Bending of Canonical and G/T Mismatched DNAs.

Mismatched base pairs alter the flexibility and intrinsic curvature of DNA. The role of such DNA features is not fully understood in the mismatch repair pathway. MutS/DNA complexes exhibit DNA bending, PHE intercalation, and changes of base-pair parameters near the mismatch. Recently, we have shown that base-pair opening in the absence of MutS can discriminate mismatches from canonical base pairs better than DNA bending. However, DNA bending in the absence of MutS was found to be rather challenging to describe correctly. Here, we present a computational study on the DNA bending of canonical and G/T mismatched DNAs. Five types of geometric parameters covering template-based bending toward the experimental DNA structure, global, and local geometry parameters were employed in biased molecular dynamics in the absence of MutS. None of these parameters showed higher discrimination than the base-pair opening. Only roll could induce a sharply localized bending of DNA as observed in the experimental MutS/DNA structure. Further, we demonstrated that the intercalation of benzene mimicking PHE decreases the energetic cost of DNA bending without any effect on mismatch discrimination.

Importance of base-pair opening for mismatch recognition.

Mismatch repair is a highly conserved cellular pathway responsible for repairing mismatched dsDNA. Errors are detected by the MutS enzyme, which most likely senses altered mechanical property of damaged dsDNA rather than a specific molecular pattern. While the curved shape of dsDNA in crystallographic MutS/DNA structures suggests the role of DNA bending, the theoretical support is not fully convincing. Here, we present a computational study focused on a base-pair opening into the minor groove, a specific base-pair motion observed upon interaction with MutS. Propensities for the opening were evaluated in terms of two base-pair parameters: Opening and Shear. We tested all possible base pairs in anti/anti, anti/syn and syn/anti orientations and found clear discrimination between mismatches and canonical base-pairs only for the opening into the minor groove. Besides, the discrimination gap was also confirmed in hotspot and coldspot sequences, indicating that the opening could play a more significant role in the mismatch recognition than previously recognized. Our findings can be helpful for a better understanding of sequence-dependent mutability. Further, detailed structural characterization of mismatches can serve for designing anti-cancer drugs targeting mismatched base pairs.

High-quality and universal empirical atomic charges for chemoinformatics applications.

BACKGROUND: Partial atomic charges describe the distribution of electron density in a molecule and therefore provide clues to the chemical behaviour of molecules. Recently, these charges have become popular in chemoinformatics, as they are informative descriptors that can be utilised in pharmacophore design, virtual screening, similarity searches etc. Especially conformationally-dependent charges perform very successfully. In particular, their fast and accurate calculation via the Electronegativity Equalization Method (EEM) seems very promising for chemoinformatics applications. Unfortunately, published EEM parameter sets include only parameters for basic atom types and they often miss parameters for halogens, phosphorus, sulphur, triple bonded carbon etc. Therefore their applicability for drug-like molecules is limited. RESULTS: We have prepared six EEM parameter sets which enable the user to calculate EEM charges in a quality comparable to quantum mechanics (QM) charges based on the most common charge calculation schemes (i.e., MPA, NPA and AIM) and a robust QM approach (HF/6-311G, B3LYP/6-311G). The calculated EEM parameters exhibited very good quality on a training set ([Formula: see text]) and also on a test set ([Formula: see text]). They are applicable for at least 95 % of molecules in key drug databases (DrugBank, ChEMBL, Pubchem and ZINC) compared to less than 60 % of the molecules from these databases for which currently used EEM parameters are applicable. CONCLUSIONS: We developed EEM parameters enabling the fast calculation of high-quality partial atomic charges for almost all drug-like molecules. In parallel, we provide a software solution for their easy computation (http://ncbr.muni.cz/eem_parameters). It enables the direct application of EEM in chemoinformatics.

AtomicChargeCalculator: interactive web-based calculation of atomic charges in large biomolecular complexes and drug-like molecules.

BACKGROUND: Partial atomic charges are a well-established concept, useful in understanding and modeling the chemical behavior of molecules, from simple compounds, to large biomolecular complexes with many reactive sites. RESULTS: This paper introduces AtomicChargeCalculator (ACC), a web-based application for the calculation and analysis of atomic charges which respond to changes in molecular conformation and chemical environment. ACC relies on an empirical method to rapidly compute atomic charges with accuracy comparable to quantum mechanical approaches. Due to its efficient implementation, ACC can handle any type of molecular system, regardless of size and chemical complexity, from drug-like molecules to biomacromolecular complexes with hundreds of thousands of atoms. ACC writes out atomic charges into common molecular structure files, and offers interactive facilities for statistical analysis and comparison of the results, in both tabular and graphical form. CONCLUSIONS: Due to high customizability and speed, easy streamlining and the unified platform for calculation and analysis, ACC caters to all fields of life sciences, from drug design to nanocarriers. ACC is freely available via the Internet at http://ncbr.muni.cz/ACC.

The use of the direct optimized probabilistic calculation method in design of bolt reinforcement for underground and mining workings.

The load-carrying system of each construction should fulfill several conditions which represent reliable criteria in the assessment procedure. It is the theory of structural reliability which determines probability of keeping required properties of constructions. Using this theory, it is possible to apply probabilistic computations based on the probability theory and mathematic statistics. Development of those methods has become more and more popular; it is used, in particular, in designs of load-carrying structures with the required level or reliability when at least some input variables in the design are random. The objective of this paper is to indicate the current scope which might be covered by the new method-Direct Optimized Probabilistic Calculation (DOProC) in assessments of reliability of load-carrying structures. DOProC uses a purely numerical approach without any simulation techniques. This provides more accurate solutions to probabilistic tasks, and, in some cases, such approach results in considerably faster completion of computations. DOProC can be used to solve efficiently a number of probabilistic computations. A very good sphere of application for DOProC is the assessment of the bolt reinforcement in the underground and mining workings. For the purposes above, a special software application-"Anchor"-has been developed.

Influence of the soil genesis on physical and mechanical properties.

The paper deals with the influence of soil genesis on the physical-mechanical properties. The presented case study was conducted in the region of the Ostrava Basin where there is a varied genetic composition of the Quaternary geological structure on the underlying Neogeneous sediments which are sediments of analogous granulometry but different genesis. In this study, 7827 soil samples of an eolian, fluvial, glacial, and deluvial origin and their laboratory analyses results were used. The study identified different values in certain cases, mostly in coarser-grained foundation soils, such as sandy loam S4 (MS) and clayey sand F4 (CS). The soils of the fluvial origin manifest different values than other genetic types. Next, based on regression analyses, dependence was proved neither on the deposition depth (depth of samples) nor from the point of view of the individual foundation soil classes or the genetic types. The contribution of the paper is to point at the influence of genesis on the foundation soil properties so that engineering geologists and geotechnicians pay more attention to the genesis during engineering-geological and geotechnical investigations.

Predicting p Ka values from EEM atomic charges.

: The acid dissociation constant p Ka is a very important molecular property, and there is a strong interest in the development of reliable and fast methods for p Ka prediction. We have evaluated the p Ka prediction capabilities of QSPR models based on empirical atomic charges calculated by the Electronegativity Equalization Method (EEM). Specifically, we collected 18 EEM parameter sets created for 8 different quantum mechanical (QM) charge calculation schemes. Afterwards, we prepared a training set of 74 substituted phenols. Additionally, for each molecule we generated its dissociated form by removing the phenolic hydrogen. For all the molecules in the training set, we then calculated EEM charges using the 18 parameter sets, and the QM charges using the 8 above mentioned charge calculation schemes. For each type of QM and EEM charges, we created one QSPR model employing charges from the non-dissociated molecules (three descriptor QSPR models), and one QSPR model based on charges from both dissociated and non-dissociated molecules (QSPR models with five descriptors). Afterwards, we calculated the quality criteria and evaluated all the QSPR models obtained. We found that QSPR models employing the EEM charges proved as a good approach for the prediction of p Ka (63% of these models had R2 > 0.9, while the best had R2 = 0.924). As expected, QM QSPR models provided more accurate p Ka predictions than the EEM QSPR models but the differences were not significant. Furthermore, a big advantage of the EEM QSPR models is that their descriptors (i.e., EEM atomic charges) can be calculated markedly faster than the QM charge descriptors. Moreover, we found that the EEM QSPR models are not so strongly influenced by the selection of the charge calculation approach as the QM QSPR models. The robustness of the EEM QSPR models was subsequently confirmed by cross-validation. The applicability of EEM QSPR models for other chemical classes was illustrated by a case study focused on carboxylic acids. In summary, EEM QSPR models constitute a fast and accurate p Ka prediction approach that can be used in virtual screening.

An indicative method for determination of the most hazardous changes in slopes of the subsidence basins in underground coal mining area in Ostrava (Czech Republic).

Considering growing population and decreasing mineral resource reserves, the issue of undermining has been and shall remain very topical. This study aims to identify the mutual connections between mined out panels of a deposit and the final manifestations on the ground surface related to deep black coal mining. On the grounds of the identified connections, the study describes a method to simplify a common evaluation of undermined areas according to building site categories. Within the study, a demarcation of the areas was conducted in two localities in Czech Republic influenced by the effects of undermining in the Upper-Silesian Basin. In the allotment of the CSM Mine, an area unsuitable for founding structures was defined from the centre of the worked out workings to the distance of 175 m from the panel's edge, for which the corresponding break angle is 78.3°. Similarly, in the allotment of the Paskov Mine, an area unsuitable for founding structures was determined to the distance of 500 m from the panel's edge, for which the corresponding break angle is 50.2°. This demarcation may be implemented prior to deposit mining being aware of several physical-mechanical parameters of rocks in the deposit's overburden. Having mined out a particular section of a deposit, it is recommended to verify the values of break angle using the method described herein. The study may be applied as a relatively fast and effective method to evaluate future land use for planning.

Predicting pK(a) values of substituted phenols from atomic charges: comparison of different quantum mechanical methods and charge distribution schemes.

The acid dissociation (ionization) constant pK(a) is one of the fundamental properties of organic molecules. We have evaluated different computational strategies and models to predict the pK(a) values of substituted phenols using partial atomic charges. Partial atomic charges for 124 phenol molecules were calculated using 83 approaches containing seven theory levels (MP2, HF, B3LYP, BLYP, BP86, AM1, and PM3), three basis sets (6-31G*, 6-311G, STO-3G), and five population analyses (MPA, NPA, Hirshfeld, MK, and Löwdin). The correlations between pK(a) and various atomic charge descriptors were examined, and the best descriptors were selected for preparing the quantitative structure-property relationship (QSPR) models. One QSPR model was created for each of the 83 approaches to charge calculation, and then the accuracy of all these models was analyzed and compared. The pK(a)s predicted by most of the models correlate strongly with experimental pK(a) values. For example, more than 25% of the models have correlation coefficients (R²) greater than 0.95 and root-mean-square errors smaller than 0.49. All seven examined theory levels are applicable for pK(a) prediction from charges. The best results were obtained for the MP2 and HF level of theory. The most suitable basis set was found to be 6-31G*. The 6-311G basis set provided slightly weaker correlations, and unexpectedly also, the STO-3G basis set is applicable for the QSPR modeling of pK(a). The Mulliken, natural, and Löwdin population analyses provide accurate models for all tested theory levels and basis sets. The results provided by the Hirshfeld population analysis were also acceptable, but the QSPR models based on MK charges show only weak correlations.