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Ibrahim B.,Friedrich - Schiller University of Jena | Ibrahim B.,University of Umm Al - Qura | Ibrahim B.,Al Qunfudah Center for Scientific Research
Molecular BioSystems | Year: 2015

In response to the activation of the mitotic spindle assembly checkpoint (SAC), distinct inhibitory pathways control the activity of the anaphase-promoting complex (APC/C). It remains unclear whether the different regulatory mechanisms function in separate pathways or as part of an integrated signalling system. Here, five variant models of APC/C regulation were constructed and analysed. The simulations showed that all variant models were able to reproduce the wild type behaviour of the APC. However, only one model, which included both the mitotic checkpoint complex (MCC) as well as BubR1 as direct inhibitors of the APC/C, was able to reproduce both wild and mutant type behaviour of APC/C regulation. Interestingly, in this model, the MCC as well as the BubR1 binding rate to the APC/C was comparable to the known Cdc20-Mad2 binding rate and could not be made higher. Mad2 active transport towards the spindle mid-zone accelerated the inhibition speed of the APC/C but not its concentration level. The presented study highlights the principle that a systems biology approach is critical for the SAC mechanism and could also be used for predicting hypotheses to design future experiments. The presented work has successfully distinguished between five potent inhibitors of the APC/C using a systems biology approach. Here, the favoured model contains both BubR1 and MCC as direct inhibitors of the APC/C. © The Royal Society of Chemistry 2015. Source


Henze R.,Friedrich - Schiller University of Jena | Huwald J.,Friedrich - Schiller University of Jena | Mostajo N.,Friedrich - Schiller University of Jena | Dittrich P.,Friedrich - Schiller University of Jena | And 3 more authors.
BioSystems | Year: 2015

Large multi-molecular complexes like the kinetochore are lacking of suitable methods to determine their spatial structure. Here, we use and evaluate a novel modeling approach that combines rule-bases reaction network models with spatial molecular geometries. In particular, we introduce a method that allows to study in silico the influence of single interactions ( e.g. bonds) on the spatial organization of large multi-molecular complexes and apply this method to an extended model of the human inner-kinetochore. Our computational analysis method encompasses determination of bond frequency, geometrical distances, statistical moments, and inter-dependencies between bonds using mutual information. For the analysis we have extend our previously reported human inner-kinetochore model by adding 13 new protein interactions and three protein geometry details. The model is validated by comparing the results of in silico with reported in vitro single protein deletion experiments. Our studies revealed that most simulations mimic the in vitro behavior of the kinetochore complex as expected. To identify the most important bonds in this model, we have created 39 mutants in silico by selectively disabling single protein interactions. In a total of 11,800 simulation runs we have compared the resulting structures to the wild-type. In particular, this allowed us to identify the interaction Cenp-W-H3 and Cenp-S-Cenp-X as having the strongest influence on the inner-kinetochore's structure. We conclude that our approach can become a useful tool for the in silico dynamical study of large, multi-molecular complexes. © 2014 Elsevier Ireland Ltd. Source


Ibrahim B.,Friedrich - Schiller University of Jena | Ibrahim B.,University of Umm Al - Qura | Ibrahim B.,Al Qunfudah Center for Scientific Research
OMICS A Journal of Integrative Biology | Year: 2015

Correct DNA segregation is a fundamental process that ensures the precise and reliable inheritance of genomic information for the propagation of cell life. Eukaryotic cells have evolved a conserved surveillance control mechanism for DNA segregation named the Spindle Assembly Checkpoint (SAC).The SAC ensures that the sister chromatids of the duplicated genome are not separated and distributed to the spindle poles before all chromosomes have been properly linked to the microtubules of the mitotic spindle. Biochemically, the SAC delays cell cycle progression by preventing activation of the anaphase-promoting complex (APC/C) or cyclosome whose activation by Cdc20 is required for sister-chromatid separation; this marks the transition into anaphase. In response to activation of the checkpoint, various species control the activity of both APC/C and Cdc20. However, the underlying regulatory pathways remain largely elusive. In this study, five possible model variants of APC/C regulation were constructed, namely BubR1, Mad2, MCC, MCF2, and an all-pathways model variant. These models were validated with experimental data from the literature. A wide range of parameter values has been tested to find the critical values of the APC/C binding rate. The results show that all variants are able to capture the wild-type behavior of the APC/C. However, only one model variant, which included both MCC as well as BubR1 as potent inhibitors of the APC/C, was able to reproduce both wild-type and mutant type behavior of APC/C regulation. In conclusion, the presented work informs the regulation of fundamental processes such as SAC and APC/C in cell biology and has successfully distinguished between five competing dynamical models using a systems biology approach. The results attest that systems-level approaches are vital for molecular and cell biology. © 2015, Mary Ann Liebert, Inc. Source


Ibrahim B.,Friedrich - Schiller University of Jena | Ibrahim B.,University of Umm Al - Qura | Ibrahim B.,Al Qunfudah Center for Scientific Research
Computational and Structural Biotechnology Journal | Year: 2015

The spindle checkpoint assembly (SAC) ensures genome fidelity by temporarily delaying anaphase onset, until all chromosomes are properly attached to the mitotic spindle. The SAC delays mitotic progression by preventing activation of the ubiquitin ligase anaphase-promoting complex (APC/C) or cyclosome; whose activation by Cdc20 is required for sister-chromatid separation marking the transition into anaphase. The mitotic checkpoint complex (MCC), which contains Cdc20 as a subunit, binds stably to the APC/C. Compelling evidence by Izawa and Pines (Nature 2014; 10.1038/nature13911) indicates that the MCC can inhibit a second Cdc20 that has already bound and activated the APC/C. Whether or not MCC per se is sufficient to fully sequester Cdc20 and inhibit APC/C remains unclear. Here, a dynamic model for SAC regulation in which the MCC binds a second Cdc20 was constructed. This model is compared to the MCC, and the MCC-and-BubR1 (dual inhibition of APC) core model variants and subsequently validated with experimental data from the literature. By using ordinary nonlinear differential equations and spatial simulations, it is shown that the SAC works sufficiently to fully sequester Cdc20 and completely inhibit APC/C activity. This study highlights the principle that a systems biology approach is vital for molecular biology and could also be used for creating hypotheses to design future experiments. © 2015 Ibrahim. Published by Elsevier B.V. Source


Al-rashdi A.A.,University of Umm Al - Qura | Al-rashdi A.A.,Al Qunfudah Center for Scientific Research
Analytical Chemistry Research | Year: 2015

Organosulphur compounds were determined in seawater samples by gas chromatography using a pulse flame detection method. The analytical method involved the use of octyl-diol mesoporous silica as a replacement for organic solvents in the extraction and pre-concentration of organosulphur compounds from seawater samples based on the solid phase dispersion extraction technique. The detection limits were in the range 0.6-2ngS/L, while the repeatability and reproducibility were 7-12% and 13-16% respectively. Relative standard deviations (%) for recovery of n-ethanthiol (n-EtSH), di-n-ethyl sulphide (n-Et2S) and di-n-ethyl disulphide (n-Et2S2) in spiked water samples were in the range 2.2-6.6% (at 0.5μg/L level). Under the experimental conditions used, quantitative extraction of n-EtSH, n-Et2S and n-Et2S2 was achieved with recoveries ranging from 93% to 99%. The procedure has been successfully applied to organosulphur determination in seawater samples collected from Jeddah beach (West of Saudi Arabia). © 2015 The Author. Source

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