS!/
Nagy, G.N. ; Marton, L. ; Krámos, B. ; Oláh, J. ; Révész, A. ; Vékey, K. ; Delsuc, F. ; Hunyadi-Gulyas, E. ; Medzihradszky, K.F. ; Lavigne, M.; Vial, H.; Cerdan, L.; Vértessy, B.G. FEBS Journal, 2013, 280, 3132-3148.
DOI PubMed REAL WoS Scopus

Quantum Mechanical Modeling: A Tool for the Understanding of Enzyme Reactions /OPEN ACCESS!/
Náray-Szabó, G. ; Oláh, J. ; Krámos, B. Biomolecules, 2013, 3, 662-702.
DOI Scopus

Direct Hydride Shift Mechanism and Stereoselectivity of P450nor Confirmed by QM/MM Calculations
Krámos, B. ; Menyhárd, D.K. ; Oláh, J. J. Phys. Chem. B, 2012, 116, 872-885.
DOI WoS Scopus

Does Compound I Vary Significantly between Isoforms of Cytochrome P450? /OPEN ACCESS!/
Lonsdale, R. ; Oláh, J. ; Harvey, J.N. ; Mulholland, A.J. J. Am. Chem. Soc., 2011, 133, 15464-15474.
DOI WoS Scopus

Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450 /OPEN ACCESS!/
Oláh, J. ; Mulholland, A.J. ; Harvey, J.N. Proc. Natl. Acad. Sci. USA, 2011, 108, 6050-6055.
DOI WoS Scopus

Biomimetic nitrogen fixation

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 is supported by the New National Excellence Program of the Ministry of Human Capacities of Hungary.

Our publications in this topic:

Exploring Hydrogen Evolution Accompanying Nitrogen Reduction on Biomimetic Nitrogenase Analogs: Can Fe-NxHy Intermediates Be Active Under Turnover Conditions?
Benedek, Z. ; Papp, M. ; Oláh, J. ; Szilvási, T. Inorg. Chem., 2019, 58, 7969-7977.
DOI PubMed

Identifying the Rate-Limiting Elementary Steps of Nitrogen Fixation with Single-Site Fe Model Complexes /OPEN ACCESS!/
Benedek, Z. ; Papp, M. ; Oláh, J. ; Szilvási, T. Inorg. Chem., 2018, 57, 8499-8508.
DOI PubMed REAL WoS Scopus

Low-valent silicon and germanium compounds

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).

Our publications in this topic:

Theoretical Evidence for the Utilization of Low-Valent Main-Group Complexes as Rare-Synthon Equivalents
Benedek, Z.; Orbán, B.; Szilvási, T. Chem. Eur. J., 2017, 23, 17908-17914.
DOI PubMed

Theoretical Assessment of Low-Valent Germanium Compounds as Transition Metal Ligands: Can They Be Better than Phosphines or NHCs?
Benedek, Z.; Szilvási, T. Organometallics, 2017, 36, 1591-1600.
DOI

Can low-valent silicon compounds be better transition metal ligands than phosphines and NHCs? /OPEN ACCESS!/
Benedek, Z.; Szilvási, T. RSC Adv., 2015, 5, 5077-5086.
DOI

Molecular tailoring: a possible synthetic route to hexasilabenzene
Benedek, Z.; Szilvási, T.; Veszprémi, T. Dalton Trans., 2014, 43, 1184-1190.
DOI PubMed

Combining the chemistries of silylene and sulfur-nitrogen compounds - SiS2N2 and related systems
Oláh, J. ; Veszprémi, T. ; Woollins, J.D. ; Blockhuys, F. Dalton Trans., 2010, 39, 3256-3263.
DOI WoS Scopus

Nucleophilicity and electrophilicity of silylenes from a molecular electrostatic potential and dual descriptor perspectives
Correa, J.V. ; Jaque, P. ; Oláh, J. ; Toro-Labbe, A. ; Geerlings, P. Chem. Phys. Lett., 2009, 470, 180-186.
DOI WoS Scopus

Mechanism of water addition to silatriafulvenes and silapentafulvenes
Oláh, J. ; Veszprémi, T. Organometallics, 2008, 27, 2723-2729.
DOI WoS Scopus

Silylenes: A unified picture of their stability, acid-base and spin properties, nucleophilicity, and electrophilicity via computational and conceptual density functional theory
Oláh, J. ; Veszprémi, T. ; De Proft, F. ; Geerlings, P. J. Phys. Chem. A, 2007, 111, 10815-10823.
DOI WoS Scopus

Relationship between electrophilicity and spin-philicity of divalent and monovalent species of group 14 and 15 elements
Oláh, J. ; De Proft, F. ; Veszprémi, T. ; Geerlings, P. J. Mol. Struct. (THEOCHEM), 2006, 771, 135-140.
DOI WoS Scopus

Hard-soft acid-base interactions of silylenes and germylenes
Oláh, J. ; De Proft, F. ; Veszprémi, T. ; Geerlings, P. J. Phys. Chem. A, 2005, 109, 1608-1615.
DOI WoS Scopus

Spin-philicity and spin-donicity of substituted carbenes, silylenes, germylenes, and stannylenes
Oláh, J. ; De Proft, F. ; Veszprémi, T. ; Geerlings, P.J. Phys. Chem. A, 2004, 108, 490-499.
DOI WoS Scopus

Relationship between stability and dimerization ability of silylenes
Oláh, J. ; Veszprémi, T. J. Organomet. Chem., 2003, 686, 112-117.
DOI WoS Scopus

Hydrogen-bond network structure

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.

Our publications in this topic:

How can we detect hydrogen bond local cooperativity in liquid water: A simulation study
Bakó, I. ; Lábas, A. ; Hermansson, K. ; Oláh, J. J. Mol. Liq., 2017, 245, 140-146.
DOI REAL WoS Scopus

Hydration sphere structure of proteins: A theoretical study
Lábas, A. ; Bakó, I. ; Oláh, J. J. Mol. Liq., 2017, 238, 462-469.
DOI REAL WoS Scopus

Water-Formamide Mixtures: Topology of the Hydrogen-Bonded Network
Bakó, I. ; Oláh, J. ; Lábas, A. ; Bálint, S. ; Pusztai, L. ; Funel, M.C.B. J. Mol. Liq., 2017, 228, 25-31.
DOI REAL WoS Scopus

Hydrogen bond network topology in liquid water and methanol: a graph theory approach /OPEN ACCESS!/
Bakó, I. ; Bencsura, Á. ; Hermannson, K. ; Bálint, S. ; Grósz, T. ; Chihaia, V. ; Oláh, J. Phys. Chem. Chem. Phys., 2013, 15, 15163-15171.
DOI PubMed REAL WoS Scopus