SEARCH · PubMed Health
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
In this paper, after a brief description on our approach to simulations of chemical systems, some of the results obtained are discussed. Four examples are reported: 1) liquid water simulation which takes in account a four-body potential; 2) hydration networks in a crystal; 3) water and ion structures in DNA; 4) proton tunneling in DNA base pairs. We include also a short description of a parallel system we have assembled.
A cost effective color graphics representation of molecular electrostatic potential surfaces employing the cumulative atomic or bond multipole moments has been described. A general description of the method used to obtain cumulative multipole moments directly from ab-initio wavefunctions is given, along with an outline of the algorithm for generating electrostatic potential surfaces in the molecular graphics programs MOL17 (FORTRAN 77, Silicon Graphics 3130 and 4D series workstations) and PCMCAMM (Turbo Pascal, IBM PC and PS/2 computers). Examples are given that illustrate the convergence of the multiple expansion, the degree of basis-set dependence compensated by the use of higher atomic moments, and the effect of placing additional expansion centers along the bonds.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
The H2 receptor activation mechanism model proposed by Weinstein et al. [Mol. Pharmacol. 12:738-745 (1976)] has been considered for the set of H2 agonists. The energetics of the model proton transfer processes from a proton-donor site to the heterocycle ring of the agonist molecule and from this one to a proton acceptor site have been studied by using the semiempirical AM1 and MNDO quantum mechanical methods. The STO-3G ab initio molecular electrostatic potential for each compound in its active form has also been computed. Results show the mechanistic model to be satisfactory and lead to a qualitative and quantitative explanation of the H2 activity data.
The general requirements for balancing of detectors in a multiple detector CT scanner are discussed, and the specific requirements for software balancing using data acquired within the body section during the scan are outlined. A particular technique which can be implemented in a scanner employing a simultaneous translation and rotation of the source/detector package is presented. The technique produces an exact balancing offset and gain factors, to within accuracy limits imposed by the statistical uncertainty due to noise in the measurements. However, the technique admits a redundancy of solutions with allows the statistical sample to be expanded to include virtually all data acquired during the scan, thereby suppressing detector imbalance artifacts to the same level as overall quantum noise in the image.
A survey of higher types of number, with more sophisticated arithmetics than square root -1, is presented. Such powerful embodiments of the number concept are capable of representing entities and operations in the bio-sciences, where phenomena are characteristically more recondite than in naively reductionist, mechanistic physics or chemistry, which today even quantum theory (which itself deploys two kinds of hypernumber) has shown to be inadequate to explain observed phenomena. When the bio-sciences enter the picture, four other kinds of hypernumber are needed, one of them (w) relating also to the frontiers of quantum theory, in terms of the resolution of problems such as the breakdown of parity conservation and of time reversal, and the concomitant elimination of unwanted divergences (infinities). A brief statement of the relevance of each of the additional kinds of hypernumbers in bio-scientific computing is furnished, as an introduction to an approach that is not only viable in terms of digital computing, but is fraught with new implications for bio-scientific research.
Spectroscopy at a biochemical active site is influenced by local fields and hydrogen-bonds. Quantum calculations of the electronic structure of the entire biomolecule is, of course, impossible, but the chemical system can be modeled by dividing it into an active region (A) described quantum mechanically, and a spectator region (S) that influences A with strong fields and hydrogen-bonds. The all-electron interaction between A and S is replaced by an effective fragment potential (EFP) which represents the interaction as electrostatic, polarization and exchange repulsion terms. The EFP are derived entirely by ab initio model calculations of the S electronic properties and interactions and have been implemented in the quantum chemistry code, GAMESS. Spectroscopic analysis of enzyme active sites using the EFP will examine rhodanese and glutathione bound to glutathione S-transferase. The effect of specific hydrogen-bonds and local helices on spectral shifts is determined.
Explore the source record for details and available documents.
Computer-assisted methods can be used to investigate the relationships between the molecular structures of compounds and their biological activity. A number of approaches have been reported in the literature, including correlations of activity with substituent constants, conformational analysis and display, quantum mechanical methods, and methods relying on discriminant development and pattern-recognition techniques. Application areas for this technology include drug design, agricultural chemical design, and studies of chemical toxicity and genetic toxicity (mutagenic or carcinogenic potential). These structure-activity methods are introduced, and citations are given. Several current structure-activity relationship (SAR) studies using pattern recognition are presented as examples of typical projects that are feasible with this approach. These include the investigation of a set of 122 antiinflammatory steroids, a study of 153 retinoids for cancer prevention, and a study of chemicals that have been tested in a sister chromatid exchange mutagen screen.
Detection of cancer in early stages with hematoporphyrin derivatives (HpD) is highly limited by the low fluorescence quantum yield, the strong autofluorescent components of the tissue, and the low contrast between normal and tumoral tissue when fluorescent photographs are taken. A new computer analysis based on digital subtraction of photographs before and after the administration of HpD, allows a total autofluorescence extraction, resulting in a remarkable increase of contrast between tumors and normal tissue. Experiments, with this computerized imaging system in adenocarcinoma of the stomach in Wistar rats, confirms the reliability of this method.
Derivation of quantitative structure-activity relationships between pharmacological potencies and the electronic structure of molecules may often result in chance correlations, because of the large number of quantum chemical indices. Interrelationships between the parameters complicate the interpretation of the results. Quantum chemical indices of benzylamines, tetracyclines, and 1,4-benzodiazepines were transformed into mutually independent components using principal component analysis. The number of essential components was 3, 4, and 3, respectively. The computational efforts needed to develop multivariate linear regression equations between these components and the pharmacological activities were reduced, since the regression coefficients were not affected by the inclusion of new parameters. In each example, the first component, which accounted for the highest part of the total sample variance in the electronic structure, was the most important one in determining pharmacological activity. It seems that besides the electrostatic forces, charge transfer also affected the inhibitory potencies of benzylamines.
In vivo convulsant activities profiles and receptor binding studies together with the techniques of theoretical chemistry were used to characterize 15 compounds, from five different chemical families, known to bind to the BDZ receptor. The experimental goals of this study were to determine the affinity of these analogs for this receptor, the effect of gamma-aminobutyric acid on the affinity, and, in a self-consistent manner, the nature of the activity, agonist (anticonvulsant), antagonist, or inverse agonist (proconvulsant, convulsant), elicited by binding to this receptor. To these ends, in vivo studies were made to determine the proconvulsant, convulsant, and anticonvulsant activities and antagonism to anticonvulsant activities of the 15 analogs. Their receptor affinities at 25 degrees were also determined by competitive inhibition of [3H] flunitrazepam and [3H]Ro 15-1788 in the absence and presence of gamma-aminobutyric acid. The goal of the theoretical studies was to identify and calculate molecular properties that modulate these affinities and types of activities and from them to develop a model of receptor recognition and activation that could consistently explain observed behavior and predict new results. Thus, molecular orbital calculations were carried out for all analogs, using semiempirical quantum mechanical methods. In addition to the optimization of structures, a number of electronic properties, such as polarizations, partition coefficients, and proton and electron affinities were computed and examined for their ability to modulate relative affinities and modes of activation of the receptor. From these studies, a model for receptor recognition involving two anchoring hydrogen bond-acceptor sites and for activation involving interaction of the most lipophilic aromatic region of each compound with the receptor was developed, which could systematically account for the three different types of behavior, agonist, antagonist, and inverse agonist, observed for these analogs. Electronic rather than structural properties were found to be the principal modulator of both recognition and activation. A possible mechanism of agonist activation of the receptor involving electron transfer to the agonist, as well as a possible induced conformational change in the receptor, is also suggested by these results. Finally, by complementarity, some steric and electronic characteristics of the receptor binding site could be deduced.
A study of the binding behaviour of ellipticine compounds, derivatives of pyrido (4-3b) carbazole, has been carried out to elucidate the relationship between the drug-activity and demethylation of ellipticine. An all valence electron method (CNDO/2) has been employed to compute molecular charge distribution corresponding to various atomic centres of ellipticines and DNA base pairs. Using these atomic charges and dipoles, intermolecular interaction energy has been calculated with the help of second order perturbation theory and multicentered-multipole expansion technique. A comparative analysis of the binding patterns for nor-5,11-dimethyl-ellipticine and nor-11-methyl-ellipticine has been presented vis-a-vis ellipticine. Attempt has been made to correlate interaction energy studies with demethylation of ellipticine and the possible binding patterns.
Three components of the magnetic field generated by the heart over the anterior aspect of the chest in a normal subject were detected using a Superconducting Quantum Interference Device (SQUID) magnetometer with a single detecting coil in a magnetically shielded room. Contour maps and color density maps of the field were prepared by computer. Movies of sequential magnetic fields of the vertical component on the anterior aspect of the chest were made from these maps. In the movies, the maximum moved from the upper central portion to right lower portion in the early stage of ventricular excitation. It moved to the central portion in the middle stage, then returned to the upper central portion in the late stage. Three-dimensional maps of instantaneous magnetic fields over the anterior portion of the chest were derived from maps of three components of the field, and from presumed heart vectors and were drawn as arrows, based on the Viot-Savart theorem. Heart vectors from these field maps corresponded well with septal forces in the early stage, left ventricular free wall force in the middle stage and the basal force in the late stage, respectively. However, large circulating vectors in the form of clockwise rotation in the central portion were also presumed. These circulating heart vectors did not correspond with the sequence of cardiac excitation as reported by Durrer et al. This discrepancy may have been caused by the fact that the vertical electric current could not be expressed from our display for presuming an electric force. Therefore, new displays and interpretations may be required for the expression of heart vectors.
The structure of d(AC)4.d(GT)4 is investigated by constrained molecular dynamics simulations. The constraints include proton pair distances derived from 2D NOE intensities by using the iterative relaxation matrix analysis algorithm MARDIGRAS and sugar pucker phases and amplitudes derived from double-quantum-filtered COSY spectra. Molecular dynamics runs on simulated intensity and distance sets as well as the experimental data were carried out to determine the effects of starting structure, distance constraint derivation, energy functions, and experimental errors on the end result. It was found that structural details could not be elucidated within about 1.5-A overall atomic deviation. This limitation is due in part to the accuracy of the experimental data but, more importantly, is attributable to the quantity of experimental constraints available and to imperfections in the force field utilized in the molecular dynamics calculations. Within the limits of the method, some structural characteristics of d(AC)4.d(GT)4 could be elucidated.
Monte Carlo computer simulation techniques have been used to model non-pair-additive (cooperative) effects in the water organization around several biomolecules. Although most models for water assume pair-additive potentials, both quantum mechanical calculations and experimental data indicate that cooperative effects are not negligible in hydrogen-bounded systems such as water. The many-body polarizable electropole (PE) model for water is used to examine the extent and the consequences of this cooperative behavior in several biomolecule hydrate crystals. Increases in the dipole moments of water molecules are predicted in all systems studied so far and can be as much as 50% more than the monomer value of 1.855 debyes. The average value of the individual dipole moments for any one system differs from that of another system and, therefore, should be considered a property of the system and not of the water molecule itself. When this previously calculated average value of the dipole moment for water molecules in a given system is used as a fixed parameter in the simulation, we find differences between this fixed calculation and the original unfixed simulation. An alternative procedure, which allows for a spread in dipole moments and is not dependent on a predetermined average value, has been developed to make simulations of large water-protein systems, including cooperative effects, computationally feasible.
A reappraisal has been made of interatomic potential functions for protein structure calculations using the all-atom approximation (except CH, CH2 and CH3, which are treated as "united atoms"). Some key problems are identified and treated. The potential functions are somewhat novel in form and consistent with more efficient and robust folding algorithms. In addition, the potentials are calibrated for for the rigid geometry approximation, since use of fixed standard bond lengths and valence angles (and fixed trans planar peptide groups) reduces the number of conformational variables and saves a great deal of computer time. Though these algorithms demand the use of potential functions of this special type, these functions can be readily implemented in more classical programs for the conformational analysis of proteins. They are calibrated or tested against a large body of experimental data, including extended basis set ab initio, quantum mechanical calculations, nuclear magnetic resonance spectroscopic data and dipole moment data for di- and oligopeptides, characteristic ratio data for random coil homopolypeptides, extensive data from peptide solubility studies, and experimental structures of polyalanine fibres and globular proteins. This paper will form the basis of a further report, which will include investigations of how water might be more realistically represented subject to the computing power available.