Slovenian National Institute of Chemistry

Ljubljana, Slovenia

Slovenian National Institute of Chemistry

Ljubljana, Slovenia
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Stare J.,Slovenian National Institute of Chemistry
RSC Advances | Year: 2017

This work addresses the sampling issue commonly accompanying the simulation of chemical reactions. Very often the sampling is severely limited by complexity of the phase space, possibly leading to poorly converged or inaccurate free energy profiles. We explored the factors governing the completeness of reaction path sampling for the rate limiting step of phenylethylamine oxidation by lumiflavin in the gas phase, a reaction important for the pharmacology of the central nervous system. The simulations utilize the free energy perturbation sampling technique together with the empirical valence bond methodology for the free energy calculations. The simplicity of the system allows for the acquisition of fully converged free energy profiles, even for simulation free of restraints. The bottleneck for convergence is in the noticeably poorer sampling statistics in the transition state region, which is resolved by performing sufficiently long simulation to ensure reversibility of all processes accompanying the reaction. In the present case, convergence is attained in microseconds of simulation, but the required simulation time generally depends on the complexity of the potential energy surface pertinent to the reaction. Accordingly, the use of restraints reduces the complexity of the phase space, decreasing the required time by about an order of magnitude. In the case of elementary nucleophilic substitution with even simpler potential energy surface convergence is reached already at a timescale of few nanoseconds. For related biomolecular reactions embedded in an enzyme, significantly longer simulation times may be needed, rendering the sampling problem exceedingly difficult and representing a challenge for advanced sampling techniques. Accordingly, suggestions are given for optimal simulation of biomolecular reactions based on the presently employed techniques and under the aforementioned limitations. © The Royal Society of Chemistry.

Likozar B.,Slovenian National Institute of Chemistry | Levec J.,University of Ljubljana
Fuel Processing Technology | Year: 2014

Detailed reaction kinetics of oil transesterification were studied based on mechanism and reaction scheme of individual triglyceride, diglyceride, monoglyceride, glycerol and fatty acid methyl ester containing different combinations of gadoleic, linoleic, linolenic, oleic, palmitic and stearic acids determined by high-performance liquid chromatography. Pre-exponential factors and activation energies were correlated with molecular structure in terms of chain lengths and double bonds by response surface models. The activation energies of forward reactions were 47-61 kJ mol- 1 with backward ones being 31-49 kJ mol- 1, depending on component structure. Mass transfer during initial emulsion phase was acknowledged by determining diffusivities, distribution coefficients, molar volumes, boiling points and viscosities of individual components. Model was validated for a wide range of temperatures, hydrodynamic conditions, dispersed and continuous phase ratios, and methanolysis catalyst concentrations. Rotational speed had the most profound influence on the duration of transport phenomena-limited region spanning the latter to 27 min upon use of 100 rpm. Economics of the process were finally evaluated in terms of alcoholysis cost and price breakdown. Proposed methodology may be usefully applied to transesterification syntheses employing heterogeneous catalysis and enzymes, as well as various renewable resources such as microalgae lipids, waste oils, bioethanol and biobutanol. © 2014 Elsevier B.V.

Biljan I.,Slovenian National Institute of Chemistry
Current topics in medicinal chemistry | Year: 2013

Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the conformational conversion of the cellular prion protein, PrP(C), into a pathological form known as prion or PrP(Sc). They can be classified into sporadic, inherited and infectious forms. Spontaneous generation of PrP(Sc) in inherited forms of prion diseases is caused by mutations in the human prion protein gene (PRNP). A major goal in prion biology is unraveling the molecular mechanism by which PrP(C) misfolds and leads to development of diseases. Structural characterization of various human PrP (HuPrP) variants may be helpful for better understanding of the earliest stages of the conformational changes leading to spontaneous generation of prions. Here, we review the results of the recent high-resolution nuclear magnetic resonance (NMR) structural studies on HuPrPs with pathological Q212P and V210I mutations linked with Gerstmann-Sträussler-Scheinker (GSS) syndrome and familial Creutzfeldt-Jakob disease (fCJD), respectively, and HuPrP carrying naturally occurring E219K polymorphism considered to protect against sporadic CJD (sCJD). We describe subtle local differences between the three-dimensional (3D) structures of HuPrP mutants and the wild-type (WT) protein, providing new insights into the possible key structural determinants underlying conversion of PrP(C) into PrP(Sc). Also highlighted are the most recent findings from NMR studies about the effect of pH on the structural features of HuPrP with V210I mutation.

Pogorelcnik B.,Slovenian National Institute of Chemistry | Perdih A.,Slovenian National Institute of Chemistry | Solmajer T.,Slovenian National Institute of Chemistry
Current Pharmaceutical Design | Year: 2013

DNA topoisomerases are an important family of enzymes that catalyze the induction of topological changes in the DNA molecule. Their ability to modulate the topology of the DNA makes DNA topoisomerases a key player in several vital cell processes such as replication, transcription, chromosome separation and segregation. Consequently, they already represent an important collection of macromolecular targets for some of the established anticancer drugs on the market as well as serve as templates in the development of novel anticancer drugs especially supported by recent structural advances in the field. The aim of this review is to provide an overview of the recent developments in the field of DNA poisons - a major class of human topoisomerase IIα inhibitors - of which several are already in clinical use. Due to frequently experienced occurrence of serious side effects of these molecules during therapy, especially cardiotoxicity issues, further drug design efforts were initiated already yielding novel promising compounds that have overcome this issue and already entered into clinical studies. Some of the presented and discussed chemical classes include intercalators, non-intercalators and redox-dependent poisons of human topoisomerase IIα. In particular, this review focuses on the currently available structure-based standpoint of molecular design and on the medicinal chemist's perspective of this field of anticancer drug design. © 2013 Bentham Science Publishers.

Konc J.,Slovenian National Institute of Chemistry | Janezic D.,University of Primorska
Nucleic Acids Research | Year: 2014

The ProBiS-ligands web server predicts binding of ligands to a protein structure. Starting with a protein structure or binding site, ProBiS-ligands first identifies template proteins in the Protein Data Bank that share similar binding sites. Based on the superimpositions of the query protein and the similar binding sites found, the server then transposes the ligand structures from those sites to the query protein. Such ligand prediction supports many activities, e.g. drug repurposing. The ProBiS-ligands web server, an extension of the ProBiS web server, is open and free to all users at si/ligands. © 2014 The Author(s).

Konc J.,Slovenian National Institute of Chemistry | Konc J.,U.S. National Institutes of Health | Janezic D.,University of Primorska
Current Opinion in Structural Biology | Year: 2014

While structural genomics resulted in thousands of new protein crystal structures, we still do not know the functions of most of these proteins. One reason for this shortcoming is their unique sequences or folds, which leaves them assigned as proteins of 'unknown function'. Recent advances in and applications of cutting edge binding site comparison algorithms for binding site detection and function prediction have begun to shed light on this problem. Here, we review these algorithms and their use in function prediction and pharmaceutical discovery. Finding common binding sites in weakly related proteins may lead to the discovery of new protein functions and to novel ways of drug discovery. © 2013 Elsevier Ltd.

Godec A.,Slovenian National Institute of Chemistry | Merzel F.,Slovenian National Institute of Chemistry
Journal of the American Chemical Society | Year: 2012

The hydrophobic effect (HE) is commonly associated with the demixing of oil and water at ambient conditions and plays the leading role in determining the structure and stability of biomolecular assembly in aqueous solutions. On the molecular scale HE has an entropic origin. It is believed that hydrophobic particles induce order in the surrounding water by reducing the volume of configuration space available for hydrogen bonding. Here we show with computer simulation results that this traditional picture, based on average structural features of hydration water, configurational properties of single water molecules, and up to pairwise correlations, is not correct. Analyzing collective fluctuations in water clusters we are able to provide a fundamentally new picture of HE based on pronounced many-body correlations affecting the switching of hydrogen bonds (HBs) between molecules. These correlations emerge as a nonlocal compensation of reduced fluctuations of local electrostatic fields in the presence of an apolar solute. We propose an alternative view which may also be formulated as a maximization principle: The electrostatic noise acting on water molecules is maximized under the constraint that each water molecule on average maintains as many HBs as possible. In the presence of the solute the maximized electrostatic noise is a result of nonlocal fluctuations in the labile HB network giving rise to strong correlations among at least up to four water molecules. © 2012 American Chemical Society.

Konc J.,Slovenian National Institute of Chemistry | Janezic D.,Slovenian National Institute of Chemistry
Nucleic Acids Research | Year: 2012

The ProBiS web server is a web server for detection of structurally similar binding sites in the PDB and for local pairwise alignment of protein structures. In this article, we present a new version of the ProBiS web server that is 10 times faster than earlier versions, due to the efficient parallelization of the ProBiS algorithm, which now allows significantly faster comparison of a protein query against the PDB and reduces the calculation time for scanning the entire PDB from hours to minutes. It also features new web services, and an improved user interface. In addition, the new web server is united with the ProBiS-Database and thus provides instant access to pre-calculated protein similarity profiles for over 29000 non-redundant protein structures. The ProBiS web server is particularly adept at detection of secondary binding sites in proteins. It is freely available at, and the new ProBiS web server is at © 2012 The Author(s).

Randic M.,Slovenian National Institute of Chemistry
Chemical Physics Letters | Year: 2014

For a selection of smaller benzenoid hydrocarbons we calculated ring bond orders (RBO) by adding the Pauling bond orders for CC bonds forming individual benzene rings. The RBO show full parallelism with qualitative expectations based on Clar's intuitive sextet theory. The highest RBO values belong to sextets of a single Clar structure, intermediate values to 'migrating' sextets and the smallest values to the 'empty' rings, and rings involving essentially single CC bond. This novel quantitative upgrading of the Clar structural formulas of aromatic benzenoid hydrocarbons offers numerical characterization of individual benzene rings as fully aromatic, intermediate, and weakly aromatics. © 2014 Published by Elsevier B.V.

Randic M.,Slovenian National Institute of Chemistry
Chemical Physics Letters | Year: 2010

We consider calculation of induced currents of π-electrons over the molecular network when molecules are placed in a magnetic field. The approach is based on consideration of current contributions arising from conjugated circuits within each individual Kekulé valence structure. The calculation is illustrated for an isomer of coronene C 24H 12 for which ab initio computations of π-electron current densities are available. Agreement is found between the quantum chemical ab initio computations that make no assumptions on ring contributions and the graph theoretical models based on conjugated circuit currents. © 2010 Elsevier B.V. All rights reserved.

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