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-01935588] The major β-catenin/E-cadherin junctional binding site is a primary molecular mechano-transductor of differentiation in vivo
Date: 20 déc 2022 - 22:56
Desc: In vivo, the primary molecular mechanotransductive events mechanically initiating cell differentiation remain unknown. Here we find the molecular stretching of the highly conserved Y654-β-catenin-D665-E-cadherin binding site as mechanically induced by tissue strain. It triggers the increase of accessibility of the Y654 site, target of the Src42A kinase phosphorylation leading to irreversible unbinding. Molecular dynamics simulations of the β-catenin/E-cadherin complex under a force mimicking a 6 pN physiological mechanical strain predict a local 45% stretching between the two α-helices linked by the site and a 15% increase in accessibility of the phosphorylation site. Both are quantitatively observed using FRET lifetime imaging and non-phospho Y654 specific antibody labelling, in response to the mechanical strains developed by endogenous and magnetically mimicked early mesoderm invagination of gastrulating Drosophila embryos. This is followed by the predicted release of 16% of β-catenin from junctions, observed in FRAP, which initiates the mechanical activation of the β-catenin pathway process.
[hal-04245366] Optimizing the Design of Oligonucleotides for Homology Directed Gene Targeting
Date: 17 oct 2023 - 10:26
Desc: Background: Gene targeting depends on the ability of cells to use homologous recombination to integrate exogenous DNA into their own genome. A robust mechanistic model of homologous recombination is necessary to fully exploit gene targeting for therapeutic benefit. Methodology/Principal Findings: In this work, our recently developed numerical simulation model for homology search is employed to develop rules for the design of oligonucleotides used in gene targeting. A Metropolis Monte-Carlo algorithm is used to predict the pairing dynamics of an oligonucleotide with the target double-stranded DNA. The model calculates the base-alignment between a long, target double-stranded DNA and a probe nucleoprotein filament comprised of homologous recombination proteins (Rad51 or RecA) polymerized on a single strand DNA. In this study, we considered different sizes of oligonucleotides containing 1 or 3 base heterologies with the target; different positions on the probe were tested to investigate the effect of the mismatch position on the pairing dynamics and stability. We show that the optimal design is a compromise between the mean time to reach a perfect alignment between the two molecules and the stability of the complex. Conclusion and Significance: A single heterology can be placed anywhere without significantly affecting the stability of the triplex. In the case of three consecutive heterologies, our modeling recommends using long oligonucleotides (at least 35 bases) in which the heterologous sequences are positioned at an intermediate position. Oligonucleotides should not contain more than 10% consecutive heterologies to guarantee a stable pairing with the target dsDNA. Theoretical modeling cannot replace experiments, but we believe that our model can considerably accelerate optimization of oligonucleotides for gene therapy by predicting their pairing dynamics with the target dsDNA.
[hal-01498000] Water Determines the Structure and Dynamics of Proteins
Date: 29 Mar 2017 - 17:03
Desc: Water is an essential participant in the stability, structure, dynamics, and function of proteins and other biomolecules. Thermodynamically, changes in the aqueous environment affect the stability of biomolecules. Structurally, water participates chemically in the catalytic function of proteins and nucleic acids and physically in the collapse of the protein chain during folding through hydrophobic collapse and mediates binding through the hydrogen bond in complex formation. Water is a partner that slaves the dynamics of proteins, and water interaction with proteins affect their dynamics. Here we provide a review of the experimental and computational advances over the past decade in understanding the role of water in the dynamics, structure, and function of proteins. We focus on the combination of X-ray and neutron crystallography, NMR, terahertz spectroscopy, mass spectroscopy, thermodynamics, and computer simulations to reveal how water assist proteins in their function. The recent advances in computer simulations and the enhanced sensitivity of experimental tools promise major advances in the understanding of protein dynamics, and water surely will be a protagonist.
[hal-00880345] Blind prediction of interfacial water positions in CAPRI
Date: 5 nov 2013 - 19:21
Desc: We report the first assessment of blind predictions of water positions at protein-protein interfaces, performed as part of the critical assessment of predicted interactions (CAPRI) community-wide experiment. Groups submitting docking predictions for the complex of the DNase domain of colicin E2 and Im2 immunity protein (CAPRI Target 47), were invited to predict the positions of interfacial water molecules using the method of their choice. The predictions-20 groups submitted a total of 195 models-were assessed by measuring the recall fraction of water-mediated protein contacts. Of the 176 high- or medium-quality docking models-a very good docking performance per se-only 44% had a recall fraction above 0.3, and a mere 6% above 0.5. The actual water positions were in general predicted to an accuracy level no better than 1.5 Å, and even in good models about half of the contacts represented false positives. This notwithstanding, three hotspot interface water positions were quite well predicted, and so was one of the water positions that is believed to stabilize the loop that confers specificity in these complexes. Overall the best interface water predictions was achieved by groups that also produced high-quality docking models, indicating that accurate modelling of the protein portion is a determinant factor. The use of established molecular mechanics force fields, coupled to sampling and optimization procedures also seemed to confer an advantage. Insights gained from this analysis should help improve the prediction of protein-water interactions and their role in stabilizing protein complexes.
[hal-01084644] Game on, science - how video game technology may help biologists tackle visualization challenges.
Date: 19 nov 2014 - 16:56
Desc: The video games industry develops ever more advanced technologies to improve rendering, image quality, ergonomics and user experience of their creations providing very simple to use tools to design new games. In the molecular sciences, only a small number of experts with specialized know-how are able to design interactive visualization applications, typically static computer programs that cannot easily be modified. Are there lessons to be learned from video games? Could their technology help us explore new molecular graphics ideas and render graphics developments accessible to non-specialists? This approach points to an extension of open computer programs, not only providing access to the source code, but also delivering an easily modifiable and extensible scientific research tool. In this work, we will explore these questions using the Unity3D game engine to develop and prototype a biological network and molecular visualization application for subsequent use in research or education. We have compared several routines to represent spheres and links between them, using either built-in Unity3D features or our own implementation. These developments resulted in a stand-alone viewer capable of displaying molecular structures, surfaces, animated electrostatic field lines and biological networks with powerful, artistic and illustrative rendering methods. We consider this work as a proof of principle demonstrating that the functionalities of classical viewers and more advanced novel features could be implemented in substantially less time and with less development effort. Our prototype is easily modifiable and extensible and may serve others as starting point and platform for their developments. A webserver example, standalone versions for MacOS X, Linux and Windows, source code, screen shots, videos and documentation are available at the address: http://unitymol.sourceforge.net/.
Autres contacts
Institut de Biologie Physico-Chimique (IBPC)
13, rue Pierre et Marie Curie
75252 PARIS CEDEX 05