Josef Melcr | Thinker, writer, scientist. Husband and dad.

Projects

Current projects

  • Protyon — startup in health tech. By leveraging the latest scientific advances in computational molecular modeling we are embarking on a mission to introduce personalized precision medicine to clinical practice. That is the reason why we started Protyon. 🚀 And as it goes with startups, we are building our spaceship at the same time as we fly it. To boldly go where no man has gone before!

  • Antimicrobial peptides against drug-resistant bacterial strains. Microscopy techniques are powerful and images are usually easy to interpret, but lack the molecular detail – and that is where Molecular Dynamics (MD) simulations come in! We are working together with research teams from the Netherlands and Norway to discover how recently developed antimicrobial agents selectively destroy the methicilin-resistant strains of Staphylococus Aureus. The molecular details from my MD simulations bring a few surprises … and more is coming soon in an close-to-finished manuscript … but you can take a sneak peek into the research already now by watching the pitch of the leading researcher on YouTube! (I was behind the camera and did the cut this time.)

Finished projects

  • Permeability of biological membranes: accurate exerimental measurements of small solutes permeability gets explained by my Molecular Dynamics (MD) simulations in the context of the yeast plasma membrane and its very special properties. From our systematic analysis we conclude two important new discoveries; the yeast plasma membrane is in a highly rigid physical state comparable to model membranes of saturated lipids with approximately 15% ergosterol. Ergosterol, the main sterol in yeast membranes, changes the membrane properties including the permeability coefficient smoothly, allowing it to act as a membrane rigidity regulator in yeast—but cholesterol cannot do that in such a rigid regime. Now published in Nature Communications, DOI: 10.1038/s41467-022-29272-x.

  • International conference on the bioscience of lipids ICBL2021. I am involved in organizing this event and in the design of its visual identity and ICBL2021 logo. Take a look here: icbl2021.nl — how do you like the flipping gif?

  • MeMBrane project: Enhancing industrial bioprocesses in yeast and bacteria via membrane optimization MeMBrane project aims at improving and creating possible new industries using cell factories and biomass. As the in silico “dry lab” members of the project, we use MD simulation experiments in collaboration with expert in vitro and in vivo research teams, to describe and understand the perturbing effects of ethanol on the cell membranes, yeast membranes especially, driving the strain development in the best possible direction. We have developed improved strains through laboratory evolution, and now we are working on a manuscript summarizing the surprising findings that ethanol does not only affect the membrane thickness or elasticity, but also its phase behaviour – a very important feature for the yeast plasma membrane, which contains several coexisting phases at normal conditions! (ref e.g. 📚JBC2010)

  • Martini 3: Development of the new Martini 3 lipids. I am coordinating an international group of researchers to develp the next generation of the highly popular Martini Coarse-grained model for lipids, which has reached an important new milestone — Martini 3! Using 🦊GitLab as our workhorse for communication and staying in sync, we build a community of experts from diverse fields across the globe to make the best possible models of our precious chemicals, lipids!

  • Mechanism of protein channels and transporters - GlTk. GlTk is a trimeric membrane protein, which is involved in glutamate and aspartate uptake. We use cutting-edge polarizable force fields and Markov state modeling to follow the pathways of the sodium cations to and from their active sites in the GlTk protein complex. We have discovered several crucial amino acid residues that interact with the cations and modulate the whole process.

  • Mechanism of protein channels and transporters - CorA. Many cells maintain their divalent cations homeostasis by employing membrane proteins from the CorA family. We use atomistic and coarse-grained Molecular Dynamics (MD) simulations to describe the mechanistic behaviour of these proteins. Only CG Martini combined with GO-like potentials was capable of capturing the complicated large-scaled chaotic motions of CorA protein complex—see for yourselves in JCIM 2021!.

  • Determination of protein sctructure with optical polarization microscopy Polarization microscopy allows sensitive observations of changes in protein conformation in living cells and organisms (ref.). For fluorescent proteins with a resolved structure, it is possible to link the polarization microscopy measurements and transition dipole moment orientations to protein strucutre (press release, 📚PNAS2020). In this project, I have used quantum mechanical calculations of absorption properties and molecular dynamics simulations to help determine the orientations of membrane-attached fluorescent proteins
    and to independently verify the results from software analysis of optical microscopy images. This work is now published in Communications Biology 2021; 📚 Quantitative Linear Dichroism Imaging of Molecular Processes in Living Cells Made Simple by Open Software Tools.
    This project is run in a close collaboration with the group of Josef Lazar.

  • ECC-lipids - implicitly polarizable lipid models showing accurate interactions with ionic molecules ECC-lipids is the first MD model to implicitly account for polarizability in molecules. Will it launch a new “polarizable” era of MD modeling? Current development of ECC-lipids is held in the GitHub repository ecc_lipids with a separate web page with documentation.

  • Transmembrane potential modeling in molecular simulation All eukaryotic cells maintain a nonzero transmembrane potential across their plasma membranes. It is a crucial feature for many kinds of our organs, e.g. brain, heart, pancreas. In this project, I assay current approaches for the modeling of transmembrane potential in molecular simulation and describe the electrical processes at biomembranes at a molecular resolution. Published in Journal of Chemical Theory and Computation, 12 (5), 2016. DOI: 10.1021/acs.jctc.5b01202.

  • Development of membrane-bound probes of cellular functions We use molecular dynamics (MD) simulations to rationally develop probes of cellular functions, especially neural activity. Such probes are intended to work with accurate polarization microscopy measurements, which can detect their structural changes. Development of fluorescent molecular probes of cell membrane voltage promises to deliver the ability of observing the electrical activity of neuronal assemblies using an optical microscope. This project is run in a close collaboration with the group of Josef Lazar.

  • Development of classical force field parameters for organometallic compounds compatible with Amber force field.

  • Enzymatic activity of EF-Tu, a protein factor that takes part in the process of translation on the Ribozome.