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- Bermúdez, Eduardo, et al.
(författare)
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Improved homology model of cyclohexanone monooxygenase from Acinetobacter calcoaceticus based on multiple templates
- 2014
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Ingår i: Computational biology and chemistry. - : Elsevier BV. - 1476-9271 .- 1476-928X. ; 49, s. 14-22
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Tidskriftsartikel (refereegranskat)abstract
- A new homology model of cyclohexanone monooxygenase (CHMO) from Acinetobacter calcoaceticus is derived based on multiple templates, and in particular the crystal structure of CHMO from Rhodococcus sp. The derived model was fully evaluated, showing that the quality of the new structure was improved over previous models. Critically, the nicotinamide cofactor is included in the model for the first time. Analysis of several molecular dynamics snapshots of intermediates in the enzymatic mechanism led to a description of key residues for cofactor binding and intermediate stabilization during the reaction, in particular Arg327 and the well known conserved motif (FxGxxxHxxxW) in Baeyer-Villiger monooxygenases, in excellent agreement with known experimental and computational data. © 2014 Elsevier Ltd.
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| 3. |
- Mischenko, Kateryna, et al.
(författare)
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Assessing a multiple QTL search using the variance component model
- 2010
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Ingår i: Computational biology and chemistry (Print). - : Elseiver. - 1476-9271 .- 1476-928X. ; 34:1, s. 34-41
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Tidskriftsartikel (refereegranskat)abstract
- Development of variance component algorithms in genetics has previously mainly focused on animal breeding models or problems in human genetics with a simple data structure. We study alternative methods for constrained likelihood maximization in quantitative trait loci (QTL) analysis for large complex pedigrees. We apply a forward selection scheme to include several QTL and interaction effects, as well as polygenic effects, with up to five variance components in the model. We show that the implemented active set and primal-dual schemes result in accurate solutions and that they are robust. In terms of computational speed, a comparison of two approaches for approximating the Hessian of the log-likelihood shows that the method using an average information matrix is the method of choice for the five-dimensional problem. The active set method, with the average information method for Hessian computation, exhibits the fastest convergence with an average of 20 iterations per tested position, where the change in variance components <0.0001 was used as convergence criterion.
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| 4. |
- Nordling, Erik, et al.
(författare)
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Colonic amyloidosis, computational analysis of the major amyloidogenic species, Serum Amyloid A
- 2012
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Ingår i: Computational biology and chemistry (Print). - : Elsevier. - 1476-9271 .- 1476-928X. ; 39, s. 29-34
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Tidskriftsartikel (refereegranskat)abstract
- Amyloidosis is characterized by misfolding of proteins. The clinical gastrointestinal manifestations of amyloidosis may mimic other disease, such as inflammatory bowel disease or colonic cancer. As these patients have a high risk for bleeding and poor wound healing following surgery it is important to diagnose them correctly and do a careful preoperative assessment. The most common form of colonic amyloidosis is caused by Serum Amyloid A (SAA), an acute phase protein of unknown function. It is expressed in response to inflammation and the increased levels may lead to amyloidosis. The main treatment is to suppress the acute phase response and thereby reduce production of SAA. less thanbrgreater than less thanbrgreater thanAs no structure for SAA is available we aim to perform an in silico assessment of its structural and fibrillation properties. In the paper we propose an ab initio model of the structure of SAA, which consists of a five membered helical bundle with a fold related to the tetratricopeptide repeat domain. As there are uncertainties relating to the packing of the helices, each helical region is subjected to triplicate molecular dynamics simulations to assess the integrity of the structural region. The first helix, stretching from residues 1 to 13, is the least stable according to the simulations: almost all of the helical conformation is lost during the 10 ns simulations, whereas the other helices maintain portions that remain in an helical conformation in at least 80% of the simulations. All helices are also subjected to a single 100 ns simulation to investigate how the secondary structure develops over time. In them helix 1 adopts a beta-hairpin structure similar to other fibril forming proteins. The beta-hairpin can in turn multimerise and form a mature fibril structure. The mechanism behind the conformational transition appears to be driven by interactions of side chains of charged residues, particularly Arginine 1. It exchanges interaction partners in the simulation and stabilizes intermediate conformations on the folding pathway to the final beta-hairpin.
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| 5. |
- Serçinoğlu, Onur, et al.
(författare)
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In silico and in vitro assessment of androgen receptor antagonists
- 2021
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Ingår i: Computational biology and chemistry (Print). - : Elsevier. - 1476-9271 .- 1476-928X. ; 92
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Tidskriftsartikel (refereegranskat)abstract
- There is a growing concern for male reproductive health as studies suggest that there is a sharp increase in prostate cancer and other fertility related problems. Apart from lifestyle, pollutants are also known to negatively affect the reproductive system. In addition to many other compounds that have been shown to alter androgen signaling, several environmental pollutants are known to disrupt androgen signaling via binding to androgen receptor (AR) or indirectly affecting the androgen synthesis. We analyzed here the molecular mechanism of the interaction between the human AR Ligand Binding Domain (hAR-LBD) and two environmental pollutants, linuron (a herbicide) and procymidone (a pesticide), and compared with the steroid agonist dihydrotestosterone (DHT) and well-known hAR antagonists bicalutamide and enzalutamide. Using molecular docking and dynamics simulations, we showed that the co-activator interaction site of the hAR-LBD is disrupted in different ways by different ligands. Binding free energies of the ligands were also ordered in increasing order as follows: linuron, procymidone, DHT, bicalutamide, and enzalutamide. These data were confirmed by in vitro assays. Reporter assay with MDA-kb2 cells showed that linuron, procymidone, bicalutamide and enzalutamide can inhibit androgen mediated activation of luciferase activity. Gene expression analysis further showed that these compounds can inhibit the expression of prostate specific antigen (PSA) and microseminoprotein beta (MSMB) in prostate cell line LNCaP. Comparative analysis showed that procymidone is more potent than linuron in inhibiting AR activity. Furthermore, procymidone at 10 μM dose showed equivalent and higher activity to AR inhibitor enzalutamide and bicalutamide respectively.
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| 7. |
- Viljoen, S, et al.
(författare)
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A state-time epidemiology model of tuberculosis: Importance of re-infection
- 2012
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Ingår i: Computational biology and chemistry (Print). - : Elsevier. - 1476-9271 .- 1476-928X. ; 36, s. 15-22
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Tidskriftsartikel (refereegranskat)abstract
- An epidemiological model is presented that considers five possible states of a population: susceptible (S), exposed (W), infectious (Y), in treatment (Z) and recovered (R). in certain instances transition rates (from one state to another) depend on the time spent in the state; therefore the states W, Y and Z depend on time and length of stay in that state - similar to age-structured models. The model is particularly amenable to describe delays of exposed persons to become infectious and re-infection of exposed persons. Other transitions that depend on state time include the case finding and diagnosis, increased death rate and treatment interruption. The mathematical model comprises of a set of partial differential and ordinary differential equations. Non-steady state solutions are first presented, followed by a bifurcation study of the stationary states.
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| 8. |
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| 9. |
- Hassan, Sameer, et al.
(författare)
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In silico based screening of WRKY genes for identifying functional genes regulated by WRKY under salt stress
- 2019
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Ingår i: Computational Biology and Chemistry. - : Elsevier BV. - 1476-9271. ; 83
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Tidskriftsartikel (refereegranskat)abstract
- Soil salinization is an increasing global threat to economically important agricultural crops such as bread wheat (Triticum aestivum L.). A main regulator of plants’ responses to salt stress is WRKY transcription factors, a protein family that binds to DNA and alters the rate of transcription for specific genes. In this study, we identified 297 WRKY genes in the Chinese Spring wheat genome (Ensembl Plants International Wheat Genome Sequencing Consortium (IWGSC)), of which 126 were identified as putative. We classified 297 WRKY genes into three Groups: I, II (a–e) and III based on phylogenetic analysis. Principal component analysis (PCA) of WRKY proteins using physicochemical properties resulted in a very similar clustering as that observed through phylogenetic analysis. The 5‘ upstream regions (−2 000 bp) of 107 891 sequences from the wheat genome were used to predict WRKY transcription factor binding sites, and from this we identified 31 296 genes with putative WRKY binding motifs using the Find Individual Motif Occurrences (FIMO) tool. Among these predicted genes, 47 genes were expressed during salt stress according to a literature survey. Thus, we provide insight into the structure and diversity of WRKY domains in wheat and a foundation for future studies of DNA-binding specificity and for analysis of the transcriptional regulation of plants’ response to different stressors, such as salt stress, as addressed in this study. © 2019 Elsevier Ltd
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| 10. |
- Parate, Shaddha, 1990, et al.
(författare)
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Investigation of Macrocyclic mTOR Modulators of Rapamycin Binding Site via Pharmacoinformatics Approaches
- 2023
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Ingår i: Computational Biology and Chemistry. - 1476-9271. ; 104
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Tidskriftsartikel (refereegranskat)abstract
- The PI3K/Akt/mTOR is an essential intracellular signaling pathway in which the serine/threonine mTOR kinase portrays a major role in cell growth, proliferation and survival. The mTOR kinase is frequently dysregulated in a broad spectrum of cancers, thus making it a potential target. Rapamycin and its analogs (rapalogs) allosterically inhibit mTOR, thereby dodging the deleterious effects prompted by ATP-competitive mTOR inhibitors. However, the available mTOR allosteric site inhibitors exhibit low oral bioavailability and suboptimal solubility. Bearing in mind this narrow therapeutic window of the current allosteric mTOR inhibitors, an in silico study was designed in search of new macrocyclic inhibitors. The macrocycles from the ChemBridge database (12,677 molecules) were filtered for their drug-likeness properties and the procured compounds were subjected for molecular docking within the binding cleft between FKBP25 and FRB domains of mTOR. The docking analysis resulted with 15 macrocycles displaying higher scores than the selective mTOR allosteric site inhibitor, DL001. The docked complexes were refined by subsequent molecular dynamics simulations for a period of 100 ns. Successive binding free energy computation revealed a total of 7 macrocyclic compounds (HITS) demonstrating better binding af-finity than DL001, towards mTOR. The consequent assessment of pharmacokinetic properties resulted in HITS with similar or better properties than the selective inhibitor, DL001. The HITS from this investigation could act as effective mTOR allosteric site inhibitors and serve as macrocyclic scaffolds for developing compounds targeting the dysregulated mTOR.
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