Kassel-Schwiete Research Group: Development of Pharmacological Probes

Nowadays, computational modeling and theoretical methods are an important, indispensable aspect in life sciences aiming at more and more reliable modeling of more and more complex systems. Our group uses methods which work at different spatial and temporal resolution. For one thing, we apply quantum chemical methods which are based on the calculation of the wave function of the electron cloud around the classical nuclei. Secondly, we apply classical molecular dynamics with different resolutions. For the finer atomistic resolution, every atom is modeled as one particle. In contrast, atoms are grouped together in coarse-grained simulations. This simplifies the considered molecules and enables longer simulations of larger (bio)molecular systems. In general, more accurate methods require a larger computing effort. Thus, their application is limited to shorter processes and smaller systems.

The thematic focus of our group is in the fields of biophysics and medicinal chemistry. In particular, we are working on the development and characterization of pharmacological probes. Thereby, the investigation of the interactions between proteins and small molecules is crucial. Often, the small molecules interact only with one or a small group of proteins. Firstly, we aim at understanding why a molecule interacts strongly with certain proteins and not with others. Based thereon, we can alter the molecule in a defined way to strengthen the desired interaction. The goal is to develop molecules favorably interacting with specific proteins that play a role in diseases. The resulting pharmacologically active molecules can be experimentally synthesized, tested, and further improved. Thus, our research can contribute to the development of new medicines.

You can find further research topics, our scientific publications, as well as our engagement in public outreach on the pages Research and Publications. In the following, you can read the latest news from our group.

Fellow Detail

Research and Publications

Publications

Understanding biological processes using modern computational methods

Research

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News 2022/2023

16.04.2024 — Within the Martini Force Field Initiative, we developed and extensively tested an enhanced GōMartini model in large collaborative consortium led by Paulo C. T. Souza and Sebastian. The work demonstrates the capabilities of the GōMartini 3 model for test cases ranging from protein-membrane and protein-ligand binding to single molecule force spectroscopy. Moreover, it can be used to address inaccuracies in the Martini 3 protein model. The long-awaited preprint entitled "GōMartini 3: From large conformational changes in proteins to environmental bias corrections" is out now!

05.04.2024 — Sebastian attended the CECAM flagship workshop on frontiers of coarse-grained models in Lyon this week. In his talk, Sebastian presented developments and applications of the Martini 3 protein model and light-switchable molecules. Thanks to Paulo C. T. Souza and the other organizers for putting together such a nice program!

24.03.2024 — G protein-coupled receptors are an important class of cell receptors which reside in the membrane. Using coarse-grained molecular dynamics simulations, we showed that they can also facilitate membrane crossing of drug molecules. Our results are now available in a preprint entitled "GPCR surface creates a favorable pathway for membrane permeation of drug molecules".

15.03.2024 — In the last two days, the Scientific Advisory Board visited the FIAS to get an overview of the diverse research activities at FIAS. Cristina, Saara, and Thilo presented the projects of the Thallmair Group with much commitment!

12.03.2024 — Today, Sebastian gave a talk entitled "Unraveling protein function and dysfunction by means of coarse-grained molecular dynamics" at the Max Planck Institute for Polymer Research in Mainz. It was great meeting old friends and making new connections! Thanks for the invitation and the exciting discussions!

07.03.2024 — In the FIAS Forum Lecture Series, FIAS Fellows present current scientific topics to a broader audience. Tonight, Sebastian will give a talk (in German) entitled "Wie Lichtschalter in Medikamenten der Zukunft eingesetzt werden können". Last-minute participants can find more information in the announcement.

09.02.2024 — Cristina will attend this year's Biophysical Society Meeting in Philadelphia (PA, US), where she will present a poster entitled "Exploring Lipid and Ligand Flip-Flop on the Surface of a GPCR: A Martini 3 Study".

02.02.2024 — We are glad that the SCALE Initiative is invited to submit a full proposal within the Excellence Initiative! Sebastian contributes to the proposal as an associated PI. Congratulations to all collaborators!

01.01.2024 — The Thallmair Group wishes a Happy New Year and looks forward to great collaborations, exciting research results, and interesting conferences!

05.12.2023 — Sebastian visited the University of Münster for two days. Today, he gave a talk in the Plant Biology Colloquium entitled "Modeling protein-lipid interactions: From LHCII lipid fingerprints to specific lipid binding sites". Thanks a lot for the invitation and the exciting discussions!

31.10.2023 — We have to say goodbye to Marieli Goncalves Dias today. After spending one year as guest PhD candidate in the Thallmair Group, she goes back to the University of Campinas (Brasil). It was great having Marieli in our group! We wish you all the best, Marieli!

05.10.2023 — Cholesterol is a key component of cell membranes and thus an important molecule in biomolecular simulations. Our paper about the development and validation of the cholesterol model for the coarse-grained Martini 3 force field was accepted in the Journal of Chemical Theory and Computation. It is entitled "Martini 3 Coarse-Grained Force Field for Cholesterol".

01.10.2023 — We cordially welcome Saara Lautala and Thilo Duve in the Thallmair Group! Saara will work as postdoctoral researcher on membrane contact sites within the SCALE initiative in close collaboration with the group of Florian Wilfling (MPI of Biophysics). Thilo will study light-switchable kinase inhibitors in his Master thesis.

03.08.2023 — This week, our PhD students Cristina and Marieli attend the EBSA congress in Stockholm, Sweden. Each of them presents a poster with their results about G-protein coupled receptors and nuclear receptors, respectively.

24.07.2023 — In collaboration with researchers at Philipps-University Marburg, we were able to show that the Tubby protein localizes to contact sites between endoplasmic reticulum and plasma membrane. It binds to specific lipids as well as to a protein, which only occurs in the contact sites. You can read more about it in our publication entitled "Localization of the tubby domain, a PI(4,5)P₂ biosensor, to E-Syt3-rich ER-PM junctions" in the Journal of Cell Science.

17.07.2023 — Cristina will present her research results at the CMMS-Retreat, which takes place at the Rursee in the Eifel mountain region from 17.-21.07.2023. In addition, Sebastian will give an introduction to coarse-grained molecular dynamics simulations.

13.07.2023 — The FIAS-News article entitled "Sensor enables analysis of an important cellular scavenger" tells you more about the novel sensor for glutathione, which we published in Nature Chemistry recently.

11.07.2023 — Today, Sebastian Thallmair presents a keynote lecture entitled "Protein-lipid Interactions Resolved by Coarse-grained Molecular Dynamics" at the "10th European Symposium on Plant Lipids" in Amsterdam, the Netherlands. Thanks a lot to Teun Munnik (University of Amsterdam), the organization committee, and the Deutsche Gesellschaft für Fettwissenschaft e.V. for the invitation to the exciting conference!

16.06.2023 — Glutathione plays an important role in cells: it regulates the cellular redox potential and is involved in signalling processes. Together with researchers from the University of Zurich, we developed and characterized a quantitative sensor for glutathione. It can be applied selectively in cellular substructures, so-called organelles. Our results are now published in Nature Chemistry entitled "A Locally Activatable Sensor for Robust Quantification of Organellar Glutathione".

31.05.2023 — For the first time, the "Best FIGSS Talk" Prize was awarded to speakers of the FIGSS Seminar in the winter semester 2022/2023. The prize was initiated by Doris Hardt and Sebastian Thallmair. In the framework of the graduate school FIGSS at FIAS, doctoral students present their research in the biweekly FIGSS Seminar. Since summer semester 2022, Sebastian is Scientific Coordinator of the graduate school FIGSS.

30.05.2023 — In an international collaboration with researchers in Portugal, France, the Netherlands, Germany, Canada, and the US, we developed and validated a Martini 3 model for cholesterol. Cholesterol is a key component of biological cell membranes and thus an important molecule in biomolecular simulations. You can read more about the Martini 3 cholesterol model in our new preprint.

03.05.2023 — Together with the group of Dr. Roberto Covino, we presented our research to the Alfons und Gertrud Kassel Stiftung, the Dr. Rolf M. Schwiete Stiftung, and the Johanna Quandt Stiftung, which support our research projects. The event was entitled "Biomolecular function unraveled by the computational microscope". In addition to talks by Cristina and Sebastian, Marieli and Charlie presented posters with their results. We would like to thank the foundations for their generous support!

13.04.2023 — We are happy to welcome Dr. Paulo C. T. Souza (CNRS Lyon, France) in the first CMMS seminar of the summer semester 2023. In his talk entitled "On the road to biomolecular design with the Martini coarse-grained model" he provided an overview of the Martini 3 force field and showed its applications in drug design and drug delivery.

27.03.2023 — We cordially welcome David Grantz and Charlie Müller in the Thallmair Group! David does his PhD thesis in the lab of Ben Feringa and Wiktor Szymanski at the University of Groningen (The Netherlands). In the next two weeks he will work on docking of light-switchable antibiotics. Charlie studies Biophysis at the Goethe University Frankfurt. Duing his Bachelor thesis in the Thallmair Group, he will work on light-switchable lipids.

13.03.2023 — In the coming one and a half weeks, Sebastian will teach the lecture "Introduction to Biomolecular Simulations" together with Dr. Roberto Covino (FIAS) and Dr. Maziar Heidari (MPI for Biophysics) at Goethe University.

20.02.2023 — Our article describing the optimized Martini 2 cholesterol model entitled "Optimal Bond Constraint Topology for Molecular Dynamics Simulations of Cholesterol" appeared in the Journal of Chemical Theory and Computation. We also describe a program to diagnose problematic molecular force field topologies which lead to non-physical temperature gradients in molecular dynamics simulations. Thanks a lot for the great collaboration, Balázs Fábián and Gerhard Hummer!

02.02.2023 — We offer an interdisciplinary postdoc position to investigate membrane contact sites combining cryo-electron microscopy and molecular modelling. The position is in collaboration with the group of Florian Wilfling at the Max Planck Institute of Biophysics. You can find more details and a link to submit your application here.

30.01.2023 — Curious how to set up your Martini 3 protein model to study protein-ligand binding? We provide many details in our new book chapter entitled "Practical Introduction to Martini 3 and its Application to Protein-Ligand Binding Simulations". Congratulations Cristina and thanks to all co-authors!

01.01.2023 — The Thallmair Group wishes a Happy New Year and looks forward to great collaborations, exciting research results, and interesting conferences!

19.12.2022 — We are excited that our publication "Protein-ligand binding with the coarse-grained Martini model" is part of the collection "Molecular dynamics simulations and computational methods in life science" by Nature Communications.

16.12.2022 — Yesterday, the "2nd Molecular Modeling and Simulation Workshop" was hosted at FIAS in the framework of CMMS. In addition to the keynote lecture by Prof. Ahmad Reza Mehdipour, PhD students and postdocs of research groups in the Rhine-Main area presented their research. Cristina and Marieli presented their work as well.

14.11.2022 — Last week, Cristina and Sebastian spent three days at the "2nd Martini Developers Meeting" on Malta. They had an intense exchange with the core development groups about current and future developments of the coarse-grained Martini force field.

03.11.2022 — Welcome Marieli Goncalves Dias! Marieli is a PhD student at the University of Campinas and the Brazilian National Biosciences Laboratory in Campinas, Brazil. She will spend one year in the Thallmair group to perform molecular dynamics simulations of nuclear receptors.

20.10.2022 — We developed an optimal description of cholesterol in the coarse-grained Martini force field. This prevents artificial temperature gradients in simulations of biological membranes. Together with colleagues at the CMMS and the MPI for Biophysics, we summarized our results in a preprint.

04.10.2022 — Our publication about photoswitchable cross-linkers was highlighted in an article in ChemistryViews entitled "Light-Responsive Linkers for the Control of Biomolecules".

08.09.2022 — The Tubby protein plays an important role for cellular communication. In collaboration with scientists from Marburg and Groningen, we were able to identify a previously unknown, second binding site for the signalling lipid PI(4,5)P₂. It substantially increases the sensitivity of Tubby for the signalling lipid. You can find more details in this FIAS News article as well as in our Science Advances publication entitled "Two cooperative binding sites sensitize PI(4,5)P₂ recognition by the tubby domain".

03.09.2022 — Photoswitchable cross-linkers are able to bind to biomolecules at two positions. Then, they can modulate the function of the biomolecules by means of light. Together with researchers of the University of Groningen, we developed and characterized such cross-linkers with improved water solubility. The results are now published entitled "Photoswitchable, water-soluble bis-azobenzene cross-linkers with enhanced properties for biological applications" in the journal ChemPhotoChem.

24.06.2022 — Our article on the frequency of crashes in molecular dynamics simulations entitled "Small ionic radii limit time step in Martini 3 molecular dynamics simulations" is now published in The Journal of Chemical Physics. In collaboration with researchers in CMMS and the MPI for Biophysics we developed solutions to enable larger time steps in Martini 3 simulations and thus to increase their efficiency. Thanks a lot for the nice collaboration, Balázs Fábián and Gerhard Hummer!

09.05.2022 — Last week, Cristina gave a talk entitled "Coarse-grained modeling of salbutamol and salmeterol binding to β2-adrenergic receptor" in the PhD student edition of the BioExcel webinar series. In case you missed Cristina's talk, have a look at the recording available at the BioExcel website.

13.04.2022 — Too large time steps in molecular dynamics simulations result in regular crashes of a simulation. We developed a statistical model for the frequency of these crashes together with colleagues at the CMMS and the MPI for Biophysics. The model as well as an analysis of crashes in simulations with the coarse-grained force field Martini 3 are summarized in our preprint.

11.04.2022 — Glutathione is responsible for the cellular redox potential and involved in cellular signaling pathways. In collaboration with researchers from Switzerland, we developed and characterized a quantitative sensor for glutathione. We show in our preprint that the sensor can be used in whole cells as well as in specific organells to determine the amount of glutathione.

01.04.2022 — Cristina was awarded a poster prize at the virtual school "BioExcel School on Biomolecular Simulations" for her poster "Coarse-grained modeling of salbutamol and salmeterol binding to β2-adrenergic receptor"! Now, she will present her research results in a talk during a BioExcel webinar on May 3rd. Congratulations, Cristina!

01.04.2022 — In collaboration with researchers of the University of Groningen, we wrote a perspective article about catalysis-induced motion of enzymes and its potential impact on cellular metabolism. You can read more about it in our publication entitled "Perspective: A stirring role for metabolism in cells" published in Molecular Systems Biology.

08.03.2022 — The development of light-switchable drugs is particularly challenging, because it combines elements of medicinal chemistry and photochemistry. Together with researchers from the Netherlands and Germany, we show in our publication in the Journal of Medicinal Chemistry how computational methods successfully contributed to design light-switchable inhibitors for a bacterial enzyme.

03.01.2022 — At high-light conditions, photosynthetic organisms have to protect themselves against too much light energy. In collaboration with scientists from the Netherlands and Italy we discovered that the protein structure and lipid affinity changes during a known regulatory mechanism. You can read more about the NMR experiments and coarse-grained MD simulations in our recent publication in Biophysical Journal.

01.01.2022 — The Thallmair Group wishes a Happy New Year!

2021

16.12.2021 — Deep eutectic solvents are an environmentally friendly and cost-effective alternative to ionic liquids, which gain more and more importance in chemical industry. In collaboration with scientists from the University of Groningen and the CNRS in Lyon, we developed a model to simulate the properties of deep eutectic solvents. You can read more about it in our recent publication in ACS Sustainable Chemistry and Engineering.

15.10.2021 — ω-Transaminases catalyze the transformation of ketones to chiral amines. This renders them interesting for chemical industry for instance for the synthesis of pharmaceuticals. We present an efficient computational protocol to predict the enatioselectivity and catalytic selectivity of ω-transaminases in the Journal of Chemical Information and Modeling. We show its predictive power in comparison to 62 experimental data points for the ω-transaminase of Vibrio fluvialis.

07.09.2021 — The Martini Workshop marked the beginning of a month with multiple presentations about our research. Sebastian Thallmair will give an invited lecture at the CLiCConference. Moreover, he will present the research group at the PhD Days of the FIAS and give a talk at the virtual autumn meeting of the German Physical Society.

03.09.2021 — Today, the three-day online Martini Workshop ended successfully. It included tutorials, recorded lectures, as well as corresponding Q&A sessions which were provided live. Sebastian Thallmair presented the protein models in Martini 3 in an invited talk and supervised the protein tutorials. Cristina Gil Herrero participated at the workshop as well.

17.08.2021 — When simulating lipid bilayers with cholesterol, artificial temperature gradients can build up which impact membrane properties. Together with researchers at the Czech Academy of Sciences and the University of Groningen, we found out that this issue occurs in coarse-grained as well as atomistic simulations. In our recent publication in The Journal of Physical Chemistry B we discuss how these artifacts can be avoided.

16.08.2021 — Our protein engineering study of an ω-transaminase in collaboration with researchers at the University of Groningen is now published in ACS Catalysis. We used a computational design protocol to increase the substrate scope of the thermostable, synthetically attractive transaminase and verified the results experimentally.

02.08.2021 — Welcome Cristina Gil Herrero! Cristina, who did her Master studies in Theoretical Chemistry and Computational Modeling at the Autonomous University of Madrid, joins us for her PhD to work on protein-ligand interactions.

12.07.2021 — We happily welcome Timo Bachmann from the University of Vienna in the Thallmair Group! He will do a research internship in the framework of an Erasmus+ fellowship.

09.07.2021 — Today's online mini-symposium comprised contributions by the four CMMS junior groups as well as additional junior groups from the Rhein-Main area. The mini-symposium which was initiated by Roberto Covino and Sebastian Thallmair included seven exciting presentations in the field of modeling and computational biology.

16.06.2021 — An online Martini workshop will take place from 1-3 September 2021. The focus of the three-day workshop will be on the new version of the coarse-grained force field, Martini 3. There will be lectures by the key developers as well as supervised tutorial sessions. Sebastian Thallmair will present a lecture as well. More information and a link for registration are available here.

29.03.2021 — The eagarly awaited and completely reparametrized version of the coarse-grained force field Martini 3 is now published after countless iterations of optimizations. The publication entitled "Martini 3: A General Purpose Force Field for Coarse-Grained Molecular Dynamics" is published in Nature Methods. All details and the vast collection of test systems are discussed in the 116 (!) pages of supporting information. The force field parameters can be downloaded here.

18.03.2021 — Starting from sulfonamide inhibitors, we developed two light-switchable inhibitors in collaboration with researchers at the University of Groningen and the University Medical Center Groningen. You can read more about it in our publication "Biaryl Sulfonamides as cisoid Azosteres for Photopharmacology" published in Chemical Communications.

03.03.2021 — The Thallmair Group is one of the four young research groups established at the FIAS within the CMMS project in 2020. If you would like to know more about the four groups, please enjoy our short movie. It was prepared in the framework of the "Giersch - Summerschool & International Conference".

05.02.2021 — We offer a PhD position in "Microscopic Modeling of Protein-Drug Binding" and look forward to receiving your application before 28.02.2021. More information is provided in the job advertisement.

27.01.2021 — The editors of Nature Communications feature our article "Protein-ligand binding with the coarse-grained Martini model" in the Editor's Highlights on the topic "Structural biology, biochemistry and biophysics". Thanks and congratulations to all coauthors from Groningen, Lugano, Lyon and Chicago!

01.01.2021 — The Thallmair Group wishes a Happy New Year!

2020

10.12.2020 — It has been a while since Sebastian Thallmair worked experimentally in a chemistry lab. Some of his work on synthesis and characterization of Fe(II) spin-crossover complexes appeared now in the Journal of Inorganic and General Chemistry.