Laboratoire de Biochimie Théorique
Présentation
The Laboratory of Theoretical Biochemistry (LBT) is one of five laboratories within Institut de Biologie Physico-Chimique (IBPC) in Paris.
LBT belongs to the French national research agency CNRS through its Institute of Chemistry, and is associated with Paris Diderot University. The laboratory was created at IBPC in 1958 as Laboratoire de Biochimie Théorique. Our field is theoretical and computational biochemistry, at the interface between biology, chemistry, physics, and computing.
Our strategic objectives are twofold: invent simulation algorithms to reproduce and predict physical properties of biomolecules either in vitro or in the cell, and understand the molecular or conformational factors responsible for the biological functions of living systems, and diseases. The equilibrium between these two aspects is the key point of the laboratory policy.
LBT is organized as a team of independent researchers with complementary interests and domains of expertise, both in method development and in biophysical, biochemical, and biomedical applications. Advances in each of these domains emerge from the association of different sets of researchers around individual projects.
Thèmes de recherche
Les axes de recherches du LBT se concentrent sur les développements méthodologiques et algorithmiques pour l’étude de la structure, la dynamique, la mécanique et les interactions des macromolécules biologiques.
Les objectifs sont donc d'utiliser les ordinateurs pour ouvrir des fenêtres vers le monde moléculaire, en aidant à comprendre les facteurs qui sous-tendent des faits expérimentaux, et en prédisant les propriétés et le comportement des molécules biologiques.
Equipes de recherche
Directeur : Marc Baaden
[hal-04112694] It takes tau to tango: investigating the fuzzy interaction between the tau-R2 repeat and tubulin C-terminal tails
Date: 1 Jun 2023 - 00:10
Desc: Fuzzy complexes are a relatively new type of protein interaction involving one or more intrinsically disordered elements which proved more and more biologically important in the past two decades [2]. Intrinsically disordered protein Tau is known to stabilize microtubules (MT), but little is known regarding its interaction with the intrinsically disordered C-terminal tails (CTTs) of tubulins [3]. We used all-atom molecular dynamics simulations to decipher the behavior of the R2 repeat domain of the Tau protein in complex with 3 tubulin monomers β-α-β. We built the C-terminal tails corresponding to isotypes βI-αI-βI and βIII-αI-βIII by homology. Our analysis confirmed the existence of a highly stable interface area involving Ser289, a serine notably phosphorylated in Alzheimer’s disease [4], and revealed a modification of the dynamics of CTTs in presence of R2. The latter result gives more weight to Lessard and Berger’s idea that interactions between kinesins and MT could be indirectly mediated by the presence of Tau [5]. We also propose a “wrapping mechanism” of the CTTs around R2 which might provide more insight regarding the stabilizing impact of CTTs in Tau/MT complexes observed by Hinrichs et al [3]. References 1 Marien J, Prévost C, and Sacquin-Mora S (2023) It takes Tau to tango : Investigating the fuzzy interaction between the Tau-R2 repeat domain and the C-terminal tails of tubulins, bioRxiv 2023.02.09.527845; doi: https://doi.org/10.1101/2023.02.09.527845 2 Sacquin-Mora S, Prévost C. When Order Meets Disorder: Modeling and Function of the Protein Interface in Fuzzy Complexes. Biomolecules. 2021 Oct 16;11(10):1529. doi: 10.3390/biom11101529. PMID: 34680162; PMCID: PMC8533853. 3 Hinrichs, M. H., Jalal, A., Brenner, B., Mandelkow, E., Kumar, S., and Scholz, T. (2012) Tau protein diffuses along the microtubule lattice, The Journal of biological chemistry 287, 38559-38568, doi: 10.1074/jbc.M112.369785 4 Drummond E, Pires G, MacMurray C, Askenazi M, Nayak S, Bourdon M, Safar J, Ueberheide B, and Wisniewski T. (2020) Phosphorylated tau interactome in the human Alzheimer's disease brain. Brain. 2020 Sep 1;143(9):2803-2817. doi: 10.1093/brain/awaa223. PMID: 32812023; PMCID: PMC7526722. 5 Lessard, D., and Berger, C. (2021) The Microtubule Associated Protein Tau Regulates KIF1A Pausing Behavior and Motility, bioRxiv, 2021.2008.2011.455914 ,doi: https://doi.org/10.1101/2021.08.11.455914
[hal-04177051] It Takes Tau to Tango: Investigating the Fuzzy Interaction between the R2-Repeat Domain and Tubulin C-Terminal Tails
Date: 3 Ago 2023 - 20:55
Desc: The microtubule-associated protein (MAP) tau plays a key role in the regulation of microtubule assembly and spatial organization. Tau hyperphosphorylation affects its binding on the tubulin surface and has been shown to be involved in several pathologies such as Alzheimer’s disease. As the tau binding site on the microtubule lays close to the disordered and highly flexible tubulin C-terminal tails (CTTs), these are likely to impact the tau-tubulin interaction. Since the disordered tubulin CTTs are missing from the available experimental structures, we used homology modeling to build two complete models of tubulin heterotrimers with different isotypes for the β-tubulin subunit (βI/αI/βI and βIII/αI/βIII). We then performed long timescale classical Molecular Dynamics simulations for the tau-R2/tubulin assembly (in systems with and without CTTs) and analyzed the resulting trajectories to obtain a detailed view of the protein interface in the complex and the impact of the CTTs on the stability of this assembly. Additional analyses of the CTT mobility in the presence, or in the absence, of tau also highlight how tau might modulate the CTT activity as hooks that are involved in the recruitment of several MAPs. In particular, we observe a wrapping phenomenon, where the β-tubulin CTTs form a loop over tau-R2, thus stabilizing its interaction with the tubulin surface and simultaneously reducing the CTT availability for interactions with other MAPs.
[hal-01400465] Visualization of Biomolecular Structures: State of the Art Revisited
Date: 13 Ene 2023 - 14:05
Desc: Structural properties of molecules are of primary concern in many fields. This report provides a comprehensive overview on techniques that have been developed in the fields of molecular graphics and visualization with a focus on applications in structural biology. The field heavily relies on computerized geometric and visual representations of three-dimensional, complex, large and time-varying molecular structures. The report presents a taxonomy that demonstrates which areas of molecular visualization have already been extensively investigated and where the field is currently heading. It discusses visualizations for molecular structures, strategies for efficient display regarding image quality and frame rate, covers different aspects of level of detail and reviews visualizations illustrating the dynamic aspects of molecular simulation data. The survey concludes with an outlook on promising and important research topics to foster further success in the development of tools that help to reveal molecular secrets.
[inserm-02438969] An inter‐dimer allosteric switch controls NMDA receptor activity
Date: 14 Ene 2020 - 14:09
Desc: NMDA receptors (NMDARs) are glutamate-gated ion channels that are key mediators of excitatory neurotransmission and synaptic plasticity throughout the central nervous system. They form massive heterotetrameric complexes endowed with unique allosteric capacity provided by eight extracellular clamshell-like domains arranged as two superimposed layers. Despite an increasing number of full-length NMDAR structures, how these domains cooperate in an intact receptor to control its activity remains poorly understood. Here, combining single-molecule and macroscopic electrophysiological recordings, cysteine biochemistry, and in silico analysis, we identify a rolling motion at a yet unexplored interface between the two constitute dimers in the agonist-binding domain (ABD) layer as a key structural determinant in NMDAR activation and allosteric modulation. This rotation acts as a gating switch that tunes channel opening depending on the conformation of the membrane-distal N-terminal domain (NTD) layer. Remarkably, receptors locked in a rolled state display "super-activity" and resistance to NTD-mediated allosteric modulators. Our work unveils how NMDAR domains move in a concerted manner to transduce long-range conformational changes between layers and command receptor channel activity.
[hal-02345061] Design Games and Game Design: Relations Between Design, Codesign and Serious Games in Adult Education
Date: 4 Nov 2019 - 13:36
Desc: This chapter defines, explores and illustrates the terms "design", "design games", "game design", "codesign", "games", "serious games" and "gamification". It explores links between design and serious play. The chapter also identifies the different approaches people know about in order to design a serious game, illustrates it with examples and checks on a case-by-case basis whether the deep mises en abymes currently associated with the design game can also be found in the cases presented. The DICE model allows us to identify an iterative approach that leads to the creation of serious games, some of which may target the adult education market. In a design game approach, the idea is to gamify the design process. The chapter shows that the gaming experience depends largely on the player. Playing on the context to modify the game experience can be an approach used to influence the user experience around a design game.
Autres contacts
Institut de Biologie Physico-Chimique (IBPC)
13, rue Pierre et Marie Curie
75252 PARIS CEDEX 05
