TY - BOOK A1 - Reuter, Bernhard T1 - Generalisierte Markov-Modellierung N2 - Markov State Models (MSM) sind der Goldstandard zur Modellierung biomolekularer Dynamik, da sie die Identifizierung und Analyse metastabiler Zustände ermöglichen. Die robuste Perron-Cluster-Cluster-Analyse (PCCA+) ist ein verbreiteter Spectral-Clustering-Algorithmus, der für das Clustering hochdimensionaler MSM verwendet wird. Da die PCCA+ auf reversible Prozesse beschränkt ist, wird sie zur Generalisierten PCCA+ (G-PCCA) verallgemeinert, die geeignet ist, nichtreversible Prozesse aufzuklären. Bernhard Reuter untersucht hier mittels G-PCCA die nichtthermischen Auswirkungen von Mikrowellen auf die Proteindynamik. Dazu führt er molekulardynamische Nichtgleichgewichtssimulationen des Amyloid-β-(1–40)-Peptids durch und modelliert diese. Y1 - 2020 SN - 978-3-658-29711-4 U6 - https://doi.org/10.1007/978-3-658-29712-1 PB - Springer Spektrum, Wiesbaden ER - TY - JOUR A1 - Helfmann, Luzie A1 - Djurdjevac Conrad, Natasa A1 - Djurdjevac, Ana A1 - Winkelmann, Stefanie A1 - Schütte, Christof T1 - From interacting agents to density-based modeling with stochastic PDEs JF - Communications in Applied Mathematics and Computational Science N2 - Many real-world processes can naturally be modeled as systems of interacting agents. However, the long-term simulation of such agent-based models is often intractable when the system becomes too large. In this paper, starting from a stochastic spatio-temporal agent-based model (ABM), we present a reduced model in terms of stochastic PDEs that describes the evolution of agent number densities for large populations. We discuss the algorithmic details of both approaches; regarding the SPDE model, we apply Finite Element discretization in space which not only ensures efficient simulation but also serves as a regularization of the SPDE. Illustrative examples for the spreading of an innovation among agents are given and used for comparing ABM and SPDE models. Y1 - 2021 U6 - https://doi.org/10.2140/camcos.2021.16.1 VL - 16 IS - 1 SP - 1 EP - 32 ER - TY - JOUR A1 - Chewle, Surahit A1 - Emmerling, Franziska A1 - Weber, Marcus T1 - Effect of choice of solvent on crystallization pathway of Paracetamol: An experimental and theoretical case study JF - Crystals N2 - The choice of solvents influences crystalline solid formed during the crystallization of active pharmaceutical ingredients (API). The underlying effects are not always well understood because of the complexity of the systems. Theoretical models are often insufficient to describe this phenomenon. In this study, the crystallization behavior of the model drug paracetamol in different solvents was studied based on experimental and molecular dynamics data. The crystallization process was followed in situ using time-resolved Raman spectroscopy. Molecular dynamics with simulated annealing algorithm was used for an atomistic understanding of the underlying processes. The experimental and theoretical data indicate that paracetamol molecules adopt a particular geometry in a given solvent predefining the crystallization of certain polymorphs. Y1 - 2020 U6 - https://doi.org/10.3390/cryst10121107 VL - 10 IS - 12 SP - 1107 ER - TY - JOUR A1 - Thies, Arne A1 - Sunkara, Vikram A1 - Ray, Sourav A1 - Wulkow, Hanna A1 - Celik, M. Özgür A1 - Yergöz, Fatih A1 - Schütte, Christof A1 - Stein, Christoph A1 - Weber, Marcus A1 - Winkelmann, Stefanie T1 - Modelling altered signalling of G-protein coupled receptors in inflamed environment to advance drug design JF - Scientific Reports N2 - We previously reported the successful design, synthesis and testing of the prototype opioid painkiller NFEPP that does not elicit adverse side effects. The design process of NFEPP was based on mathematical modelling of extracellular interactions between G-protein coupled receptors (GPCRs) and ligands, recognizing that GPCRs function differently under pathological versus healthy conditions. We now present an additional and novel stochastic model of GPCR function that includes intracellular dissociation of G-protein subunits and modulation of plasma membrane calcium channels and their dependence on parameters of inflamed and healthy tissue (pH, radicals). The model is validated against in vitro experimental data for the ligands NFEPP and fentanyl at different pH values and radical concentrations. We observe markedly reduced binding affinity and calcium channel inhibition for NFEPP at normal pH compared to lower pH, in contrast to the effect of fentanyl. For increasing radical concentrations, we find enhanced constitutive G-protein activation but reduced ligand binding affinity. Assessing the different effects, the results suggest that, compared to radicals, low pH is a more important determinant of overall GPCR function in an inflamed environment. Future drug design efforts should take this into account. Y1 - 2023 U6 - https://doi.org/10.1038/s41598-023-27699-w VL - 13 IS - 607 ER - TY - JOUR A1 - Prasad, Anup K. A1 - Tiwari, Chandni A1 - Ray, Sourav A1 - Holden, Stephanie A1 - Armstrong, David A. A1 - Rosengren, K. Johan A1 - Rodger, Alison A1 - Panwar, Ajay S. A1 - Martin, Lisandra L. T1 - Secondary Structure Transitions for a Family of Amyloidogenic, Antimircobial Uperin 3 Peptides in Contact with Sodium Dodecyl Sulfate JF - ChemPlusChem Y1 - 2022 U6 - https://doi.org/10.1002/cplu.202100408 VL - 87 SP - e202100408 ER - TY - JOUR A1 - Heida, Martin A1 - Sikorski, Alexander A1 - Weber, Marcus T1 - Consistency and order 1 convergence of cell-centered finite volume discretizations of degenerate elliptic problems in any space dimension JF - SIAM Journal on Numerical Analysis N2 - We study consistency of cell-centered finite difference methods for elliptic equations with degenerate coefficients in any space dimension $d \geq 2$. This results in order of convergence estimates in the natural weighted energy norm and in the weighted discrete $L^2$-norm on admissible meshes. The cells of meshes under consideration may be very irregular in size. We particularly allow the size of certain cells to remain bounded from below even in the asymptotic limit. For uniform meshes we show that the order of convergence is at least 1 in the energy semi-norm, provided the discrete and continuous solutions exist and the continuous solution has $H^2$ regularity. Y1 - 2022 U6 - https://doi.org/10.20347/WIAS.PREPRINT.2913 ER - TY - JOUR A1 - Sechi, Renata A1 - Weber, Marcus A1 - Heyne, Karsten T1 - MSM building and projection for the analysis of time-resolved spectra JF - Proceedings in Applied Mathematics and Mechanics N2 - Understanding the kinetics between the components of time-resolved spectra is a crucial step in the study of photo-activatedprocesses. However, modeling the kinetics requires usually some a priori knowledge about the system. In our approach, webuild a Markov State Model (MSM) from the spectral data, and obtain a Koopman transition matrix K(t). With genPCCA,an invariant subspace projection, we project the process into its metastable components. The result of the application of gen-PCCA is a transition matrix Kc(t), from which we can read the transition probability between the metastable components of the reaction. We discuss the application of this analysis method to the transient absorption spectrum of brominated Al-corrole Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?https://onlinelibrary.wiley.com/doi/10.1002/pamm.202100102 IS - 21 SP - e202100102 ER - TY - JOUR A1 - Trepte, Philipp A1 - Secker, Christopher A1 - Olivet, Julien A1 - Blavier, Jeremy A1 - Kostova, Simona A1 - Maseko, Sibusiso B A1 - Minia, Igor A1 - Silva Ramos, Eduardo A1 - Cassonnet, Patricia A1 - Golusik, Sabrina A1 - Zenkner, Martina A1 - Beetz, Stephanie A1 - Liebich, Mara J A1 - Scharek, Nadine A1 - Schütz, Anja A1 - Sperling, Marcel A1 - Lisurek, Michael A1 - Wang, Yang A1 - Spirohn, Kerstin A1 - Hao, Tong A1 - Calderwood, Michael A A1 - Hill, David E A1 - Landthaler, Markus A1 - Choi, Soon Gang A1 - Twizere, Jean-Claude A1 - Vidal, Marc A1 - Wanker, Erich E T1 - AI-guided pipeline for protein–protein interaction drug discovery identifies a SARS-CoV-2 inhibitor JF - Molecular Systems Biology N2 - Protein–protein interactions (PPIs) offer great opportunities to expand the druggable proteome and therapeutically tackle various diseases, but remain challenging targets for drug discovery. Here, we provide a comprehensive pipeline that combines experimental and computational tools to identify and validate PPI targets and perform early-stage drug discovery. We have developed a machine learning approach that prioritizes interactions by analyzing quantitative data from binary PPI assays or AlphaFold-Multimer predictions. Using the quantitative assay LuTHy together with our machine learning algorithm, we identified high-confidence interactions among SARS-CoV-2 proteins for which we predicted three-dimensional structures using AlphaFold-Multimer. We employed VirtualFlow to target the contact interface of the NSP10-NSP16 SARS-CoV-2 methyltransferase complex by ultra-large virtual drug screening. Thereby, we identified a compound that binds to NSP10 and inhibits its interaction with NSP16, while also disrupting the methyltransferase activity of the complex, and SARS-CoV-2 replication. Overall, this pipeline will help to prioritize PPI targets to accelerate the discovery of early-stage drug candidates targeting protein complexes and pathways. KW - Applied Mathematics KW - Computational Theory and Mathematics KW - General Agricultural and Biological Sciences KW - General Immunology and Microbiology KW - General Biochemistry, Genetics and Molecular Biology KW - Information Systems Y1 - 2024 U6 - https://doi.org/https://doi.org/10.1038/s44320-024-00019-8 SN - 1744-4292 VL - 20 IS - 4 SP - 428 EP - 457 PB - Springer Science and Business Media LLC ER - TY - JOUR A1 - Bauer, Wolfgang A1 - Weber, Marcus A1 - Diehl-Wiesenecker, Eva A1 - Galtung, Noa A1 - Prpic, Monika A1 - Somasundaram, Rajan A1 - Tauber, Rudolf A1 - Schwenk, Jochen A1 - Micke, Patrick A1 - Kappert, Kai T1 - Plasma Proteome Fingerprints Reveal Distinctiveness and Clinical Outcome of SARS-CoV-2 Infection JF - Viruses N2 - We evaluated how plasma proteomic signatures in patients with suspected COVID-19 can unravel the pathophysiology, and determine kinetics and clinical outcome of the infection. We identified distinct plasma proteins linked to the presence and course of COVID-19. These plasma proteomic findings may translate to a protein fingerprint, helping to assist clinical management decisions. Y1 - 2021 U6 - https://doi.org/10.3390/v13122456 VL - 13 IS - 12 SP - 2456 ER - TY - GEN A1 - Ternes, Thomas A1 - Bauer, Karl-Heinz A1 - Brauer, Frank A1 - Drewes, Jürgen A1 - Jewell, Kevin A1 - Joss, Adriano A1 - Oehlmann, Jörg A1 - Radtke, Michael A1 - Schulte-Oehlmann, Ulrike A1 - Schwartz, Thomas A1 - Seel, Peter A1 - Völker, Jeanette A1 - Weber, Lilo A1 - Weber, Marcus T1 - Handlungsempfehlung zur integrativen Bewertung der weitergehenden Abwasserbehandlung von kommunalen Kläranlagen T2 - DWA-Themen N2 - Der DWA-Themenband beschreibt ein Konzept zur weitergehenden Abwasserbehandlung für die Bewertung von Aufbereitungsverfahren, sowohl in einer Pilotphase zur Auswahl von Verfahrensoptionen als auch für die Bewertung großtechnischer Anlagen. Emissionsseitig basiert das Konzept auf bereits regulatorisch definierten Parametern wie anorganischen Stickstoff-Verbindungen oder Phosphat sowie auf neuen noch nicht in der Abwasserverordnung regulierten Parametern. Die immissionsseitige Betrachtung erfolgt auf Basis der rechtlich durch die Europäische Wasserrahmenrichtlinie und andere Anforderungen bindenden Instrumente. Hierfür werden spezifische Vorgehensweisen vorgeschlagen. Anhand zweier ausgewählter Praxisbeispiele wird deutlich, dass es zur Bewertung der Verfahrensoptionen an einem Standort dienlich ist, ausgewählte Reduktionen bzw. Entfernungen von Stoffen, Organismen und Effekten zu bestimmen. Y1 - 2023 VL - T1/2023 PB - DWA ER - TY - JOUR A1 - Lelievre, Tony A1 - Stoltz, Gabriel A1 - Zhang, Wei T1 - Multiple projection MCMC algorithms on submanifolds JF - IMA Journal of Numerical Analysis N2 - We propose new Markov Chain Monte Carlo algorithms to sample probability distributions on submanifolds, which generalize previous methods by allowing the use of set-valued maps in the proposal step of the MCMC algorithms. The motivation for this generalization is that the numerical solvers used to project proposed moves to the submanifold of interest may find several solutions. We show that the new algorithms indeed sample the target probability measure correctly, thanks to some carefully enforced reversibility property. We demonstrate the interest of the new MCMC algorithms on illustrative numerical examples. Y1 - 2022 U6 - https://doi.org/10.1093/imanum/drac006 ER - TY - JOUR A1 - Zhang, Wei A1 - Li, Tiejun A1 - Schütte, Christof T1 - Solving eigenvalue PDEs of metastable diffusion processes using artificial neural networks JF - Journal of Computational Physics N2 - In this paper, we consider the eigenvalue PDE problem of the infinitesimal generators of metastable diffusion processes. We propose a numerical algorithm based on training artificial neural networks for solving the leading eigenvalues and eigenfunctions of such high-dimensional eigenvalue problem. The algorithm is useful in understanding the dynamical behaviors of metastable processes on large timescales. We demonstrate the capability of our algorithm on a high-dimensional model problem, and on the simple molecular system alanine dipeptide. Y1 - 2021 U6 - https://doi.org/10.1016/j.jcp.2022.111377 VL - 465 ER -