Implicit methods for modeling protein electrostatics require dielectric properties of the system to be known, in particular, the value of the dielectric constant of protein. While numerous values of the internal protein dielectric constant were reported in the literature, still there is no consensus of what the optimal value is. Perhaps this is due to the fact that the protein dielectric constant is not a "constant" but is a complex function reflecting the properties of the protein's structure and sequence. Here, we report an implementation of a Gaussian-based approach to deliver the dielectric constant distribution throughout the protein and surrounding water phase by utilizing the 3D structure of the corresponding macromolecule. In contrast to previous reports, we construct a smooth dielectric function throughout the space of the system to be modeled rather than just constructing a "Gaussian surface" or smoothing molecule-water boundary. Analysis on a large set of proteins shows that (a) the average dielectric constant inside the protein is relatively low, about 6-7, and reaches a value of about 20-30 at the protein's surface, and (b) high average local dielectric constant values are associated with charged residues while low dielectric constant values are automatically assigned to the regions occupied by hydrophobic residues. In terms of energetics, a benchmarking test was carried out against the experimental pKa's of 89 residues in staphylococcal nuclease (SNase) and showed that it results in a much better RMSD (= 1.77 pK) than the corresponding calculations done with a homogeneous high dielectric constant with an optimal value of 10 (RMSD = 2.43 pK).

On the Dielectric "Constant" of Proteins: Smooth Dielectric Function for Macromolecular Modeling and Its Implementation in DelPhi.

This is cne of the r-are text books written in the discipline of Nuclear Reactor Analysis, where the author has considered the interests of both scientists and practising engineers, in addition to serving the needs of the academia. The most attractive feature of this book is a balanced treatment of theory and practice of the subject matter. The theoretical foundations of the reactor design methods are explained with simplified definitions and relevant practical illustrations. The author scans through quickly the traditional aspects of the so-called reactor physics and takes the reader through the details of the analytical aspects in a conventional manner. Hcwever, there is a definite departure from the classical method of approach in order to avoid lengthy and repetitive discussions, that are available in many standard text books on reactor physics. The chief departure fran tradition is the priority accorded to the treatment of the energy part of the problems as opposed to the spatial Dart normally devoted to by other authors . A similar unorthodox approach has been applied while dealing with the solution of the various equations by giving priority to computer oriented mrethods as opposed to the classical solutions.

Nuclear reactor analysis

Enzyme assisted extraction of biomolecules as an approach to novel extraction technology: A review.

A reverse pH gradient is a hallmark of cancer metabolism, manifested by extracellular acidosis and intracellular alkalization While consequences of extracellular acidosis are known, the roles of intracellular alkalization are incompletely understood By reconstructing and integrating enzymatic pH-dependent activity profiles into cell-specific genome-scale metabolic models, we develop a computational methodology that explores how intracellular pH (pHi) can modulate metabolism We show that in silico, alkaline pHi maximizes cancer cell proliferation coupled to increased glycolysis and adaptation to hypoxia (ie, the Warburg effect), whereas acidic pHi disables these adaptations and compromises tumor cell growth We then systematically identify metabolic targets (GAPDH and GPI) with predicted amplified anti-cancer effects at acidic pHi, forming a novel therapeutic strategy Experimental testing of this strategy in breast cancer cells reveals that it is particularly effective against aggressive phenotypes Hence, this study suggests essential roles of pHi in cancer metabolism and provides a conceptual and computational framework for exploring pHi roles in other biomedical domains Tumors often exhibit a pH gradient, with an acidic extracellular space and alkaline cytoplasm Here the authors develop a computational model to show how alkaline pHi supports changes inherent to cancer cell metabolism and acidification disables these adaptations, and demonstrate the effect of acidic pHi on breast cancer cell survival

/pdf/systems-analysis-of-intracellular-ph-vulnerabilities-for-58pvotv9a1.pdf

Systems analysis of intracellular pH vulnerabilities for cancer therapy.

https://www.ncbi.nlm.nih.gov/CBBresearch/Panchenko/web_phospho/structure.pdf

Phosphorylation in Protein-Protein Binding: Effect on Stability and Function

Biological macromolecules evolved to perform their function in specific cellular environment (subcellular compartments or tissues); therefore, they should be adapted to the biophysical characteristics of the corresponding environment, one of them being the characteristic pH. Many macromolecular properties are pH dependent, such as activity and stability. However, only activity is biologically important, while stability may not be crucial for the corresponding reaction. Here we show that the pH-optimum of activity (the pH of maximal activity) is correlated with the pHoptimum of stability (the pH of maximal stability) on a set of 310 proteins with available experimental data. We speculate that such a correlation is needed to allow the corresponding macromolecules to tolerate small pH fluctuations that are inevitable with cellular function. Our findings rationalize the efforts of correlating the pH of maximal stability and the characteristic pH of subcellular compartments, since only pH of activity is subject of evolutionary pressure. In addition, our analysis confirmed the previous observation that pH-optimum of activity and stability are not correlated with the isoelectric point, pI, or with the optimal temperature.

/pdf/on-the-ph-optimum-of-activity-and-stability-of-proteins-usr5lovak7.pdf

On the pH‐optimum of activity and stability of proteins

Accurate predictions of pKa values of titratable groups require taking into account all relevant processes associated with the ionization/deionization. Frequently, however, the ionization does not involve significant structural changes and the dominating effects are purely electrostatic in origin allowing accurate predictions to be made based on the electrostatic energy difference between ionized and neutral forms alone using a static structure. On another hand, if the change of the charge state is accompanied by a structural reorganization of the target protein, then the relevant conformational changes have to be taken into account in the pKa calculations. Here we report a hybrid approach that first predicts the titratable groups, which ionization is expected to cause conformational changes, termed “problematic” residues, then applies a special protocol on them, while the rest of the pKa’s are predicted with rigid backbone approach as implemented in multiconformation continuum electrostatics (MCCE) method. The backbone representative conformations for “problematic” groups are generated with either molecular dynamics simulations with charged and uncharged amino acid or with ab-initio local segment modeling. The corresponding ensembles are then used to calculate the pKa of the “problematic” residues and then the results are averaged.

/pdf/developing-hybrid-approaches-to-predict-pka-values-of-5fb76p7nkg.pdf

Developing hybrid approaches to predict pKa values of ionizable groups

Recent advancements in experimental and theoretical nuclear physics have yielded new data and models that more accurately describe the decay of fission products compared to historical data currently used for many applications. This work examines the effect of the adopting the Effective Density Model theory for beta-delayed neutron emission probability on calculations of delayed-neutron production and fission product nuclide concentrations after fission bursts as well as the total delayed neutron fraction in comparison with the Keepin 6-group model. We use ORIGEN within the SCALE code package for these calculations. We show quantitative changes to the isotopic concentrations for fallout nuclides and delayed neutron production after fission bursts on the order of a few percent. We also show that the changes are larger at small times for short lived fission products, and that corrections to the cumulative fission product yields has an impact upon the total delayed neutron fraction for U [Uranium 235]. The effect of modeling the β2n [beta delayed double neutron emission] decay mode is also studied but no significant changes from the single beta-delayed neutron emission is currently seen.

/pdf/beta-delayed-neutron-data-and-models-for-scale-1u4hbmn2b5.pdf

Beta-Delayed Neutron Data and Models for SCALE

Calculations of electrostatic properties of protein-protein complexes are usually done within framework of a model with a certain set of parameters. In this paper we present a comprehensive statistical analysis of the sensitivity of the electrostatic component of binding free energy (ΔΔGel) with respect with different force fields (Charmm, Amber, and OPLS), different values of the internal dielectric constant, and different presentations of molecular surface (different values of the probe radius). The study was done using the largest so far set of entries comprising 260 hetero and 2148 homo protein-protein complexes extracted from a previously developed database of protein complexes (ProtCom). To test the sensitivity of the energy calculations with respect to the structural details, all structures were energy minimized with corresponding force field, and the energies were recalculated. The results indicate that the absolute value of the electrostatic component of the binding free energy (ΔΔGel) is very sensitive to the force field parameters, the minimization procedure, the values of the internal dielectric constant, and the probe radius. Nevertheless our results indicate that certain trends in ΔΔGel behavior are much less sensitive to the calculation parameters. For instance, the fraction of the homo-complexes, for which the electrostatics was found to oppose binding, is 80% regardless of the force fields and parameters used. For the hetero-complexes, however, the percentage of the cases for which electrostatics opposed binding varied from 43% to 85%, depending on the protocol and parameters employed. A significant correlation was found between the effects caused by raising the internal dielectric constant and decreasing the probe radius. Correlations were also found among the results obtained with different force fields. However, despite of the correlations found, the absolute ΔΔGel calculated with different force field parameters could differ more than tens of kcal/mol in some cases. Set of rules of obtaining confident predictions of absolute ΔΔGel and ΔΔGel sign are provided in the conclusion section.

/pdf/on-the-electrostatic-component-of-protein-protein-binding-30orycwtu3.pdf

On the electrostatic component of protein-protein binding free energy

Radiation measurement is an effective way to detect and locate nuclear threats. Moving the detector and monitoring the count rate during searches is a common way for finding the source. To minimize exposure and prevent operators from getting too close to the source, an alternative method for locating the source by occlusion is devised. This work explores the use of two NaI detectors and an absorber for estimating the direction of a radiation source. Measurements were carried out for the source located between 0° and 90° in 15° intervals. The ratios of total counts in the detector, counts in the full-energy peaks, and mean energy of the energy spectrum for the far-side detector to the near-side detector as a function of angle are studied for 57Co, 60Co, 137Cs, and 232Th sources. Comparisons are made for placing a piece of tungsten or stainless steel plate between the two detectors with no absorber. When a metal plate is sandwiched between two detectors, the counts in the energy spectra change more quickly between the two detectors with the source angle. Furthermore, the gamma attenuation for tungsten is higher than stainless steel. As a result, the occlusion by tungsten is more effective and useful for estimating the source direction. The 232Th data were also analyzed by dividing the energy spectrum into three windows to examine the ratio of counts in each window between the two detectors. It is found that the source direction of 137Cs and 60Co can be deduced by using the 232Th data as a reference. In order to reduce the size, weight, and power for man-portable and unmanned systems, it is feasible to use only two detectors and a metal plate inserted in-between to quickly obtain the direction of a radiation source.

Enhanced directional detection of gamma sources

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