Date: 23 September 2025
Time: 15:00 CET
This special edition of the BioExcel webinar series features student speakers who were awarded poster prizes at the BioExcel Summer School 2025. Read along to find out more about our speakers and their research.
Jan van Elteren
Jan is a first year PhD student at the National Institute of Chemistry and the Faculty of Pharmacy in Ljubljana, Slovenia. His academic journey began at the Faculty of Chemistry and Chemical Technology in Ljubljana, where he did a bachelor’s in analytical chemistry. After realizing the wet lab was something he rather disliked, he decided to pursue a double master’s degree in chemistry and chemoinformatics from the Universities of Ljubljana and Strasbourg, respectively. He first encountered biomolecular simulations while doing an internship at the Laboratoire d’Ingénierie des Fonctions Moléculaires in Strasbourg, where his Master’s project was focused on improving the efficiency of conformational space sampling of a large biological system for subsequent Markov state model construction. His current project revolves around type IIA topoisomerases, with a primary interest on molecular modelling and a secondary interest in drug discovery leading to novel anticancer drugs.
Title: Investigating catalytic inhibition of full-length topoisomerase IIA through all-atom molecular simulations
Type IIA topoisomerases (topo IIs) are complex molecular motors that alter the topological state of DNA. Their mechanism follows a complex catalytic cycle in which three gates open and close sequentially, enabling controlled passage of an intact DNA strand (T-segment) through a transiently cleaved one (G-segment). As they are crucial in maintaining genomic stability, they are broadly used as anticancer targets. Two mechanistically different classes of inhibitors are being investigated – topo II poisons and catalytic inhibitors. Topo II poisons trap the enzyme in a DNA-cleaved state, leading to cell death but also posing a risk of secondary cancers due to the accumulation of DNA double-strand breaks. To reduce the risk, catalytic inhibitors are being developed that inhibit the enzyme without causing DNA damage.
Using all-atom molecular dynamics simulations, we investigated how two ATP-competitive catalytic inhibitors affect the overall dynamics of the full-length topo IIA. We compared the dynamics of catalytic inhibitor-bound complexes with native ATP-bound counterparts to identify key effects of ligand binding. Our simulations showed that catalytic inhibitors stabilize the closed conformation of the N-gate, clamping the T-segment and preventing its progression through the cleaved G-segment. Further differences were observed in interdomain tilting and twisting angles, average anti-correlations as well as hydrogen-bond patterns at the protein-DNA interface. These findings deepen the mechanistic understanding of the ATP-competitive catalytic inhibition of topo IIA and offer valuable guidelines for the rational design of next-generation catalytic inhibitors.
Gesa Freimann
Gesa Freimann is a first-year PhD student in the Protein Evolution Department, led by Prof. Andrei Lupas, at the Max Planck Institute for Biology in Tübingen, Germany. Her research explores protein function by examining atomistic-level dynamics, with a focus on signal transduction proteins.
Driven by the question, “What makes us alive on the molecular level?” Gesa began her academic journey with a Bachelor’s degree in molecular biology, studying virus maturation using light and electron microscopy. She then pursued a Master’s degree in biophysics, investigating the dynamics of myosin molecules in vivo using single-molecule tracking and light sheet microscopy. Her growing interest in computational methods then led her to pursue a second Master’s degree in bioinformatics, during which she developed a machine learning tool to detect protein communities in interaction networks.
Having touched and begun to love the beautiful world of proteins, Gesa chose to pursue a PhD in protein sciences. Early in her PhD, she realized that for many proteins, both their function and their underlying molecular mechanisms are largely unknown. Although advances like AlphaFold have improved structure prediction, static structures alone often cannot explain how proteins work. It is the dynamic behavior of proteins that underpins their function. This understanding shapes her current research, which aims to uncover protein function by studying their dynamics.
Outside of work, she enjoys cooperative board games, Hatha yoga, and participating in science communication events, such as the Soapbox Science event in Tübingen this year.
Bluesky: @gfreimann.bsky.social
LinkedIn: @gesa-laura-freimann
Title: Molecular Dynamics Simulations of Af1503 – A Model Protein for Transmembrane Signaling
Two-component signal transduction (TCST) receptors transmit information on small-molecule binding from extracellular sensory to intracellular effector domains along a transmembrane, four-helical coiled-coil backbone. Despite extensive research, the conformational changes underlying this process remain a matter of debate. Due to the difficulty of obtaining full-length experimental structures, previous studies have relied on receptor fragments or mutants, resulting in multiple, often conflicting, models of signal transduction—including vertical helix displacement (‘piston’), a scissor or see-saw motion of the transmembrane helices, and rotational motions in the plane of the membrane. In fact, no one has yet observed a complete receptor in action. Recently, Andrei Lupas and colleaques resolved the first full-length structure of a TCST receptor, Af1503 from Archaeoglobus fulgidus, identified palmitic acid as its ligand, and established it as a model protein for TCST research. This development, together with recent advances in computational power, now enables detailed investigations of transmembrane signal transduction using unbiased all-atom molecular dynamics (MD) simulations. Here, I present MD simulation results based on the experimentally determined Af1503 structure. Our analyses include simulations of the HAMP domain, the cytosolic coiled-coil region, and the complete receptor upon ligand binding. I discuss the structural dynamics revealed by these simulations and their implications for mechanistic models of TCST signaling.
Zuzana Janáčková
Zuzana Janáčková is currently working on her PhD at the Institute of Organic Chemistry and Biochemistry in Prague, Czech Republic. With a background in biochemistry and structural biology, she has transitioned to computational modeling of biological systems. Her research focuses on the interaction between lipid membranes and oligoarginine peptides, with an emphasis on uncovering their passive penetration mechanisms. She combines her biological expertise with enhanced molecular dynamics simulations to investigate these complex processes.
LinkedIn: @zuzana-janackova, @iocb-prague
Title: Oligoarginine peptides bind preferentially to concave phospholipid membranes and induce membrane multilamellarity
Oligoarginine peptides are potent cell-penetrating agents, yet the molecular mechanisms underlying their passive membrane translocation remain poorly understood. Using a combination of atomistic molecular dynamics simulations, enhanced sampling techniques, and cryo-electron microscopy, we investigate how membrane curvature and multilamellarity influence peptide–membrane interactions. Our simulations reveal that for R9 oligoarginine peptides the binding is significantly enhanced by negative membrane curvature. The increased affinity to concave surfaces likely arises from both geometric enclosure and a higher local density of accessible lipid headgroups. Furthermore, in the double-membrane systems, R9 peptides effectively bridge adjacent membranes and drive their spontaneous “zipping,” which is consistent with the multilamellarity observed in the cryo-EM experiments. These results provide direct atomistic evidence supporting experimental observations and highlight membrane curvature and multilamellarity as key contributors to the passive translocation mechanism of oligoarginine peptides.
