The Faculty of Mathematics and Natural Sciences

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The Faculty of Mathematics and Natural Sciences (MNF) employs more than 800 Scientists in seven departments: Biology, Chemistry, Computer Sciences, Mathematics, Pharmacy, Physics and Psychology. Among the wide-ranging research areas covered by the faculty, several cooperative programmes put specific emphasis on Life Sciences and Physics.

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    Anomalous phylogenetic behavior of ribosomal proteins in metagenome assembled asgard archaea
    (Genome Biology and Evolution, 2020) Garg, SG; Kapust, N; Lin, W; Knopp, M; Tria, FDK; Nelson-Sathi, S; Gould, SB; Fan, L; Zhu, R; Zhang, C; Martin, WF
    Supplement to a paper in GBE (title: Anomalous phylogenetic behavior of ribosomal proteins in metagenome assembled asgard archaea)
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    Chaperone/ETR1 Structural Models for: Molecular Mechanism and Structural Models of Protein-Mediated Copper Transfer to the Arabidopsis thaliana Ethylene Receptor ETR1 at the ER Membrane
    (N/A, 2025) Dluhosch, Dominik; Kersten, Lisa Sophie; Minges, Alexander; Schott-Verdugo, Stephan; Gohlke, Holger; Groth, Georg
    In plants, the gaseous plant hormone ethylene regulates a wide range of developmental processes and stress responses. The small unsaturated hydrocarbon is detected by a family of receptors (ETRs) located in the membrane of the endoplasmic reticulum, which rely on a monovalent copper cofactor to detect this hydrocarbon. The copper-transporting P-type ATPase RAN1 (HMA7), located in the same membrane, is known to be essential for the biogenesis of ETRs. Still, the precise molecular mechanism by which the receptors acquire their copper cofactor remains unclear. A recent study by our laboratory demonstrated a direct interaction between RAN1 and soluble copper chaperones of the ATX1 family with the model ethylene receptor ETR1, providing initial insights into the mechanism by which copper is transferred from the cytosol to the membrane-bound receptors. In this study, we further investigated these interactions with respect to the function of individual domains in complex formation. To this end, we combined biochemical experiments and computational predictions and unraveled the processes and mechanisms by which copper is transferred to ETR1 at the molecular level.
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    Data for "Influence of ionic liquids on enzymatic asymmetric carboligations"
    (N/A, 2025) El Harrar, Till; Gohlke, Holger
    The asymmetric mixed carboligation of aldehydes catalyzed by thiamine diphosphate (ThDP)-dependent enzymes provides a sensitive system for monitoring changes in activity, chemo-, and enantioselectivity. While previous studies have shown that organic cosolvents influence these parameters, we now demonstrate that similar effects occur upon addition of water-miscible ionic liquids (ILs). In this study, six ThDP-dependent enzymes were analyzed in the presence of 14 ILs under comparable conditions to assess their influence on enzymatic carboligation reactions yielding 2-hydroxy ketones. ILs exerted a moderate to strong influence on activity and, more notably, altered enantioselectivity. (R)-selective reactions were generally stable upon IL addition, while (S)-selective reactions frequently showed reduced selectivity or even inversion to the (R)-enantiomer. The most significant change was observed for the ApPDC_E469G variant of pyruvate decarboxylase from Acetobacter pasteurianus, where the enantiomeric excess shifted from 86% (S) to 60% (R) in the presence of 9% (w/v) Ammoeng 102. Control experiments indicated that this shift was primarily due to the Ammoeng cation rather than the anion. To explore the molecular basis of this phenomenon, all-atom molecular dynamics (MD) simulations were performed on wild-type ApPDC and the E469G variant in Ammoeng 101 and Ammoeng 102. The simulations revealed that hydrophobic and hydrophilic regions of the Ammoeng cations interact with the (S)-selective binding pocket, thereby favoring formation of the (R)-product. These results highlight the potential of solvent engineering for modulating enzyme selectivity and demonstrate that MD simulations can capture functionally relevant enzyme–solvent interactions at the atomic level.
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    Data for "TopEC: Improved classification of enzyme function by a localized 3D protein descriptor and 3D Graph Neural Networks"
    (N/A, 2024-08-25) van der Weg, Karel; Merdivan, Erinc; Piraud, Marie; Gohlke, Holger
    Accurately annotating molecular function of enzymes remains challenging. Computational methods can aid in this and allow for high-throughput annotation. Tools available for inferring enzyme function from general sequence, fold, or evolutionary information are generally successful. However, they can lead to misclassification if for certain sequences a deviation in local structural features influences the function. Here, we present TopEC, a 3D graph neural network based on a localized 3D descriptor to learn chemical reactions of enzymes from (predicted) enzyme structures and predict Enzyme Commission (EC) classes. Using the message passing frameworks from SchNet and DimeNet++, we include distance and angle information to improve the predictive performance compared to regular 2D graph neural networks. We obtained significantly improved EC classification prediction (F-score: 0.72) to 2D GNNs, without fold bias at residue and atomic resolutions and trained networks that can classify both experimental and computationally generated enzyme structures for a vast functional space (> 800 ECs). Our model is robust to uncertainties in binding site locations and similar functions in distinct binding sites. By investigating the importance of each graph node to the predictive performance, we see that TopEC networks learn from an interplay between biochemical features and local shape-dependent features. TopEC is available as a repository, including accompanying data, on github: https://github.com/IBG4-CBCLab/TopEC. The data in this repository is available under the CC-BY-NC-SA 4.0 license.
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    Electronic Supporting Information for MOLSTRUC-D-21-03929
    (Journal of Molecular Structure, 2021) Hebestreit, Marie-Luise
    This collection gives a) the experimental and simulated zero-field spectrum of the electronic origin of 6-methylindole b) the experimental and simulated Stark spectrum of the electronic origin of 6-methylindole at 425.49 V/cm
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    Example input data for FCFit
    (No, 2022) Michael, Schmitt
    Collection of example input data for FCFit
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    FC-Fit
    (No, 2022) Krügler, Daniel; Schmitt, Michael
    FCfit is program for the simulation and fit of vibronic absorption and emission spectra based on the evaluation of relative Franck-Condon (FC) factors and/or Franck-Condon-Herzberg-Teller (FCHT) theory. The program computes the FC integrals of multidimensional, harmonic oscillators mainly based on the recursion formula given in the papers of Doktorov, Malkin, and Man’ko.
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    Ferredoxin reduction by hydrogen with iron functions as an evolutionary precursor of flavin-based electron bifurcation
    (Institute of Molecular Evolution, 2023) Brabender, Max; Henriques Pereira, Delfina P.; Mrnjavac, Natalia; Schlikker, Manon Laura; Kimura, Zen-Ichiro; Sucharitakul, Jeerus; Kleinermanns, Karl; Tüysüz, Harun; Buckel, Wolfgang; Preiner, Martina; Martin, William F.
    Raw data of UV-VIS spectra
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    Functional and structural characterization of interactions between opposite subunits in HCN pacemaker channels
    (N/A, 2021-08-05) Kondapuram, Mahesh; Frieg, Benedikt; Yüksel, Sezin; Schwabe, Tina; Sattler, Christian; Lelle, Marco; Schweinitz, Andrea; Schmauder, Ralf; Benndorf, Klaus; Gohlke, Holger; Kusch, Jana
    Hyperpolarization-activated and cyclic nucleotide (HCN) modulated channels are tetrameric cation channels. In each of the four subunits, the intracellular cyclic nucleotide-binding domain (CNBD) is coupled to the transmembrane domain via a helical structure, the C-linker. High-resolution channel structures suggest that the C-linker enables functionally relevant interactions with the opposite subunit, which might be critical for coupling the conformational changes in the CNBD to the channel pore. We combined mutagenesis, patch-clamp technique, confocal patch-clamp fluorometry, and molecular dynamics simulations to show that residue K464 of the C-linker is essential for stabilizing the closed state of the mHCN2 channel by forming interactions with the opposite subunit. MD simulations revealed that both cAMP and K464E induce a rotation of the intracellular domain relative to the channel pore, weakening the autoinhibitory effect of the unoccupied CL-CNBD region. The adopted poses are in excellent agreement with structural results.
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    Manual for FCFit
    (No, 2022) Schmitt, Michael; Krügler, Daniel
    Manual for FCFit
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    MD simulation data for: "Molecular Mechanisms Underlying Medium-Chain Free Fatty Acid-regulated Activity of the Phospholipase PlaF from Pseudomonas aeruginosa"
    (N/A, 2023-11) Gentile, Rocco; Schott-Verdugo, Stephan; Gohlke, Holger
    PlaF is a membrane-bound phospholipase A1 from P. aeruginosa that is involved in remodeling membrane glycerophospholipids (GPLs) and modulation of virulence-associated signaling and metabolic pathways. Previously, we identified the role of medium-chain free fatty acids (FFA) in inhibiting PlaF activity and promoting homodimerization, yet the underlying molecular mechanism remained elusive. Here, we used unbiased and biased molecular dynamics simulations and free energy computations to assess how PlaF interacts with FFAs localized in the water milieu surrounding the bilayer or within the bilayer, and how these interactions regulate PlaF activity. Medium-chain FFAs localized in the upper bilayer leaflet can stabilize inactive dimeric PlaF, likely through interactions with charged surface residues as experimentally validated. Potential of mean force (PMF) computations indicate that membrane-bound FFAs may facilitate the activation of monomeric PlaF by lowering the activation barrier of changing into a tilted, active configuration. We estimated that the coupled equilibria of PlaF monomerization-dimerization and tilting at the physiological concentration of PlaF lead to the majority of PlaF forming inactive dimers when in a cell membrane loaded with decanoic acid (C10). This is in agreement with a suggested in vivo product feedback loop and GC-MS profiling results indicating that PlaF catalyzes the release of C10 from P. aeruginosa membranes. Additionally, we found that C10 in the water milieu can access the catalytic site of active monomeric PlaF, contributing to the competitive component of C10-mediated PlaF inhibition. Our study provides mechanistic insights into how medium-chain FFA may regulate the activity of PlaF, a potential bacterial drug target.
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    MD simulation data for: "The cyclophilin A binding loop of the capsid regulates the human TRIM5α sensitivity of nonpandemic HIV-1"
    (N/A, 2023-11) Becker, Daniel; Münk, Carsten; Gohlke, Holger
    All MD input structures, MD infiles, umbrella sampling files, and scripts that were used to analyze the umbrella sampling results are provided in this supporting repository.
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    Millisecond-long sampling for a comprehensive energetic evaluation of aqueous ionic liquid effects on amino acid interactions
    (N/A, 2022-09-01) El Harrar, Till; Gohlke, Holger
    The interactions of amino acid side-chains confer diverse energetic contributions and physical properties to a protein's stability and function. Various computational tools estimate the effect of changing a given amino acid on the protein's stability based on parametrized (free) energy functions. When parametrized for the prediction of protein stability in water, such energy functions can lead to suboptimal results for other solvents, such as ionic liquids (IL), aqueous ionic liquids (aIL), or salt solutions. However, to our knowledge, no comprehensive data is available describing the energetic effect of aIL on intramolecular protein interactions. Here, we present the most comprehensive set of potential of mean force (PMF) profiles of pairwise protein-residue interactions to date, covering 50 relevant interactions in water, the two biotechnologically relevant aIL [BMIM/Cl] and [BMIM/TfO], and [Na/Cl]. These results are based on a cumulated simulation time of > 1 ms. aIL and salt ions can weaken, but also strengthen, specific residue interactions by more than 3 kcal mol 1, depending on the residue pair, residue-residue configuration, participating ions, and concentration, necessitating considering such interactions specifically. These changes originate from a complex interplay of competitive or cooperative noncovalent ion-residue interactions, changes in solvent structural dynamics, or unspecific charge screening effects and occur at the contact distance but also at larger, solvent-separated distances. This data provides explanations at the atomistic and energetic level for complex IL effects on protein stability and should help improve the prediction accuracy of computational tools that estimate protein stability based on (free) energy functions.
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    Molecular dynamics simulations data and analysis scripts used for Grx5 in the publication "Quantitative assessment of the determinant structural differences between redox-active and inactive glutaredoxins"
    (N/A, 2020-02) Wäschenbach, Lucas; Gohlke, Holger
    The files in this directory contain the molecular dynamics simulations data and analysis scripts for Grx5 used in the publication "Quantitative assessment of the determinant structural differences between redox-active and inactive glutaredoxins"
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    Molecular dynamics simulations data and analysis scripts used for Grx7 in the publication "Quantitative assessment of the determinant structural differences between redox-active and inactive glutaredoxins"
    (N/A, 2020-02) Wäschenbach, Lucas; Gohlke, Holger
    The files in this directory contain the molecular dynamics simulations data and analysis scripts for Grx7 used in the publication "Quantitative assessment of the determinant structural differences between redox-active and inactive glutaredoxins"
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    Movie for: The architecture of the 10-23 DNAzyme and its implications for DNA-mediated catalysis
    (N/A, 2022-09-19) Christoph, Gertzen; Jan, Borggräfe; Aldino, Viegas; Manuel, Etzkorn; Holger, Gohlke
    Understanding the molecular features of catalytically active DNA sequences, so-called DNAzymes, is not only essential for our understanding of the fundamental properties of catalytic nucleic acids in general but may well be the key to unraveling their full potential via tailored modifications. Our recent findings contributed to the endeavor to assemble a mechanistic picture of DNA-mediated catalysis by providing high-resolution structural insights into the 10-23 DNAzyme (Dz) and exposing a complex interplay between the Dz´s unique molecular architecture, conformational plasticity, and dynamic modulation by metal ions as central elements of the DNA catalyst. To illustrate the sampled conformational space, the movie depicts one MD trajectory of the Dz:RNA complex.
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    Petersilie et al. 2024 - Figure 1
    (iScience, 2024) Petersilie, Laura; Heiduschka, Sonja; Nelson, Joel S. E.; Neu, Louis A.; Le, Stephanie; Anand, Ruchika; Kafitz, Karl W.; Prigione, Alessandro; Rose, Christine R.
    Brain organoids derived from human pluripotent stem cells are a promising tool for studying human neurodevelopment and related disorders. Here, we generated long-term cultures of cortical brain organoid slices (cBOS) grown at the air-liquid interphase from regionalized cortical organoids. We show that cBOS host mature neurons and astrocytes organized in complex architecture. Whole-cell patch clamp demonstrated subthreshold synaptic inputs and action potential firing of neurons. Spontaneous intracellular calcium signals turned into synchronous large-scale oscillations upon combined disinhibition of NMDA receptors and blocking of GABAA receptors. Brief metabolic inhibition to mimic transient energy restriction in the ischemic brain induced reversible intracellular calcium loading of cBOS. Moreover, metabolic inhibition induced a reversible decline in neuronal ATP as revealed by ATeam1.03YEMK. Overall, cBOS provide a powerful platform to assess morphological and functional aspects of human neural cells in intact minimal networks and to address the pathways that drive cellular damage during brain ischemia.
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    Petersilie et al. 2024 - Figure 2
    (iScience, 2024) Petersilie, Laura; Heiduschka, Sonja; Nelson, Joel S. E.; Neu, Louis A.; Le, Stephanie; Anand, Ruchika; Kafitz, Karl W.; Prigione, Alessandro; Rose, Christine R.
    Brain organoids derived from human pluripotent stem cells are a promising tool for studying human neurodevelopment and related disorders. Here, we generated long-term cultures of cortical brain organoid slices (cBOS) grown at the air-liquid interphase from regionalized cortical organoids. We show that cBOS host mature neurons and astrocytes organized in complex architecture. Whole-cell patch clamp demonstrated subthreshold synaptic inputs and action potential firing of neurons. Spontaneous intracellular calcium signals turned into synchronous large-scale oscillations upon combined disinhibition of NMDA receptors and blocking of GABAA receptors. Brief metabolic inhibition to mimic transient energy restriction in the ischemic brain induced reversible intracellular calcium loading of cBOS. Moreover, metabolic inhibition induced a reversible decline in neuronal ATP as revealed by ATeam1.03YEMK. Overall, cBOS provide a powerful platform to assess morphological and functional aspects of human neural cells in intact minimal networks and to address the pathways that drive cellular damage during brain ischemia.
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    Petersilie et al. 2024 - Figure 3
    (iScience, 2024) Petersilie, Laura; Heiduschka, Sonja; Nelson, Joel S. E.; Neu, Louis A.; Le, Stephanie; Anand, Ruchika; Kafitz, Karl W.; Prigione, Alessandro; Rose, Christine R.
    Brain organoids derived from human pluripotent stem cells are a promising tool for studying human neurodevelopment and related disorders. Here, we generated long-term cultures of cortical brain organoid slices (cBOS) grown at the air-liquid interphase from regionalized cortical organoids. We show that cBOS host mature neurons and astrocytes organized in complex architecture. Whole-cell patch clamp demonstrated subthreshold synaptic inputs and action potential firing of neurons. Spontaneous intracellular calcium signals turned into synchronous large-scale oscillations upon combined disinhibition of NMDA receptors and blocking of GABAA receptors. Brief metabolic inhibition to mimic transient energy restriction in the ischemic brain induced reversible intracellular calcium loading of cBOS. Moreover, metabolic inhibition induced a reversible decline in neuronal ATP as revealed by ATeam1.03YEMK. Overall, cBOS provide a powerful platform to assess morphological and functional aspects of human neural cells in intact minimal networks and to address the pathways that drive cellular damage during brain ischemia.
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    Petersilie et al. 2024 - Figure 4
    (iScience, 2024) Petersilie, Laura; Heiduschka, Sonja; Nelson, Joel S. E.; Neu, Louis A.; Le, Stephanie; Anand, Ruchika; Kafitz, Karl W.; Prigione, Alessandro; Rose, Christine R.
    Brain organoids derived from human pluripotent stem cells are a promising tool for studying human neurodevelopment and related disorders. Here, we generated long-term cultures of cortical brain organoid slices (cBOS) grown at the air-liquid interphase from regionalized cortical organoids. We show that cBOS host mature neurons and astrocytes organized in complex architecture. Whole-cell patch clamp demonstrated subthreshold synaptic inputs and action potential firing of neurons. Spontaneous intracellular calcium signals turned into synchronous large-scale oscillations upon combined disinhibition of NMDA receptors and blocking of GABAA receptors. Brief metabolic inhibition to mimic transient energy restriction in the ischemic brain induced reversible intracellular calcium loading of cBOS. Moreover, metabolic inhibition induced a reversible decline in neuronal ATP as revealed by ATeam1.03YEMK. Overall, cBOS provide a powerful platform to assess morphological and functional aspects of human neural cells in intact minimal networks and to address the pathways that drive cellular damage during brain ischemia.