TY - JOUR A1 - Abbas, Aennes A1 - Schneider, Ilona A1 - Bollmann, Anna A1 - Funke, Jan A1 - Oehlmann, Jörg A1 - Prasse, Carsten A1 - Schulte-Oehlmann, Ulrike A1 - Seitz, Wolfram A1 - Ternes, Thomas A1 - Weber, Marcus A1 - Wesely, Henning A1 - Wagner, Martin T1 - What you extract is what you see: Optimising the preparation of water and wastewater samples for in vitro bioassays JF - Water Research N2 - The assessment of water quality is crucial for safeguarding drinking water resources and ecosystem integrity. To this end, sample preparation and extraction is critically important, especially when investigating emerging contaminants and the toxicity of water samples. As extraction methods are rarely optimised for bioassays but rather adopted from chemical analysis, this may result in a misrepresentation of the actual toxicity. In this study, surface water, groundwater, hospital and municipal wastewater were used to characterise the impacts of common sample preparation techniques (acidification, filtration and solid phase extraction (SPE)) on the outcomes of eleven in vitro bioassays. The latter covered endocrine activity (reporter gene assays for estrogen, androgen, aryl-hydrocarbon, retinoic acid, retinoid X, vitamin D, thyroid receptor), mutagenicity (Ames fluctuation test), genotoxicity (umu test) and cytotoxicity. Water samples extracted using different SPE sorbents (Oasis HLB, Supelco ENVI-Carb+, Telos C18/ENV) at acidic and neutral pH were compared for their performance in recovering biological effects. Acidification, commonly used for stabilisation, significantly altered the endocrine activity and toxicity of most (waste)water samples. Sample filtration did not affect the majority of endpoints but in certain cases affected the (anti-)estrogenic and dioxin-like activities. SPE extracts (10.4 × final concentration), including WWTP effluents, induced significant endocrine effects that were not detected in aqueous samples (0.63 × final concentration), such as estrogenic, (anti-)androgenic and dioxin-like activities. When ranking the SPE methods using multivariate Pareto optimisation an extraction with Telos C18/ENV at pH 7 was most effective in recovering toxicity. At the same time, these extracts were highly cytotoxic masking the endpoint under investigation. Compared to that, extraction at pH 2.5 enriched less cytotoxicity. In summary, our study demonstrates that sample preparation and extraction critically affect the outcome of bioassays when assessing the toxicity of water samples. Depending on the water matrix and the bioassay, these methods need to be optimised to accurately assess water quality. Y1 - 2019 U6 - https://doi.org/10.1016/j.watres.2018.12.049 VL - 152 SP - 47 EP - 60 ER - TY - JOUR A1 - Spahn, Viola A1 - Del Vecchio, Giovanna A1 - Labuz, Dominika A1 - Rodriguez-Gaztelumendi, Antonio A1 - Massaly, N. A1 - Temp, Julia A1 - Durmaz, Vedat A1 - Sabri, P. A1 - Reidelbach, Marco A1 - Machelska, Halina A1 - Weber, Marcus A1 - Stein, Christoph T1 - A nontoxic pain killer designed by modeling of pathological receptor conformations JF - Science Y1 - 2017 U6 - https://doi.org/10.1126/science.aai8636 VL - 355 IS - 6328 SP - 966 EP - 969 ER - TY - JOUR A1 - Durmaz, Vedat A1 - Weber, Marcus A1 - Becker, Roland T1 - How to Simulate Affinities for Host-Guest Systems Lacking Binding Mode Information: application to the liquid chromatographic separation of hexabromocyclododecane stereoisomers JF - Journal of Molecular Modeling Y1 - 2012 U6 - https://doi.org/10.1007/s00894-011-1239-5 VL - 18 SP - 2399 EP - 2408 ER - TY - JOUR A1 - Scharkoi, Olga A1 - Esslinger, Susanne A1 - Becker, Roland A1 - Weber, Marcus A1 - Nehls, Irene T1 - Predicting sites of cytochrome P450-mediated hydroxylation applied to CYP3A4 and hexabromocyclododecane JF - Molecular Simulation Y1 - 2014 U6 - https://doi.org/10.1080/08927022.2014.898845 ER - TY - THES A1 - Durmaz, Vedat T1 - Atomistic Binding Free Energy Estimations for Biological Host–Guest Systems N2 - Accurate quantifications of protein–ligand binding affinities by means of in silico methods increasingly gain importance in various scientific branches including toxicology and pharmacology. In silico techniques not only are generally less demanding than laboratory experiments regarding time as well as cost, in particular, if binding assays or synthesis protocols need to be developed in advance. At times, they also provide the only access to risk assessments on novel chemical compounds arising from biotic or abiotic degradation of anthropogenic substances. However, despite the continuous technological and algorithmic progress over the past decades, binding free energy estimations through molecular dynamics simulations still pose an enormous computational challenge owed to the mathematical complexity of solvated macromolecular systems often consisting of hundreds of thousands of atoms. The goals of this thesis can roughly be divided into two categories dealing with different aspects of host–guest binding quantification. On the one side algorithmic strategies for a comprehensive exploration and decomposition of conformational space in conjunction with an automated selection of representative molecular geometries and binding poses have been elaborated providing initial structures for free energy calculations. In light of the dreaded trapping problem typically associated with molecular dynamics simulations, the focus was laid on a particularly systematic generation of representatives covering a broad range of physically accessible molecular conformations and interaction modes. On the other side and ensuing from these input geometries, binding affinity models based on the linear interaction energy (LIE) method have been developed for a couple of (bio)molecular systems. The applications included a successful prediction of the liquid-chromatographic elution order as well as retention times of highly similar hexabromocyclododecane (HBCD) stereoisomers, a novel empirical LIE–QSAR hybrid binding affinity model related to the human estrogen receptor α (ERα), and, finally, the (eco)toxicological prioritization of transformation products originating from the antibiotic sulfamethoxazole with respect to their binding affinities to the bacterial enzyme dihydropteroate synthase. Altogether, a fully automated approach to binding mode and affinity estimation has been presented that is content with an arbitrary geometry of a small molecule under observation and a spatial vector specifying the binding site of a potential target molecule. According to our studies, it is superior to conventional docking and thermodynamic average methods and primarily suggesting binding free energy calculation on the basis of several heavily distinct complex geometries. Both chromatographic retention times of HBCD and binding affinities to ERα yielded squared coefficients of correlation with experimental results significantly higher than 0.8. Approximately 85 % (100 %) of predicted receptor–ligand binding modes deviated less than 1.53 Å (2.05 Å) from available crystallographic structures. KW - molecular modelling KW - molecular dynamics KW - molecular simulation KW - binding affinity KW - prediction KW - free energy KW - receptor ligand KW - retention time KW - liquid chromatography Y1 - 2016 UR - http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000103765 PB - FU Dissertationen Online ER - TY - JOUR A1 - Schütte, Christof A1 - Nielsen, Adam A1 - Weber, Marcus T1 - Markov State Models and Molecular Alchemy JF - Molecular Physics N2 - In recent years Markov State Models (MSMs) have attracted a consid- erable amount of attention with regard to modelling conformation changes and associated function of biomolecular systems. They have been used successfully, e.g., for peptides including time-resolved spectroscopic experiments, protein function and protein folding , DNA and RNA, and ligand-receptor interaction in drug design and more complicated multivalent scenarios. In this article a novel reweighting scheme is introduced that allows to construct an MSM for certain molecular system out of an MSM for a similar system. This permits studying how molecular properties on long timescales differ between similar molecular systems without performing full molecular dynamics simulations for each system under con- sideration. The performance of the reweighting scheme is illustrated for simple test cases including one where the main wells of the respective energy landscapes are located differently and an alchemical transformation of butane to pentane where the dimension of the state space is changed. KW - MSM KW - Reweighting KW - Girsanov Y1 - 2015 U6 - https://doi.org/10.1080/00268976.2014.944597 VL - 113 IS - 1 SP - 69 EP - 78 ER - TY - GEN A1 - Schütte, Christof A1 - Nielsen, Adam A1 - Weber, Marcus T1 - Markov State Models and Molecular Alchemy N2 - In recent years Markov State Models (MSMs) have attracted a consid- erable amount of attention with regard to modelling conformation changes and associated function of biomolecular systems. They have been used successfully, e.g., for peptides including time-resolved spectroscopic ex- periments, protein function and protein folding , DNA and RNA, and ligand-receptor interaction in drug design and more complicated multi- valent scenarios. In this article a novel reweighting scheme is introduced that allows to construct an MSM for certain molecular system out of an MSM for a similar system. This permits studying how molecular proper- ties on long timescales differ between similar molecular systems without performing full molecular dynamics simulations for each system under con- sideration. The performance of the reweighting scheme is illustrated for simple test cases including one where the main wells of the respective en- ergy landscapes are located differently and an alchemical transformation of butane to pentane where the dimension of the state space is changed. T3 - ZIB-Report - 14-05 KW - Girsanov Theorem KW - Stochastic Differential Equation KW - Importance Sampling Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:0297-zib-46718 SN - 1438-0064 ER - TY - JOUR A1 - Durmaz, Vedat A1 - Schmidt, Sebastian A1 - Sabri, Peggy A1 - Piechotta, Christian A1 - Weber, Marcus T1 - A hands-off linear interaction energy approach to binding mode and affinity estimation of estrogens JF - Journal of Chemical Information and Modeling Y1 - 2013 VL - 53 IS - 10 SP - 2681 EP - 2688 ER - TY - JOUR A1 - Heye, Katharina A1 - Becker, Dennis A1 - Lütke-Eversloh, Christian A1 - Durmaz, Vedat A1 - Ternes, Thomas A1 - Oetken, Matthias A1 - Oehlmann, Jörg T1 - Effects of carbamazepine and two of its metabolites on the non-biting midge Chironomus riparius in a sediment full life cycle toxicity test JF - Water Research N2 - The antiepileptic drug carbamazepine (CBZ) and its main metabolites carbamazepine-10,11-epoxide (EP-CBZ) and 10,11-dihydro-10,11-dihydroxy-carbamazepine (DiOH-CBZ) were chosen as test substances to assess chronic toxicity on the non-biting midge Chironomus riparius. All three substances were tested in a 40-day sediment full life cycle test (according to OECD 233) in which mortality, emergence, fertility, and clutch size were evaluated. In addition, these parameters were integrated into the population growth rate to reveal population relevant effects. With an LC50 of 0.203 mg/kg (time-weighted mean), the metabolite EP-CBZ was significantly more toxic than the parent substance CBZ (LC50: 1.11 mg/kg). Especially mortality, emergence, and fertility showed to be sensitive parameters under the exposure to CBZ and EP-CBZ. By using classical molecular dynamics (MD) simulations, the binding of CBZ to the ecdysone receptor was investigated as one possible mode of action but showed to be unlikely. The second metabolite DiOH-CBZ did not show any effects within the tested concentration rage (0.171 – 1.22 mg/kg). Even though CBZ was less toxic compared to EP-CBZ, CBZ is found in the environment at much higher concentrations and causes therefore a higher potential risk for sediment dwelling organisms compared to its metabolites. Nevertheless, the current study illustrates the importance of including commonly found metabolites into the risk assessment of parent substances. Y1 - 2016 VL - 98 SP - 19 EP - 27 ER - TY - JOUR A1 - Djurdjevac Conrad, Natasa A1 - Weber, Marcus A1 - Schütte, Christof T1 - Finding dominant structures of nonreversible Markov processes JF - Multiscale Modeling and Simulation Y1 - 2016 U6 - https://doi.org/10.1137/15M1032272 VL - 14 IS - 4 SP - 1319 EP - 1340 ER -