Biology subjects

Czaplicki, G.

Publications and source records attributed to Czaplicki, G..

3 recordsLinked to original sources

bioRxiv2024

Coarse-graining the recognition of a glycolipid by the C-type lectin Mincle receptor

Macrophage inducible Ca2+-dependent lectin (Mincle) receptor recognizes Mycobacterium tuberculosis glycolipids to trigger an immune response. This host membrane receptor is thus a key player in the modulation of the immune response to infection by M. tuberculosis, and has emerged as a promising target for the development of new vaccines for tuberculosis. The recent development of the Martini 3 force field for coarse-grained (CG) molecular modeling allow the study of interactions of soluble proteins with small ligands but its use for the study of interactions with lipids remains less explored. Here, we present a refined approach detailing a protocol for modeling such interactions at a CG level using the Martini 3 force field. Using this approach, we studied Mincle and identified critical parameters governing ligand recognition, such as loop flexibility and the regulation of hydrophobic groove formation by calcium ions. In addition, we assessed ligand affinity using free energy perturbation calculations. Our results offer mechanistic insight into the interactions between Mincle and glycolipids, providing a basis for rational design of molecules targeting this type of membrane receptors.

bioinformatics↗

bioRxiv2024

Glophyt: a user-friendly, general-purpose program for nonlinear and multidimensional curve fitting via a hybrid stochastic and deterministic approach

BackgroundModel validation depends on the agreement between the predicted and experimental data. However, finding solutions to problems, described by equations with many parameters, for which virtually nothing is known, is a difficult task. For example, the extraction of kinetic parameters from complex schemes representing the conversion of a substrate into a product by an enzyme in the presence of an inhibitor is extremely difficult, as even the orders of magnitude of the parameters are not known. This makes curve fitting very difficult in case of multidimensional and nonlinear data. This article presents a graphical user interface-based program employing a hybrid stochastic and deterministic approach, which allows for easy and reliable determination of model parameters. ResultsThe program has been extensively used in several laboratories at our institute and has proven to be efficient in determining model parameters in many different fields. Although its origins are related to kinetic studies in enzymology, it has been successfully tested on data from various sources, such as pharmacological studies of ligand-receptor binding, entomological studies of populations, bacterial growth, photosynthesis, toxicology, differential scanning calorimetry, isothermal titration calorimetry and nuclear magnetic resonance spectroscopy. ConclusionsThis program presents an effective solution for researchers facing the problem of extracting model parameters from multidimensional and nonlinear data where even the orders of magnitude of parameters are not known. Its graphical user interface makes it easy to use, does not require any programming skills, and it is cost-free. It is available for Windows and Linux platforms.

bioinformatics↗

bioRxiv2019

The conical shape of DIM lipids promotes Mycobacterium tuberculosis infection of macrophages

Phthiocerol dimycocerosate (DIM) is a major virulence factor of the pathogen Mycobacterium tuberculosis (Mtb). While this lipid promotes the entry of Mtb into macrophages, which occurs via phagocytosis, its molecular mechanism of action is unknown. Here, we combined biophysical, cell biology, and modelling approaches to reveal the molecular mechanism of DIM action on macrophage membranes leading to the first step of Mtb infection. MALDI-TOF mass spectrometry showed that DIM molecules are transferred from the Mtb envelope to macrophage membranes during infection. Multi-scale molecular modeling and 31P-NMR experiments revealed that DIM adopts a conical shape in membranes and aggregate in the stalks formed between two opposing lipid bilayers. Infection of macrophages pre-treated with lipids of various shapes uncovered a general role for conical lipids in promoting phagocytosis. Taken together, these results reveal how the molecular shape of a mycobacterial lipid can modulate the biological function of macrophages.

biophysics↗