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91.
Application of iterative robust model‐based optimal experimental design for the calibration of biocatalytic models
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Timothy Van Daele Krist V. Gernaey Rolf H. Ringborg Tim Börner Søren Heintz Daan Van Hauwermeiren Carl Grey Ulrich Krühne Patrick Adlercreutz Ingmar Nopens 《Biotechnology progress》2017,33(5):1278-1293
The aim of model calibration is to estimate unique parameter values from available experimental data, here applied to a biocatalytic process. The traditional approach of first gathering data followed by performing a model calibration is inefficient, since the information gathered during experimentation is not actively used to optimize the experimental design. By applying an iterative robust model‐based optimal experimental design, the limited amount of data collected is used to design additional informative experiments. The algorithm is used here to calibrate the initial reaction rate of an ω‐transaminase catalyzed reaction in a more accurate way. The parameter confidence region estimated from the Fisher Information Matrix is compared with the likelihood confidence region, which is not only more accurate but also a computationally more expensive method. As a result, an important deviation between both approaches is found, confirming that linearization methods should be applied with care for nonlinear models. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1278–1293, 2017 相似文献
92.
The biological function of chaperone complexes is to assist the folding of non-native proteins. The widely studied GroEL chaperonin is a double-barreled complex that can trap non-native proteins in one of its two barrels. The ATP-driven binding of a GroES cap then results in a major structural change of the chamber where the substrate is trapped and initiates a refolding attempt. The two barrels operate anti-synchronously. The central region between the two barrels contains a high concentration of disordered protein chains, the role of which was thus far unclear. In this work we report a combination of atomistic and coarse-grained simulations that probe the structure and dynamics of the equatorial region of the GroEL/GroES chaperonin complex. Surprisingly, our simulations show that the equatorial region provides a translocation channel that will block the passage of folded proteins but allows the passage of secondary units with the diameter of an alpha-helix. We compute the free-energy barrier that has to be overcome during translocation and find that it can easily be crossed under the influence of thermal fluctuations. Hence, strongly non-native proteins can be squeezed like toothpaste from one barrel to the next where they will refold. Proteins that are already fairly close to the native state will not translocate but can refold in the chamber where they were trapped. Several experimental results are compatible with this scenario, and in the case of the experiments of Martin and Hartl, intra chaperonin translocation could explain why under physiological crowding conditions the chaperonin does not release the substrate protein. 相似文献
93.
94.
When does community assembly lead to a predictable species composition and when does this process depend on chance events, such as the timing of species arrivals? We studied the combined effects of enrichment and predation on the occurrence of priority effects, i.e. dependency on the timing of arrival, using a model of a small food web consisting of a predator, two competing prey and interference through allelopathy. Our analysis shows the conditions under which priority effects can occur. In the system we studied, the interfering species has to be the weaker resource exploiter of the two consumers, or it has to be more susceptible to predation. When it is the weaker resource exploiter, a minimum level of nutrient input is required for interference to be strong enough to cause a priority effect. When the interfering species is more susceptible to predation, a priority effect actually requires predation, which in itself also requires a minimum level of nutrient inflow. However, the priority effect disappears when predation pressure rises above a threshold value, also when the two competitors are equally preferred by the predator. This is so because predation reduces population densities and thereby the strength of interference. Our analyses make clear how the effects of resources and predation can combine to result in the absence or presence of priority effects during community assembly. 相似文献
95.
Structural and functional characterization of a putative polysaccharide deacetylase of the human parasite Encephalitozoon cuniculi 总被引:1,自引:0,他引:1
Jonathan E. Urch Ramon Hurtado‐Guerrero Damien Brosson Zhanliang Liu Vincent G. H. Eijsink Catherine Texier Daan M. F. van Aalten 《Protein science : a publication of the Protein Society》2009,18(6):1197-1209
The microsporidian Encephalitozoon cuniculi is an intracellular eukaryotic parasite considered to be an emerging opportunistic human pathogen. The infectious stage of this parasite is a unicellular spore that is surrounded by a chitin containing endospore layer and an external proteinaceous exospore. A putative chitin deacetylase (ECU11_0510) localizes to the interface between the plasma membrane and the endospore. Chitin deacetylases are family 4 carbohydrate esterases in the CAZY classification, and several bacterial members of this family are involved in evading lysis by host glycosidases, through partial de‐N‐acetylation of cell wall peptidoglycan. Similarly, ECU11_0510 could be important for E. cuniculi survival in the host, by protecting the chitin layer from hydrolysis by human chitinases. Here, we describe the biochemical, structural, and glycan binding properties of the protein. Enzymatic analyses showed that the putative deacetylase is unable to deacetylate chitooligosaccharides or crystalline β‐chitin. Furthermore, carbohydrate microarray analysis revealed that the protein bound neither chitooligosaccharides nor any of a wide range of other glycans or chitin. The high resolution crystal structure revealed dramatic rearrangements in the positions of catalytic and substrate binding residues, which explain the loss of deacetylase activity, adding to the unusual structural plasticity observed in other members of this esterase family. Thus, it appears that the ECU11_0510 protein is not a carbohydrate deacetylase and may fulfill an as yet undiscovered role in the E. cuniculi parasite. 相似文献
96.
Peter Rigsby Catherine Ison Matthew Brierley Ron Ballard Hans-Jochen Hagedorn David A. Lewis Daan W. Notermans Jrn Riis Peter Robertson Ilkka J.T. Seppl Sjoerd Rijpkema 《Biologicals》2009,37(4):245-251
A collaborative study was designed to asses two freeze-dried human plasma preparations containing anti-Treponema pallidum antibodies, 05/132 and 05/122, for their suitability as international reference reagents for syphilis serology. Both preparations are intended as replacements of the first international standard (IS) for syphilitic serum antibodies (HS). Samples were tested by eight laboratories using the T. pallidum passive particle agglutination assay (TPPA), the venereal disease research laboratory test (VDRL) and the rapid plasma reagin test (RPR). In addition a range of immunoassays was also used. The outcome of the collaborative study revealed that candidate standard 05/132 contains T. pallidum-specific IgG and IgM and is reactive in VDRL or RPR, and that 05/122 contains T. pallidum-specific IgG but is not reactive in either the VDRL or RPR test. Both 05/132 and 05/122 are reactive in the TPPA. On the basis of these results the Expert Committee on Biological Standardization of the World Health Organization designated 05/132 as the 1st IS for human syphilitic plasma IgG and IgM with a unitage of 3 IU per ampoule relative to HS and 05/122 as the 1st IS for human syphilitic plasma IgG with a unitage of 300 mIU per ampoule relative to 05/132. 相似文献
97.
Matthijs van der Knaap Eefje Engels Henk J. Busscher Jos M. Otero Antonio L. Llamas-Saiz Mark J. van Raaij Roos H. Mars-Groenendijk Daan Noort Gijsbert A. van der Marel Herman S. Overkleeft Mark Overhand 《Bioorganic & medicinal chemistry》2009,17(17):6318-6328
The synthesis of new analogues of the cationic antimicrobial peptide gramicidin S, having a modified d-phenylalanine residue, their antibacterial properties against several Gram positive and negative strains, as well as their hemolytic activity is reported. 相似文献
98.
Daan Waanders Dennis Janssen Mark A. Miller Kenneth A. Mann Nico Verdonschot 《Journal of biomechanics》2009,42(15):2513-2519
The goal of this study was to quantify the micromechanics of the cement–bone interface under tensile fatigue loading using finite element analysis (FEA) and to understand the underlying mechanisms that play a role in the fatigue behavior of this interface. Laboratory cement–bone specimens were subjected to a tensile fatigue load, while local displacements and crack growth on the specimen's surface were monitored. FEA models were created from these specimens based upon micro-computed tomography data. To accurately model interfacial gaps at the interface between the bone and cement, a custom-written erosion algorithm was applied to the bone model. A fatigue load was simulated in the FEA models while monitoring the local displacements and crack propagation. The results showed the FEA models were able to capture the general experimental creep damage behavior and creep stages of the interface. Consistent with the experiments, the majority of the deformation took place at the contact interface. Additionally, the FEA models predicted fatigue crack patterns similar to experimental findings. Experimental surface cracks correlated moderately with FEA surface cracks (r2=0.43), but did not correlate with the simulated crack volume fraction (r2=0.06). Although there was no relationship between experimental surface cracks and experimental creep damage displacement (r2=0.07), there was a strong relationship between the FEA crack volume fraction and the FEA creep damage displacement (r2=0.76). This study shows the additional value of FEA of the cement–bone interface relative to experimental studies and can therefore be used to optimize its mechanical properties. 相似文献
99.
Elton Zeqiraj Beatrice Maria Filippi Simon Goldie Iva Navratilova Jér?me Boudeau Maria Deak Dario R. Alessi Daan M. F. van Aalten 《PLoS biology》2009,7(6)
Pseudokinases lack essential residues for kinase activity, yet are emerging as important regulators of signal transduction networks. The pseudokinase STRAD activates the LKB1 tumour suppressor by forming a heterotrimeric complex with LKB1 and the scaffolding protein MO25. Here, we describe the structure of STRADα in complex with MO25α. The structure reveals an intricate web of interactions between STRADα and MO25α involving the αC-helix of STRADα, reminiscent of the mechanism by which CDK2 interacts with cyclin A. Surprisingly, STRADα binds ATP and displays a closed conformation and an ordered activation loop, typical of active protein kinases. Inactivity is accounted for by nonconservative substitution of almost all essential catalytic residues. We demonstrate that binding of ATP enhances the affinity of STRADα for MO25α, and conversely, binding of MO25α promotes interaction of STRADα with ATP. Mutagenesis studies reveal that association of STRADα with either ATP or MO25α is essential for LKB1 activation. We conclude that ATP and MO25α cooperate to maintain STRADα in an “active” closed conformation required for LKB1 activation. It has recently been demonstrated that a mutation in human STRADα that truncates a C-terminal region of the pseudokinase domain leads to the polyhydramnios, megalencephaly, symptomatic epilepsy (PMSE) syndrome. We demonstrate this mutation destabilizes STRADα and prevents association with LKB1. In summary, our findings describe one of the first structures of a genuinely inactive pseudokinase. The ability of STRADα to activate LKB1 is dependent on a closed “active” conformation, aided by ATP and MO25α binding. Thus, the function of STRADα is mediated through an active kinase conformation rather than kinase activity. It is possible that other pseudokinases exert their function through nucleotide binding and active conformations. 相似文献
100.
Schüttelkopf AW Hamilton G Watts C van Aalten DM 《The Journal of biological chemistry》2006,281(24):16570-16575
Cystatins are important natural cysteine protease inhibitors targeting primarily papain-like cysteine proteases, including cathepsins and parasitic proteases like cruzipain, but also mammalian asparaginyl endopeptidase. Mammalian cystatin F, which is expressed almost exclusively in hematopoietic cells and accumulates in lysosome-like organelles, has been implicated in the regulation of antigen presentation and other immune processes. It is an unusual cystatin superfamily member with a redox-regulated activation mechanism and a restricted specificity profile. We describe the 2.1A crystal structure of human cystatin F in its dimeric "off" state. The two monomers interact in a fashion not seen before for cystatins or cystatin-like proteins that is crucially dependent on an unusual intermolecular disulfide bridge, suggesting how reduction leads to monomer formation and activation. Strikingly, core sugars for one of the two N-linked glycosylation sites of cystatin F are well ordered, and their conformation and interactions with the protein indicate that this unique feature of cystatin F may modulate its inhibitory properties, in particular its reduced affinity toward asparaginyl endopeptidase compared with other cystatins. 相似文献