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At least 289 records · Page 16Linked to original sources
PubMed1992

Comparative molecular modeling of the active subunit of human kininase I.

The structure of the enzymatically active subunit of human plasma carboxypeptidase N was determined by computer aided model building by homology using the structural coordinates from carboxypeptidase A. The active site of carboxypeptidase N has been well conserved in comparison with carboxypeptidase A. Differences in substrate specificity can be explained by the comparison of energetically favorable binding sites for different atomic probe groups.

Amino Acid Sequence↗
PubMed1994

An evaluation of molecular models of the cytochrome P450 Streptomyces griseolus enzymes P450SU1 and P450SU2.

P450SU1 and P450SU2 are herbicide-inducible bacterial cytochrome P450 enzymes from Streptomyces griseolus. They have two of the highest sequence indentities to camphor hydroxylase (P450cam from Pseudomonas putida), the cytochrome P450 with the first known crystal structure. We have built several models of these two proteins to investigate the variability in the structures that can occur from using different modeling protocols. We looked at variability due to alignment methods, backbone loop conformations and refinement methods. We have constructed two models for each protein using two alignment algorithms, and then an additional model using an identical alignment but different loop conformations for both buried and surface loops. The alignments used to build the models were created using the Needleman-Wunsch method, adapted for multiple sequences, and a manual method that utilized both a dot-matrix search matrix and the Needleman-Wunsch method. After constructing the initial models, several energy minimization methods were used to explore the variability in the final models caused by the choice of minimization techniques. Features of cytochrome P450cam and the cytochrome P450 superfamily, such as the ferredoxin binding site, the heme binding site and the substrate binding site were used to evaluate the validity of the models. Although the final structures were very similar between the models with different alignments, active-site residues were found to be dependent on the conformations of buried loops and early stages of energy minimization. We show which regions of the active site are the most dependent on the particular methods used, and which parts of the structures seem to be independent of the methods.

Amino Acid Sequence↗
PubMed1992

Computer-aided molecular modeling and design of DNA-inserting molecules.

Intercalators are molecules capable of sliding between base pairs without disturbing the overall stacking pattern. In addition, there may exist molecules capable of inserting into a base pair thereby disrupting the hydrogen bonds and replacing them with new hydrogen bonds. A molecule probably capable of inserting, i.e., an insertor, is the diketopiperazine cyclo-[Gly-Gly] (1). A barbiturate (2), alloxan (3), a pyrimidine derivative (4) and a hydantoin (5) were also studied as possible insertors. Furthermore, molecules such as ethyleneurea (6), succinimide (7), as well as a malonamide derivative (8) and oxamide derivatives (9-11) were studied in order to investigate the arrangement and the number of hydrogen bonds necessary for insertion. Molecules 12-14 were designed and studied for their capacity to act as bisinsertors and/or bisintercalators. These molecules feature two diketopiperazine moieties which are connected via a diphenyl(thio)ether, i.e., 12 and 13, or a bisphenol A spacer, i.e., 14. The latter molecule (14) seems a promising candidate as a bisinsertor.

Computers↗
PubMed1990

Molecular modelling of poly(aryl ether ketones). I. Aryl..aryl interactions in crystal structures.

Non-bonded potentials for the aryl..aryl interaction have been derived using crystal structure data of a number of small aromatic molecules. The potentials, based on atom-centered interactions, give an accurate reproduction of the benzene crystal geometry and sublimation energy when used in conjunction with coulombic energies evaluated using point atomic charges. An examination of the charge distribution on benzene suggested values of 0.13e (H) and -0.13e (C) to be suitable. The transferability of the potentials has been shown by prediction of crystal geometries and sublimation energies of other hydrocarbon molecules and, with additional interactions for the oxygen atom included, preliminary polymer crystal structure calculations have been carried out. These demonstrate the validity of the derived parameters by successfully predicting crystallographic unit cell dimensions and ring conformations in the poly(phenylene oxide) and poly(aryl ether ketone) crystals.

Computer Simulation↗
PubMed1992

Enantioselectivity of asocainol studied at different conditions: a novel approach to check the feasibility of molecular models of antiarrhythmic drug action.

In terms of the "guarded receptor" hypothesis, changes in potency of Na+ channel blocking drugs reflect alterations in drug access to and/or egress from a compartment facing a binding site with constant affinity. Potency is therefore assumed to be determined by changes in drug diffusion, its mobility in the electric field, protonation etc. Hence, the potencies of enantiomers, i.e. compounds with identical physicochemical properties, should be influenced in a parallel manner by the condition. To test this prediction, actions of the enantiomers of the stereoselective antiarrhythmic drug asocainol were compared at various membrane potentials and stimulus frequencies. Several experimental models indicative of Na+ channel block were used: the elevation of the rectangular pulse stimulation threshold (RPT) and the suppression of alternating-current induced arrhythmia (ACT) were studied in guinea-pig atria. The reduction of the upstroke velocity of action potentials was measured in guinea-pig papillary muscles. The inhibition of whole-cell Na+ currents was investigated in isolated guinea-pig ventricular myocytes. In all these assays, (+)-asocainol was more potent than the (-)-enantiomer. Lowering the membrane potential and/or increasing the stimulus frequency enhanced the effects of both enantiomers. However, over a certain range of conditions, the potency of (+)-asocainol was more markedly affected than that of (-)-asocainol, indicating that the eudismic ratio between potencies of the two drugs is not constant. Accordingly, these findings are inconsistent with the guarded receptor hypothesis.

Action Potentials↗
PubMed1991

Ion channels formed by amphipathic helical peptides. A molecular modelling study.

Channel forming peptides (CFPs) are amphipathic peptides, of length ca. 20 residues, which adopt an alpha-helical conformation in the presence of lipid bilayers and form ion channels with electrophysiological properties comparable to those of ion channel proteins. We have modelled CFP channels as bundles of parallel trans-bilayer helices surrounding a central ion-permeable pore. Ion-channel interactions have been explored via accessible surface area calculations, and via evaluation of changes in van der Waals and electrostatic energies as a K+ ion is translated along the length of the pore. Two CFPs have been modelled: (a) zervamicin-A1-16, a synthetic apolar peptaibol related to alamethicin, and (b) delta-toxin from Staphylococcus aureus. Both of these CFPs have previously been shown to form ion channels in planar lipid bilayers, and have been shown to have predominantly helical conformations. Zervamicin-A1-16 channels were modelled as bundles of 4 to 8 parallel helices. Two related helix bundle geometries were explored. K(+)-channel interactions have been shown to involve exposed backbone carbonyl oxygen atoms. delta-Toxin channels were modelled as bundles of 6 parallel helices. Residues Q3, D11 and D18 generate favourable K(+)-channel interactions. Rotation of W15 about its C beta-C gamma bond has been shown to be capable of occluding the central pore, and is discussed as a possible model for sidechain conformational changes in relation to ion channel gating.

Amino Acid Sequence↗