Les récepteurs pentamériques canaux (pLGICs) sont des récepteurs neuronaux impliqués dans la neurotransmission rapide et qui comprennent les récepteurs suivants : nAchR, GABAR, GlyR or 5HT3R. Lorsqu’ils ne fonctionnent pas correctement ils sont impliqués dans des pathologies comme Alzheimer ou Parkinson. Dans cette étude, nous avons réalisé des simulations de dynamique moléculaire d’un homologue procaryote des pLGICs. Grâce à l’analyse de 2.5 us de simulation nous avons pu capturer la fermeture complète dudit récepteur et décrire un mécanisme de gating. Ce mécanisme en deux étapes, 1) twisting puis 2) blooming semble compatible avec tous les pLGICs. Dans un second temps, nous avons utilisé notre connaissance du mécanisme de gating afin de faire des calculs d’énergie libre le long du twisting, pour différents complexes protéine/ligands. De cette façon, nous avons pu discriminer entre des ligands actifs et inactifs et ainsi fournir des pistes pour le design de nouveaux traitements. / Pentameric ligand gated ion channels (pLGICs) are brain receptors involved in fast neurotransmission and include nAchR, GABAR, GlyR or 5HT3R. When dysfunctioning, they are involved in diseases such as Alzheimer’s and Parkinson’s. In this study we have performed molecular dynamic simulations of an eukaryotic homologue of the pLGICs (GluCl) to understand the gating mechanism of pLGICs. Thanks to the analysis of two 2.5 us long simulations in which we could capture the full closing of the receptor we described in great details a gating mechanism in two steps, first twisting then blooming, that we believe applicable to the whole pLGICs family. In a second time we used our description of the gating mechanism to perform free energy calculations along the twisting reaction coordinate, for various ligands in complex with GluCl. Doing so we could show a significant difference between IVM-bound and non-bound states and provide hints for the design of new treatments.

Lateral diffusion of membrane components (lipids and proteins) is an important membrane property to measure since the essential process of absorption of anti-cancer and other drugs -some of which are not soluble in lipids and therefore would not be able to penetrate the cell membrane through passive diffusion- lies on it. In particular, the procedure of diffusion into the cell cytoplasm is reliant on free volumes in the membrane (passive diffusion) as well as carrier proteins (facilitated diffusion). By enhancing the mobility of lipids and/or proteins, the possibility of the carrier protein to "encapsulate" pharmacological components maxim- izes, as a "scanning" of the proteins gets performed due to the fluid phase of a biological membrane. At the same time, the increased mobility of the lipids facilitates the passage of lipid-soluble molecules into the cell. Thus, given that the success of anticancer treatments heavily depends on their absorption by the cell, a significant enhancement of the cell mem- brane permeability (permeabilisation) is rendered vital to the applicability of the technique. For this reason, there is augmented interest in combined methods such as Nanotechnology based drug delivery that is focused on the development of optimally designed therapeutic agents along with the application of shock waves to enhance the membrane permeability to the agents. This study examines the impact of shock waves on a numerical model of a biological membrane. Cont/d.

Lateral diffusion of membrane components (lipids and proteins) is an important membrane property to measure since the essential process of absorption of anti-cancer and other drugs -some of which are not soluble in lipids and therefore would not be able to penetrate the cell membrane through passive diffusion- lies on it. In particular, the procedure of diffusion into the cell cytoplasm is reliant on free volumes in the membrane (passive diffusion) as well as carrier proteins (facilitated diffusion). By enhancing the mobility of lipids and/or proteins, the possibility of the carrier protein to "encapsulate" pharmacological components maxim- izes, as a "scanning" of the proteins gets performed due to the fluid phase of a biological membrane. At the same time, the increased mobility of the lipids facilitates the passage of lipid-soluble molecules into the cell. Thus, given that the success of anticancer treatments heavily depends on their absorption by the cell, a significant enhancement of the cell mem- brane permeability (permeabilisation) is rendered vital to the applicability of the technique. For this reason, there is augmented interest in combined methods such as Nanotechnology based drug delivery that is focused on the development of optimally designed therapeutic agents along with the application of shock waves to enhance the membrane permeability to the agents. This study examines the impact of shock waves on a numerical model of a biological membrane. Cont/d.

One focus goal that science always works towards is an understanding of biological structures, with proteins being one of the main research goals. Sequencing proteins is currently a time-exhausting task, so focus is being put on trying to use nanopores in a similar way as in DNA sequencing for proteins. In this report, the neighbouring amino acids in the same peptide as the amino acid being sequenced are varied and the change in ionic current from the pore based on the neighbouring amino acids is analysed. This was done by using Molecular Dynamics program NAMD. A peptide was placed in the center of different silicon nitride pore structures inside a water box with ions and was simulated with an added electric field. The drop in current was checked for 4 different peptide systems and one check for the empty pores. The results presented in the report show that changing the neighbouring amino acids increases the current measured, therefore making the current blocking worse when mixing nearby amino acids. However, the differences are very small and similar amino acids give wildly different values. A larger evaluation with more computational power seems reasonable for a more definitive result.