Number Of Heavy Atoms Research Articles

Predicting internal protein dynamics from structures using coupled networks of hindered rotators

Internal motions in proteins, such as oscillations of internuclear vectors u(N(i)H(i) (N)) of amide bonds about their equilibrium position, can be characterized by a local order parameter. This dynamic parameter can be determined experimentally by measuring the longitudinal and transverse relaxation rates of (15)N(i) nuclei by suitable NMR methods. In this paper, it is shown that local variations of order parameters S(ii) (2) can be predicted from the knowledge of the structure. To this effect, the diffusive motion of the internuclear vector u(N(i)H(i) (N)) is described in a potential that takes into account the deviations of the angles theta(ij) between u(N(i)H(i) (N)) and neighboring vectors u(N(j)H(j) (N)) from their average value and similarly of deviations of the angles subtended between u(N(i)H(i) (N)) and u(X(j)Y(j)), where X(j) and Y(j) are heavy atoms in the vicinity of the u(N(i)H(i) (N)) vector under investigation. It is shown how the concept of vicinity can be defined by a simple cutoff threshold, i.e., by neglecting vectors u(X(j)Y(j)) with distances d(N(i),X(j))>7.5 A. The local order parameters S(ii) (2) can be predicted from the structure using a limited set of coordinates of heavy atoms. The inclusion of a larger number of heavy atoms does not improve the predictions. Applications to calmodulin, calbindin, and interleukin 4 illustrate the success and limitations of the predictions.

Phase-contrast and fluorescent X-ray imaging for biomedical researches

Synchrotron X-ray imaging systems with phase-contrast and fluorescent techniques have been developed for biomedical researches. Since phase-contrast X-ray imaging with an X-ray interferometer is a highly sensitive imaging technique to differentiate the inner soft tissue in biological object, detailed morphological structures can be imaged without the use of contrast material. Fluorescent X-ray CT detects specific heavy atomic number elements such as iodine at the order of picogram in a volume of 10 −6 ml, so the functional information with labeling agents can be obtained. Here, I describe recent in vivo and ex vivo experimental results obtained by these imaging techniques.

Crystallography of the integral membrane protein EmrE fromEscherichia coli

Crystals of the EmrE membrane-protein imposed several technical challenges for X-ray crystallography, including high mosaicity, poor diffraction and a relatively large number of heavy atoms. Consequently, the heavy-atom substructure solution was difficult to obtain. By removing the histidine tag for protein purification, the mosaicity and the diffraction quality were greatly improved. The direct-methods Shake-and-Bake program SnB was successful in locating the heavy-atom sites from a mutant of EmrE which lacks a cysteine and therefore has a reduction in the number of heavy-atom sites. The substructure solution was solved from data with anomalous difference at a resolution of 5.5 A and the structure was determined to 3.8 A.

Solvation thermodynamics of xenon in n-alkanes, n-alcohols and water

Experimental thermodynamic data for the solvation of xenon in n-alkanes, water and n-alcohols, from different sources, are analysed by means of a general theory of solvation. The standard solvation Gibbs energy change is given by the sum of the work spent to create a cavity suitable to host xenon and the energy gained to turn on xenon-solvent attractive interactions. The latter contribution is larger in magnitude than the former in both n-alkanes and n-alcohols; the reverse holds in water. This finding is due to the fact that liquid water is characterized by the largest work of cavity creation, because of the smallness of its molecules. Since the two contributions to the solvation Gibbs energy change are both larger in magnitude in n-alcohols with respect to n-alkanes of the same number of heavy atoms, the xenon solubility is not so different between the two classes of solvents. The H-bonds play an indirect role, being important to determine the density of the liquid. It is also shown that there is no clear correlation between the cohesive energy density of the liquid and the solubility of xenon in the liquid itself. The present study confirms that the effective molecular size of solvent molecules is the principal factor in controlling the solvation Gibbs energy changes.

Electrophilic Amination of Methylbenzenes with the System NaN3-AlCl3-HCl. Effects of the Solvent, Crown Ether, and Substrate Structure

Using mesitylene and o-xylene as examples, it was shown that the solvent nature strongly affects the conversion of methylbenzenes in electrophilic amination with the system NaN3-AlCl3-HCl. Two-parameter correlations were found between the substrate conversion, on the one hand, and dielectric constant and number of heavy atoms in the solvent, on the other. A considerable solvent effect on the regioselectivity of amination of o-xylene was observed. The presence of 18-crown-6 weakly affects the ratio of isomeric amines, but the conversion of o-xylene sharply decreases. Solid aromatic substrates, such as durene and pentamethylbenzene can also be involved in electrophilic amination with the system NaN3-AlCl3-HCl. On the basis of the experimental data and the results of quantum-chemical calculations, participation of a nitrenium intermediate in this reaction was postulated.

Consideration of molecular weight during compound selection in virtual target-based database screening.

Virtual database screening allows for millions of chemical compounds to be computationally selected based on structural complimentary to known inhibitors or to a target binding site on a biological macromolecule. Compound selection in virtual database screening when targeting a biological macromolecule is typically based on the interaction energy between the chemical compound and the target macromolecule. In the present study it is shown that this approach is biased toward the selection of high molecular weight compounds due to the contribution of the compound size to the energy score. To account for molecular weight during energy based screening, we propose normalization strategies based on the total number of heavy atoms in the chemical compounds being screened. This approach is computationally efficient and produces molecular weight distributions of selected compounds that can be selected to be (1) lower than that of the original database used in the virtual screening, which may be desirable for selection of leadlike compounds or (2) similar to that of the original database, which may be desirable for the selection of drug-like compounds. By eliminating the bias in target-based database screening toward higher molecular weight compounds it is anticipated that the proposed procedure will enhance the success rate of computer-aided drug design.

Properties of known drugs. 2. Side chains.

We continue our study of the common features present in drug molecules by looking in detail at drug side chains. Using shape description methods, we divide a database of commercially available drugs into a list of common drug side chains. On the basis of the atom pair shape descriptor (taking into account atom type, hybridization, and bond order), there are 1,246 different side chains among the 5,090 compounds analyzed. The average number of side chains per molecule is 4, and the average number of heavy atoms per side chain is 2. If we ignore the carbonyl side chain, then there are approximately 15,000 occurrences of side chains. Of these 15,000 approximately 11,000 are from the "top 20" group of side chains. This suggests that the diversity that side chains provide to drug molecules is quite low. We discuss ways that this work could be used to provide guidance for molecular design efforts.

The Excitation Temperatures of HC9N and Other Long Cyanopolyynes in TMC‐1

We report observations of seven different transitions of HC9N between 9.8 and 23.3 GHz in the cold, dark cloud TMC-1. Because of its lower rotational constant, HC9N is expected to yield a rotational temperature closer to the kinetic temperature of the gas than the shorter cyanopolyynes. Assuming that HC9N in TMC-1 is optically thin, we obtain a rotational temperature Trot = 7.5-8.7 K and a corresponding column density of NL(HC9N) = (5.4-2.3) × 1012 cm-2, depending on the source size L assumed. The rate of radiative cooling is less efficient in the longer cyanopolyyne chains and is approximately proportional to (n + 1)-6, where n is the number of carbon atoms in the chain. In steady state this is balanced by the collisional rate of excitation. The rotational temperatures of the cyanopolyynes are found to increase with the number of heavy atoms over the range HC5N-HC9N, in reasonable agreement with calculations. Concomitantly, we find evidence that the longer cyanopolyynes are located in regions that become progressively smaller with chain length. We also report newly measured values for the rotational and centrifugal distortion constants of HC9N that improve the accuracy of the calculated millimeter wave transitions.

Comparison of spin-orbit configuration interaction methods employing relativistic effective core potentials for the calculation of zero-field splittings of heavy atoms with a 2P o ground state

Computational strategies for the treatment of relativistic effects including spin-orbit coupling at a highly correlated level are compared for a number of heavy atoms: indium, iodine, thallium, and astatine. Initial tests with perturbation theory emphasize the importance of high-energy singly excited configurations which possess large spin-orbit matrix elements with the ground state. A contracted basis consisting of L–S CI eigenfunctions (LSC–SO–CI) is found to give an accurate representation of both spin-perturbed 2Po components as long as key np→pi* singly excited configurations are included. Comparison is made with a more extensive treatment in which all selected configurations of various L–S symmetries form the basis for the multireference–spin-orbit–configuration interaction (MR–SO–CI). Good agreement is obtained with experimental SO splittings for the In, I, and At atoms at a variety of levels of treatment, indicating that the L–S contracted SO–CI approach can be implemented quite effectively with relativistic effective core potentials (RECPs) for both very electronegative atoms and also for lighter electropositive elements up through the fifth row of the periodic table. The thallium atom SO splitting is more difficult to obtain accurately because of greater differences between its valence p1/2 and p3/2 spinors than in the other cases studied, but good results are also possible with the contracted SO–CI approach in this instance, provided proper care is given to the inclusion of key singly excited L–S states. The relationship between all-electron two-component SO–CI treatments and those employing RECPs is also analyzed, and it is concluded that triply excited configurations relative to the 2Po ground state are far less important than previously reported.

Distonic ions as reacting species

The characteristic reactions of a family of distonic radical cations show that the gas-phase chemistry of these species differs considerably from that of the isomeric conventional molecular ions. Fifteen distonic radical cations, derived from 'CH2CHZNH3+ by introduction of alkyl substituents at C or N, have been demonstrated to be stable species whose reactions are characteristic of their structure. The predominant fragmentation and isomerization processes are the following: (i) simple cleavage of a C-N bond with formation of alkene ions or alkene molecules, (ii) 1,2-migration of protonated amino groups, and (iii) formation of ammonium ions by elimination of alkenyl radicals. Chain length permitting, these reactions may be preceded or acconpanied by specific intramolecular hydrogen abstraction reactions, which lead to isomeric distonic ions with characteristically different reactions. The hydrogen abstraction reactions are generally reversible; in the presence of long alkyl groups isomerization to amine molecular ions (et vice versa) can occur. Correspondingly, the reactions of many low-energy amine molecular ions require isomerization to distonic intermediates prior to fragmentation. A considerable number of recent papers have demonstrated the existence in the gas phase of stable distonic radical cations,'-I4 and distonic ions are with increasing frequency being suggested as key intermediates in unimolecular fragmentation The collision-induced reactions of these species have often been used to establish their structural integrity, but the question of how the particular properties of distonic ions influence their reactions has not been addressed in the literature. We have studied the isomerization and dissociation reactions of a family of distonic amine ions, in order to discover the characteristic reactions of these species and to examine the difference between these reactions and those of the corresponding conventional molecular ions. The term distonic ion was coined by Radom and co-workersZ3 to describe radical cations arising (formally) by ionization of zwitterions or diradicals. The difference between the properties of stable distonic ions and those of conventional molecular ions generated by direct ionization of neutral molecules can be con- siderable, and Radom's neologism has rapidly gained acceptance among gas-phase ion chemists. However, the properties of distonic ions often vary with the number of heavy atoms separating the charge and radical bearing sites. In the present paper we employ the adjectives a-distonic, P-distonic, y-distonic, etc., to denote respectively species with charge and radical at adjacent atoms (a-distonic ions or ylidions, e.g., l), with charge and radical separated by one heavy atom (P-distonic ions, e.g. 2), by two heavy atoms (y-distonic ions), etc. Recent experimental and ab initio st~dies~'-~~~~~~ ~~~~~ of the various CHSN'+ and C2H7N'+ isomers have shown that a- and

Information of protein inner structure derived by small-angle X-ray scattering.

The radius of gyration, which is the most important structural parameter obtainable by small-angle X-ray scattering (SAXS), comprises the information of the inner structure of protein in solution as well as the bulk structure. The rough distribution of electron density is revealed by contrast variation measurement. Heavy atom labeling with contrast variation reveals the number of heavy atoms binding to the protein and the distribution of heavy atoms in the protein. In the case of the oligomeric protein, other than the radius of gyration of the whole molecule, the radius of gyration of a subunit and the distance between subunits are obtainable by SAXS. Some examples are also summarized.

Discrepancy factors for use in crystal structure analysis. II. Normalized index R2 for crystals with a few heavy atoms in the asymmetric unit belonging to the triclinic, monoclinic and orthorhombic systems

Theoretical expressions for the normalized form of the discrepancy index R2 of Wilson have been obtained for crystals containing heavy atoms of similar scattering power, with the heavy-atom part of the structure taken as the trial model. The results obtained are applicable for crystals belonging to 72 space groups of the triclinic, monoclinic and orthorhombic systems. Expressions for two limiting situations, namely complete relatedness and complete unrelatedness, have been tabulated for the commonly occurring cases corresponding to the number of heavy atoms in the asymmetric unit being one or two. Theoretical curves for this index as a function of the fractional heavy-atom contribution are also given for the various cases.

The application of direct methods to centrosymmetric structures containing heavy atoms

For those reflexions of which the sign is determined by a relatively small number of heavy atoms, the known heavy-atom contribution is subtracted from the observed structure factor to obtain the magnitude and the sign of the light-atom contribution. Thereafter the signs of the reflexions that do not have appreciable heavy atom contributions are found using the triple product sign relationship.

Vibrations of Disordered Solids

An important portion of the vibrational spectrum of an infinite disordered solid is attributed to "localized" vibrations. These can be investigated in detail through the study of the vibrations of very small solids: It is argued that any vibrational mode found in a small solid that has the property that atomic amplitudes are very small near the boundary will also be found, with at most slight perturbation, in a large solid. It is observed that such modes appear whenever a group containing light atoms occurs and is bounded by a sufficient number of heavy atoms; the number that is "sufficient" depends somewhat on force model, mass ratio, and dimensionality, but is generally small. The density of these local modes in the spectrum of the large crystal can then be computed from the probability of the occurrence in the large crystal of the configuration of masses that produces it. For the case of the one-dimensional binary alloy, the major features of the earlier direct numerical computation (Dean) can be reproduced and understood by this simple method. Similar features (peaks) are predicted for two- and three-dimensional structures, but their intensity compared to the continuous part of the spectrum is shown to be smaller.