Biological Molecular Dynamics Simulations 2.0

Molecular Dynamics (MD) simulations offer the opportunity to dynamically study complex biological and material processes at temporal and spatial resolutions beyond the scope of experimental methods. Among the biological processes, signalling pathways, enzyme regulation, protein folding and interactions, membrane composition, and transmembrane transport are of particular interest, as they are key to understanding the development, progression, and treatment of severe diseases such as cancer and neurodegenerative disorders. In our group, we are working on a wide range of corresponding research topics, including the simulation of receptor and ligands that are important for apoptosis and signalling processes, parametrization of force field parameters for post-translational modifications and metal organic frameworks, and the development of a machine learning framework for resolution transformation. Specific projects can be found here.


Research Highlights

Entropic barrier of water permeation through single-file channels

Splitting of Gibbs free energy of water permeation through single-file channels into its enthalpic and entropic contributions provides novel insight into the nature of the studied processes and may open new avenues for design of enthalpically vs entropically driven devices. In our recent paper, the combination of transition state theory with the transmission coefficient obtained from molecular dynamics and with high-resolution experimental measurements of water permeation through aquaporin-1 (AQP1) over a broad range of temperatures unravels that the total Gibbs free energy barrier of water permeation through AQP1 at 298K amounting 3.02 kcal/mol results mainly from the enthalpic barrier, being 3.16 kcal/mol. Despite orientational restriction of water molecules in the pore the barrier is slightly decreased by the entropy.

Water, shown as blue spheres, permeates membrane-embedded aquaporin-1, represented as white and purple cartoon.

Ninjurin-1 Protein - Charon of cell life

Cell death is an essential process in our body that prevents the development of tumors and the spread of pathogens in the body through the controlled elimination of damaged or infected cells. Contrary to popular belief that cells simply burst at the end of their lives, a specific protein called ninjurin-1 was recently discovered to serve as a predetermined breaking point for cell membrane rupture. Now, together with an international team of researchers from the University of Basel, the University of Lausanne, and ETH Zurich we have elucidated the exact mechanism of the final step of cell death at the atomic level. In the groundbreaking publication in the journal "Nature", we describe how ninjurin-1 assembles into filaments that rupture the plasma membrane by stabilizing membrane edges.

Not a scientist and nevertheless interested in this topic? Then check the Labour Journal Article written by Anna Sternberg summarizing our work. 

Ninjurin-1 proteins (green/yellow) assemble into filaments and rupture the cell membrane (gray) leading to complete disintegration of the cell envelope. Intracellular content is shown in blue.

Complex regulation of water permeability through an aquaglyceroporin

In our recent joint experimental (group of Andreas Horner, JKU Linz, Austria)/simulational publication we unravel that, contrary to the common notion that aquaporins posses constitutively open pores, multiple pore lining residues are responsible for modulation of water permeability through the aquaglyceroporin GlpF. The impact of each individual position was only able to be quantified using Bayesian generalized multilevel models in collaboration with Paul-Christian Bürkner (SC SimTech). Moreover, we have successfully designed and characterized mutants closing or opening the water pore.

Mysterious sorcery unmasked! How charged residues influence the membrane insertion of gasdermin-A3

In our publication in Frontiers in Cell and Developmental Biology we unveil the mystery behind the ability of gasdermin's spontaneous membrane insertion and thus the initiation of the gasdermin pore formation. Our atomistic MD simulations of monomeric gasdermin-A3 (GSDMA3) and small arcs inserted in an E. coli polar lipid extract membrane reveal the astounding effect that salt-bride formation and protein surroundings have on the energetics of GSDMA3's transmembrane passage. Furthermore, our simulations support the hypothesis of oligomers preassembling on the membrane surface prior to membrane insertion, though the oligomer can be significantly smaller than a full pre-pore rings.

The GSDMA3 monomer spontaneously slipping out of the E. coli membrane in the course of an atomistic MD simulation with uncharged E94, K97 and K100 (uuu state).

The hidden intricacies of aquaporins

Our recent publication in Small uncovers remarkable details and (dis)similarities in the common structural scaffold of aqua(glycero)porins. Thereby, MD simulations have bestowed the investigated X-ray structures the dynamics neccesarry for understanding of e.g. gating behavior by pore lining residues.

Cholesterol stabilizes GPCRs only at physiological temperature

Cholesterol is known to influence many functions in our bodies. Our recent publication in Science Signalling reveals by combination of atomic force microscopy with molecular dynamics simulations how cholesterol analog stabilizes a prominent G Protein-coupled receptor, β2-adrenergic receptor, specifically at body temperature of 37°C. The cover image depicts the receptor interacting with the cholesterol analog, shown as green surfaces, in liposomes at 37℃.


Proteolytic pore formation in lipid membranes by Gasdermin-A3

Gasdermins are main effectors of pyroptosis, an inflammatory form of cell death. In our recent publication, the combination of state-of-the-art atomic force microscopy and extensive multiscaling molecular dynamics simulations sheds light on (i) assembly of gasdermin-A3 oligomers on membrane surface, (ii) growth and reshaping of membrane-inserted gasdermin-A3 oligomers and (iii) pore formation by lipid unplugging. Related publication: Mari & Pluhackova et al. Nature Communications 2022

How YidC insertase facilitates membrane insertion

If you are interested in how our multiscaling molecular dynamics simulations revealed parts of the membrane insertase YidC responsible for membrane insertion of the protein Pf3 check our recent publication in Nature Communications. Our simulations complement a wealth of experimental investigations (performed at the ETH Zürich and at the University of Hohenheim) that altogether reveal that the initial contact between the insertase and the substrate is formed by the YidC's cytoplasmic α-helical hairpin domain. However, it is the interaction of the substrate with the hydrophilic groove of YidC which decides about the membrane insertion and its efficiency.

Pf3 extraction from YidC insertase


Process of substrate (orange and red spheres) being pulled out of the YidC (blue with the two helices at the sides of the hydrophilic groove in darker blue).

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