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PubMedDate not supplied

Characterization of the conformational domains of bradykinin by computational methods.

The AMBER 4.0 force field was used to perform a characterization of the conformational profile of the nonapeptide bradykinin. A thorough conformational search was carried out using molecular dynamics as sampling technique, by computing cycles of high (900 K) and low (300 K) temperature trajectories. A total of 2400 minima were generated and subsequently clustered using the root-mean-square of the backbone dihedral angles as criterium. After the use of a tolerance value of 20 degrees, the conformations were clustered in 233 unique conformations with energies up to 40 kcal/mol above the lowest minimum. The analysis of the low-energy conformations indicate that the peptide exhibits a high tendency to adopt a beta-turn at the C-terminus and a propensity to adopt a bent structure at the N-terminus. These results are in agreement with the experimental evidence reported in the literature and provide detailed information necessary to understand the conformational preferences of the peptide.

Amino Acid Sequence↗
PubMed2002

Discovery of regulatory elements by a computational method for phylogenetic footprinting.

Phylogenetic footprinting is a method for the discovery of regulatory elements in a set of orthologous regulatory regions from multiple species. It does so by identifying the best conserved motifs in those orthologous regions. We describe a computer algorithm designed specifically for this purpose, making use of the phylogenetic relationships among the sequences under study to make more accurate predictions. The program is guaranteed to report all sets of motifs with the lowest parsimony scores, calculated with respect to the phylogenetic tree relating the input species. We report the results of this algorithm on several data sets of interest. A large number of known functional binding sites are identified by our method, but we also find several highly conserved motifs for which no function is yet known.

Algorithms↗
PubMed1991

The application of computational methods to the study of enzyme catalysis by triose-phosphate isomerase and stabilities of variants of bacteriophage T4 lysozyme.

We review our research on triose-phosphate isomerase and bacteriophage T4 lysozyme. In our studies over the last ten years we have used electrostatic potentials, computer graphics, quantum mechanics, molecular mechanics, molecular dynamics and free energy calculations to try to understand why triose-phosphate isomerase is such an efficient enzyme and why its efficiency is dramatically decreased by several site-specific mutations. For T4 lysozyme we have used free energy methods to analyse and try to understand why Thr-157----Val and Thr-157----Ala mutations decrease protein stability by about 1-2 kcal/mol.

Amino Acid Sequence↗
PubMed2002

A fast and easy computational method to calculate the (13)C NMR chemical shift of organic species adsorbed on the zeolite surface.

Calculations of the 13C NMR chemical shifts for the methoxy and ethoxy groups adsorbed on Y and ZSM-5 zeolites were computed at GIAO/B3LYP/6-31+G*//MM+ level of theory, using a cluster representing a real part of the zeolites. The Y zeolite was represented by a cluster with 168 atoms, while ZSM-5 was represented by a cluster with 144 atoms. The calculated chemical shifts agreed well with reported experimental values, showing that the difference in chemical shifts is associated with differences in the geometry of the alkoxides on the two zeolites.

Journal Article↗
PubMed2000

A rapid computational method for lead evolution: description and application to alpha(1)-adrenergic antagonists.

The high failure rate of drugs in the development phase requires a strategy to reduce risks by generating lead candidates from different chemical classes. We describe a new three-dimensional computational approach for lead evolution, based on multiple pharmacophore hypotheses. Using full conformational models for both active and inactive compounds, a large number of pharmacophore hypotheses are analyzed to select the set or "ensemble" of hypotheses that, when combined, is most able to discriminate between active and inactive molecules. The ensemble hypothesis is then used to search virtual chemical libraries to identify compounds for synthesis. This method is very rapid, allowing very large virtual libraries on the order of a million compounds to be filtered efficiently. In applying this method to alpha(1)-adrenergic receptor ligands, we have demonstrated lead evolution from heterocyclic alpha(1)-adrenergic receptor ligands to highly dissimilar active N-substituted glycine compounds. Our results also show that the active N-substituted glycines are part of our smaller filtered library and thus could have been identified by synthesizing only a portion of the N-substituted glycine library.

Adrenergic alpha-Antagonists↗
PubMed1996

Computational methods in radionuclide dosimetry.

The various approaches in radionuclide dosimetry depend on the size and spatial relation of the sources and targets considered in conjunction with the emission range of the radionuclide used. We present some of the frequently reported computational techniques on the basis of the source/target size. For whole organs, or for sources of targets bigger than some centimetres, the acknowledged standard was introduced 30 years ago by the MIRD committee and is still being updated. That approach, based on the absorbed fraction concept, is mainly used for radioprotection purposes but has been updated to take into account the dosimetric challenge raised by therapeutic use of vectored radiopharmaceuticals. At this level, the most important computational effort is in the field of photon dosimetry. On the millimetre scale, photons can often be disregarded, and beta or electron dosimetry is generally reported. Heterogeneities at this level are mainly above the cell level, involving groups of cell or a part of an organ. The dose distribution pattern is often calculated by generalizing a point source dose distribution, but direct calculation by Monte Carlo techniques is also frequently reported because it allows media of inhomogeneous density to be considered. At the cell level, alpha and electron (low-range beta or Auger) are the predominant emissions examined. Heterogeneities in the dose distribution are taken into account, mainly to determine the mean dose at the nucleus. At the DNA level, Auger electrons or alpha-particles are considered from a microdosimetric point of view. These studies are often connected with radiobiological experiments on radionuclide toxicity.

Beta Particles↗
PubMed2001

Computational methods for protein function analysis.

Two recent advances have had the greatest impact on protein function analysis so far: the complete sequences of genomes and mRNA expression level profiles. The former has spurred the development of novel techniques to study protein function: phylogenetic profiles and gene clusters. The latter has introduced a method, not based on sequence homology, that enables one to group together functionally related genes.

Animals↗