Molecular modelling of 9-aminoellipticine interactions with abasic oligonucleotides.

We have used molecular mechanics to study the insertion of the DNA intercalating agent 9-aminoellipticine (9AE) into single and double stranded abasic oligonucleotides containing abasic sites in the aldose or furanose conformations. 9AE-abasic oligonucleotide complexes have been considered with 9AE bound at abasic sites as a covalent complex, a reversible complex or a Schiff base. Results are in good agreement with experimental data available on abasic oligonucleotides (melting temperature measurement, NMR results) and allow an analysis of different possible structures for 9AE-abasic oligonucleotide complexes. Hypotheses concerning the role of 9AE-abasic site complexes in enzymatic inhibition are formulated from these data.     

Molecular modelling of ligand-DNA minor groove binding: role of ligand-water interactions

A procedure was developed for quantitative estimation of the ligand affinity for the DNA minor groove with allowance for ligand hydration, whereby the binding energy was calculated as the difference in the energies of ligand-DNA and ligand-water interactions. Adequacy of the procedure was demonstrated with the structural motifs (pyrrolecarboxamide, benzimidazole, furancarboxamide, and phthalimide) of well-known ligands for the case of a d(GCA10CG).d(CGT10GC) duplex. On the strength of the results obtained, an indole-based motif was proposed as the basis for a highly affined minor groove binder.     

Molecular modelling studies on the interactions of human DNA topoisomerase IB with pyridoxal-compounds

Candida guilliermondii and human DNA topoisomerases I are inhibited by PL (pyridoxal), PLP (pyridoxal 5'-phosphate) and PLP-AMP (pyridoxal 5'-diphospho-5'-adenosine) (PL相似文献   

Molecular modelling of protein-carbohydrate interactions. Understanding the specificities of two legume lectins towards oligosaccharides

By means of a series of new molecular modelling tools, the conformationalbehaviour of mannose-containing di- and trisaccharides boundto either concanavalin A or Lathyrus ochrus isolectin I (LOLI)has been assessed. Tools for estimating and analysing eitherthe ‘rigid’ or the ‘relaxed’ potentialenergy surfaces, representing the conformational space availablefor carbohydrates once interacting with lectins, are reportedfor the first time. Restrictions of conformational space arepredicted to occur with different magnitudes, depending on thenature of the glycosidic linkages, as well as the size of thecarbohydrates. Results from these molecular modelling studiesare compared to existing structural data. Not only could theobserved conformations and orientations of carbohydrates incrystalline lectin–oligosaccharides complexes be reproduced,but several other likely situations were also predicted to occur.Entropy calculations have been performed for comparison withexperimental thermodynamics data. The results of the simulationcan also help giving an explanation of some observed affinityconstants at the molecular level. concanavalin A Lathyrus ochrus lectin-oligosaccharide molecular modelling     

Computer modelling of kappa carrageenam-mannan interactions

Molecular modelling has been used as a theoretical approach to investigate the kappa carrageenan structure and its interaction with mannan chains. Calculations revealed the existence of six minima for the kappa carrageenan structure in solution. Two of them were very close to the structure found in the solid state. The methodology allowed the calculation of the theoretical counterpart of the structures based on x-ray fibre diffractions studies. In the second step of this study, we have shown that there is the possibility of interactions between kappa carrageenan double helices and mannan chains. This interacting process is allowed by the flexibility of the mannan chains and structural changes of the kappa carrageenan double helices. The calculations suggest that the disaccaride mannan fragment might be required for recognition. The result of our investigation are in good agreement with a model of gel structure based on experimental data. This approach could be applied to simulate and predict other associations in molecular assemblies.     

Molecular modelling of protein-carbohydrate interactions. Docking of monosaccharides in the binding site of concanavalin A.

A general procedure is described for addressing the computer simulation of protein-carbohydrate interactions. First, a molecular mechanical force field capable of performing conformational analysis of oligosaccharides has been derived by the addition of new parameters to the Tripos force field; it is also compatible with the simulation of protein. Second, a docking procedure which allows for a systematic exploration of the orientations and positions of a ligand into a protein cavity has been designed. This so-called 'crankshaft' method uses rotations and variations about/of virtual bonds connecting, via dummy atoms, the ligand to the protein binding site. Third, calculation of the relative stability of protein ligand complexes is performed. This strategy has been applied to search for all favourable interactions occurring between a lectin [concanavalin A (ConA)] and methyl alpha-D-mannopyranoside or methyl alpha-D-glucopyranoside. For each monosaccharide, different stable orientations and positions within the binding site can be distinguished. Among them, one corresponds to very favourable interactions, not only in terms of hydrogen bonding, but also in terms of van der Waals interactions. It corresponds precisely to the binding mode of methyl alpha-D-mannopyranoside into ConA as revealed by the 2.9 A resolution of the crystalline complex (Derewenda et al., 1989). Some implications of the present modelling study with respect to the molecular basis of the specificity of the interaction of lectins with various monosaccharides are presented.     

Methods of molecular modelling of protein-protein interactions

This article reviews briefly theoretical methods attempting to predict the structure of protein aggregates from the structural features of their subunits. The authors discuss the problems of the solvent effect and the formation of protein structure. The existing methods of quaternary structure prediction are presented and an attempt at their classification is made at the end of this review.     

Formal agent-based modelling of intracellular chemical interactions

Individual-based or agent-based models have proved useful in a variety of different biological contexts. This paper presents an agent-based model using a formal computational modelling approach to model a crucial biological system--the intracellular NF-kappaB signalling pathway. The pathway is vital to immune response regulation, and is fundamental to basic survival in a range of species. Alterations in pathway regulation underlie many diseases, including atherosclerosis and arthritis. Our modelling of individual molecules, receptors and genes provides a more comprehensive outline of regulatory network mechanisms than previously possible with equation-based approaches. The model has been validated with data obtained from single cell experimental analysis.     

Molecular modelling of human CYP1B1 substrate interactions and investigation of allelic variant effects on metabolism

Molecular modelling of human CYP1B1 based on homology with the mammalian P450, CYP2C5, of known three-dimensional structure is reported. The enzyme model has been used to investigate the likely mode of binding for selected CYP1B1 substrates, particularly with regard to the possible effects of allelic variants of CYP1B1 on metabolism. In general, it appears that the CYP1B1 model is consistent with known substrate selectivity for the enzyme, and the sites of metabolism can be rationalized in terms of specific contacts with key amino acid residues within the CYP1B1 heme locus. Furthermore, a mode of binding interaction for the inhibitor, alpha-naphthoflavone, is presented which accords with currently available information. The current paper shows that a combination of molecular modelling and experimental determinations on the substrate metabolism for CYP1B1 allelic variants can aid in the understanding of structure-function relationships within P450 enzymes.     

Structural systems biology: modelling protein interactions

Much of systems biology aims to predict the behaviour of biological systems on the basis of the set of molecules involved. Understanding the interactions between these molecules is therefore crucial to such efforts. Although many thousands of interactions are known, precise molecular details are available for only a tiny fraction of them. The difficulties that are involved in experimentally determining atomic structures for interacting proteins make predictive methods essential for progress. Structural details can ultimately turn abstract system representations into models that more accurately reflect biological reality.     

Periodic solutions in modelling lagoon ecological interactions

In this paper we present and analyze a nutrient-oxygen-phytoplankton-zooplankton mathematical model simulating lagoon ecological interactions. We obtain sufficient conditions, based on principal eigenvalue criteria – for the existence of periodic solutions. A decoupled model which arises in the high nutrient regime is then considered in further detail for gathering some explicit conditions on parameters and averages of exogenous inputs needed for coexistence. An application to Italian coastal lagoons is finally obtained by parameter estimation and comparison with real data. A biological interpretation of the mathematical results is also presented. Research supported by NSERC (Canada) and Regione Toscana (Italy).     

Molecular interactions of ribosomal components

Summary The site-specific complex formed between 16S RNA and the 30S ribosomal protein S4 from Escherichia coli has been degraded with pancreatic ribonuclease. We have recovered the nuclease-resistant RNA from this complex; we call it S4aR. S4aR will bind to S4, but it will not bind to the other 30S proteins that can form site-specific complexes with 16S RNA. The data presented here as well as elsewhere (Schaup et al., 1971b) show that S4aR has a mass of about 150000 daltons and that it is made up of several separate RNA fragments, each of which enters the complex with S4. We conclude that S4 interacts with several separate binding sites on the RNA and that these probably contain a great deal of double stranded structure.     

Molecular interactions of ribosomal components

Summary The formation of a complex between individual 30S ribosomal proteins and 16S ribosomal RNA was studied by three techniques: zone centrifugation, molecular-sieve chromatography and electrophoresis in polyacrylamide gels. Five 30S proteins form a stable complex with the RNA under the conditions used to assemble ribosomes. Specific and nonspecific complex formation can be distinguished by an analysis of the concentration-dependence for complex formation. Similarly, competition experiments between heterologous proteins that bind to RNA can also be used to establish the uniquness of the RNA binding sites for ribosomal proteins. The data show that four of the five proteins bind to unique sites on the RNA. The fifth protein binds nonspecifically to the RNA. In addition, cooperative interactions between several proteins were observed; these enhance the interaction of proteins with the 16S RNA. A partial assembly sequence for the 30S ribosomal subunit is presented.     

Molecular modelling of MHC class I carbohydrates

In this article we present the results of molecular modelling of four complex carbohydrates which have been found in the MHC class I proteins. Though these proteins show diversity in their sequences, the glycosylation sites are highly conserved indicating a possible structural/functional role of the glycan chain. Similar glycan chains have been found linked with other proteins of completely different function, such as IgG, and erythropoeitin. Thus, the molecular modelling of these carbohydrates will not only provide structural/dynamic information of these complex molecules but will also provide conformational information which can be utilised to build the glycoprotein models. The results presented here indicate that although several linkages show less conformational flexibility, terminal linkages can be quite flexible.