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Institute: search.filters.UBSInstitut.Institut für ComputerphysikSubject: search.filters.subject.570

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    Solubilization of inclusion bodies : insights from explainable machine learning approaches
    (2023) Walther, Cornelia; Martinetz, Michael C.; Friedrich, Anja; Tscheließnig, Anne-Luise; Voigtmann, Martin; Jung, Alexander; Brocard, Cécile; Bluhmki, Erich; Smiatek, Jens
    We present explainable machine learning approaches for gaining deeper insights into the solubilization processes of inclusion bodies. The machine learning model with the highest prediction accuracy for the protein yield is further evaluated with regard to Shapley additive explanation (SHAP) values in terms of feature importance studies. Our results highlight an inverse fractional relationship between the protein yield and total protein concentration. Further correlations can also be observed for the dominant influences of the urea concentration and the underlying pH values. All findings are used to develop an analytical expression that is in reasonable agreement with experimental data. The resulting master curve highlights the benefits of explainable machine learning approaches for the detailed understanding of certain biopharmaceutical manufacturing steps.
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    Molecular dynamics simulations for the study of interaction between non-canonical DNA structures and biochemically relevant co-solutes
    (2023) Oprzeska-Zingrebe, Ewa Anna; Smiatek, Jens (Priv.-Doz. Dr.)
    Non-canonical nucleic acid structures, such as DNA G-quadruplexes and i-Motifs, have been proved to play an important role in key biological processes, including gene expression, replication, regulation or telomere maintenance. The presence of G-quadruplexes in promoter regions of certain oncogenes turn them into a potential target for cancer therapies. Besides their biological implications, non-canonical DNA structures are present in genomes of various organisms, who adopt certain levels of co-solutes to protect their internal structures against the harsh environment. This study presents the research on the selected non-canonical DNA structures of particular biological relevance: G-quadruplex with only two tetrads, small DNA hairpin and ssDNA strand as well as canonical double helix. The atomistic molecular dynamics (MD) simulations have been applied to elucidate the structural, configuration and solvation properties of the analyzed structures in the presence of assorted co-solutes, composing the native cellular environment in nature: urea, ectoine and trimethylamine-N-oxide (TMAO). With the application of molecular theory of solutions, one determines and exemplifies the thermodynamic properties of investigated structures in various environments close to the physiological conditions present in living cells. This study uncovers the versatile nature of DNA interaction with diverse co-solutes and water, as well as the cross-interactions between the inorganic components of the biomolecular solution. The cellular mechanisms of DNA structural stabilization and destabilization are hereby described in terms of preferential binding and preferential exclusion, with particular emphasis on the properties of solvent structure within individual solvation shells. In this regards, this work presents a comprehensive study on the intracellular interactions involving nucleic acids, thus shedding light into their microscopic properties and opening the path for further biomedical research.
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    Influence of bacterial swimming and hydrodynamics on attachment of phages
    (2024) Lohrmann, Christoph; Holm, Christian; Datta, Sujit S.
    Bacteriophages (“phages”) are viruses that infect bacteria. Since they do not actively self-propel, phages rely on thermal diffusion to find target cells - but can also be advected by fluid flows, such as those generated by motile bacteria themselves in bulk fluids. How does the flow field generated by a swimming bacterium influence how it encounters phages? Here, we address this question using coupled molecular dynamics and lattice Boltzmann simulations of flagellated bacteria swimming through a bulk fluid containing uniformly-dispersed phages. We find that while swimming increases the rate at which phages attach to both the cell body and flagellar propeller, hydrodynamic interactions strongly suppress this increase at the cell body, but conversely enhance this increase at the flagellar bundle. Our results highlight the pivotal influence of hydrodynamics on the interactions between bacteria and phages, as well as other diffusible species, in microbial environments.
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    Electronic transport properties of DNA sensing nanopores : insight from quantum mechanical simulations
    (2017) Sivaraman, Ganesh; Fyta, Maria (Jun.-Prof. Dr.)
    The translocation of DNA through nanopores is an intensively studied field as it can lead to a new perspective in DNA sequencing. During this process the DNA is electrophoretically driven through a nanoscale hole in a membrane, and use different sensing schemes to read out the sequence. Within the scope of nanopore sequencing two important sensing schemes relevant to this thesis are: 1.) Tunneling sequencers based on solid state nanopores embedded with gold electrodes 2.) 2D materials beyond graphene For scheme 1, an obvious improvement is to coat the gold electrode with molecules that have high conductance and can form instantaneous hydrogen bond bridges with the translocating polynucleotide thereby improving the transverse current signal. The molecule that we propose is the so called diamondoid which are diamond caged molecules with hydrogen termination. Before applying such a molecule to a nanopore electrode set up, one would like to understand their interaction with DNA and its nucleobases. For this purpose, hydrogen bonded complexes formed between nitrogen doped derivatives of smallest diamondoids (i.e. adamantane derivatives) and nucleobases were investigated using dispersion corrected density functional theory (DFT). Mutated and methylated nucleobases are also taken into consideration in these investigations. DFT calculations revealed that hydrogen bonds are of moderate strength. In addition, starting from the DFT predicted hydrogen bonding configuration for each complex, rotations, and translations along a reference axis was performed to capture variations in the interaction energies along the donor-acceptor groups of the hydrogen bonds. The electronic density of states analysis for the hydrogen bonded complexes revealed distinguishable signatures for each nucleobase, thereby showing the suitability for application in electrodes functionalised with such probe molecules. In the next step, an adamantane derivative is placed on one of the electrode and nucleotides are introduced in such a way that nucleobases form hydrogen bonds with the of the nitrogen group of the adamantane derivatives. Electronic transport calculations were performed for gold electrodes functionalised with 3 different adamantane derivatives. Four pristine nucleotides, one mutated, and one methylated nucleotides were considered. Analysis of the transmission spectra reveal that each of the nucleotides has a unique resonance peak far below the Fermi level. We have also proposed a gating voltage window to sample the resonance peaks of the nucleotide so that they can be distinguished from each other. An alternative to tunneling sequencers would be to use nanopores built in to ultra thin metallic nanoribbons such as graphene. The sequence can be read out from the in-plane current modulation resulting from the local field effect of the translocating nucleotides in the vicinity of the metallic pore edges. But the hydrophobicity of graphene makes it a difficult candidate in aqueous environment. Hence in scheme 2, the aim is to model an ultra thin material that can rectify the hydrophobicity of graphene and can be a very good candidate for current modulation sequencing. Ultra thin MoS2 (2H) monolayer exist as direct band gap semiconductor. Nanopores based on 2H phases have been reported in the literature and are not hydrophobic. By means of chemical exfoliation of the 2H phase, a meta stable 1T phase of MoS2 has also been synthesized by various experimental groups. The 1T phase of MoS2 is metallic. The aim of this thesis is to model a nano-biosensor template based on a hybrid MoS2 monolayer made up of a metallic (1T) phase sandwiched between semiconducting (2H) phase. The sensor that we propose, should have only metallic nanopore edges. As a first step, we have modeled the semiconductor-metal interface, and compared them with experiments. Then an investigation to understand the influence of the increase of the metallic unit on the electronic properties is performed. Since, point defects are highly relevant to electrochemical pore growth, a point sulfur defect analysis is provided to ascertain the weakest point in the sheet. Finally to understand the effect of the interface electronic transport calculations are performed. The transmission spectra reveals a clear asymmetry in the current flow across the interface by means of gating. In the end, the relevance of such a hybrid MoS2 material for nanopore sequencing is discussed.
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    Functionalized nanogap for DNA read‐out : nucleotide rotation and current‐voltage curves
    (2020) Maier, Frank C.; Fyta, Maria
    Functionalized nanogaps embedded in nanopores show a strong potential for enhancing the detection of biomolecules, their length, type, and sequence. This detection is strongly dependent on the features of the target biomolecules, as well as the characteristics of the sensing device. In this work, through quantum‐mechanical calculations, we elaborate on representative such aspects for the specific case of DNA detection and read‐out. These aspects include the influence of single DNA nucleotide rotation within the nanogap and the current‐voltage (I‐V) characteristics of the nanogap. The results unveil a distinct variation in the electronic current across the functionalized device for the four natural DNA nucleotides with the applied voltage. These also underline the asymmetric response of the rotating nucleotides on this applied voltage and the respective variation in the rectification ratio of the device. The electronic tunneling current across the nanogap can be further enhanced through the proper choice of an applied bias voltage. We were able to correlate the enhancement of this current to the nucleotide rotation dynamics and a shift of the electronic transmission peaks towards the Fermi level. This nucleotide specific shift further reveals the sensitivity of the device in reading‐out the identity of the DNA nucleotides for all different configurations in the nanogap. We underline the important information that can be obtained from both the I‐V curves and the rectification characteristics of the nanogap device in view of accurately reading‐out the DNA information. We show that tuning the applied bias can enhance this detection and discuss the implications in view of novel functionalized nanopore sequencers.