De l'unité d'assemblage à la capside : application in silico au norovirus et au virus de l'hépatite B

Viruses are characterized by a shell that protects and transports viral information. This shell is composed of several copies of proteins capable of self-assembling, around or independently of the viral information. During the life of a virus, proteins involved in this assembly have multiple roles. In addition to transport and protection, they can regulate or hijack the cellular machinery of the infected host. They can also serve as decoys against the organism's immune defenses. In this thesis, using computational methods on supercomputers, the mechanisms of assembly and interaction of these proteins are studied. This work allows to have a better idea of the assembly of the empty shell of the human gastroenteritis virus. For hepatitis B virus (HBV), these studies show the binding of zinc ions by the HBV shell protein. Zinc may play an essential role in the interaction with genetic material. This work also helps to understand how this protein transports viral information to the nucleus of liver cells.Les virus comportent une coque permettant de protéger et de transporter l’information virale. Cette coque est composée de plusieurs copies de protéines capables de s’assembler d’elles-mêmes, autour ou indépendamment de l’information virale. Au cours de la vie d’un virus, les protéines impliquées dans l’assemblage sont dotées de multiples rôles. En plus du transport et de la protection, elles peuvent réguler ou détourner la machinerie cellulaire de l’hôte infecté. Elles peuvent aussi servir de leurre face aux défenses immunitaires de l’organisme. Dans cette thèse, à l’aide de méthodes calculatoires sur des superordinateurs, les mécanismes d’assemblage et d’interaction de ces protéines sont étudiés. Ces travaux permettent d’avoir une meilleure idée de l’assemblage de la coque vide du virus de la gastroentérite de l’Homme. En ce qui concerne le virus de l’hépatite B (VHB), ces études mettent en évidence la fixation d’ions zinc par la protéine de coque du VHB. Le zinc pourrait jouer un rôle essentiel dans l’interaction avec le matériel génétique. Ces travaux aident aussi à comprendre comment cette protéine transporte l’information virale vers le noyau des cellules du foie

From assembly unit to capsid : in silico application to norovirus and hepatitis B virus

Les virus comportent une coque permettant de protéger et de transporter l’information virale. Cette coque est composée de plusieurs copies de protéines capables de s’assembler d’elles-mêmes, autour ou indépendamment de l’information virale. Au cours de la vie d’un virus, les protéines impliquées dans l’assemblage sont dotées de multiples rôles. En plus du transport et de la protection, elles peuvent réguler ou détourner la machinerie cellulaire de l’hôte infecté. Elles peuvent aussi servir de leurre face aux défenses immunitaires de l’organisme. Dans cette thèse, à l’aide de méthodes calculatoires sur des superordinateurs, les mécanismes d’assemblage et d’interaction de ces protéines sont étudiés. Ces travaux permettent d’avoir une meilleure idée de l’assemblage de la coque vide du virus de la gastroentérite de l’Homme. En ce qui concerne le virus de l’hépatite B (VHB), ces études mettent en évidence la fixation d’ions zinc par la protéine de coque du VHB. Le zinc pourrait jouer un rôle essentiel dans l’interaction avec le matériel génétique. Ces travaux aident aussi à comprendre comment cette protéine transporte l’information virale vers le noyau des cellules du foie.Viruses are characterized by a shell that protects and transports viral information. This shell is composed of several copies of proteins capable of self-assembling, around or independently of the viral information. During the life of a virus, proteins involved in this assembly have multiple roles. In addition to transport and protection, they can regulate or hijack the cellular machinery of the infected host. They can also serve as decoys against the organism's immune defenses. In this thesis, using computational methods on supercomputers, the mechanisms of assembly and interaction of these proteins are studied. This work allows to have a better idea of the assembly of the empty shell of the human gastroenteritis virus. For hepatitis B virus (HBV), these studies show the binding of zinc ions by the HBV shell protein. Zinc may play an essential role in the interaction with genetic material. This work also helps to understand how this protein transports viral information to the nucleus of liver cells

TTClust: A Versatile Molecular Simulation Trajectory Clustering Program with Graphical Summaries

WOS:000451650400002International audienceIt is extremely helpful to be able to partition the thousands of frames produced in molecular dynamics simulations into a limited number of most dissimilar conformations. While robust clustering algorithms are already available to do so, there is a distinct need for an easy-to-use clustering program with complete user control, taking as input a trajectory from any molecular dynamics (MD) package and outputting an intuitive display of results with plots allowing at-a-glance analysis. We present TTClust (for Trusty Trajectory Clustering), a python program that uses the MDTraj package to fill this need

Deciphering Adverse Outcome Pathway Network Linked to Bisphenol F Using Text Mining and Systems Toxicology Approaches

International audienceBisphenol F (BPF) is one of several Bisphenol A (BPA) substituents that is increasingly used in manufacturing industry leading to detectable human exposure. Whereas a large number of studies have been devoted to decipher BPA effects, much less is known about its substituents. To support decision making on BPF’s safety, we have developed a new computational approach to rapidly explore the available data on its toxicological effects, combining text mining and integrative systems biology, and aiming at connecting BPF to adverse outcome pathways (AOPs). We first extracted from different databases BPF-protein associations that were expanded to protein complexes using protein-protein interaction datasets. Over-representation analysis of the protein complexes allowed to identify the most relevant biological pathways putatively targeted by BPF. Then, automatic screening of scientific abstracts from literature using the text mining tool, AOP-helpFinder, combined with data integration from various sources (AOP-wiki, CompTox, etc.) and manual curation allowed us to link BPF to AOP events. Finally, we combined all the information gathered through those analyses and built a comprehensive complex framework linking BPF to an AOP network including, as adverse outcomes, various types of cancers such as breast and thyroid malignancies. These results which integrate different types of data can support regulatory assessment of the BPA substituent, BPF, and trigger new epidemiological and experimental studies

Linking Bisphenol S to Adverse Outcome Pathways Using a Combined Text Mining and Systems Biology Approach

International audienceBackground:Available toxicity data can be optimally interpreted if they are integrated using computational approaches such as systems biology modeling. Such approaches are particularly warranted in cases where regulatory decisions have to be made rapidly.Objectives:The study aims at developing and applying a new integrative computational strategy to identify associations between bisphenol S (BPS), a substitute for bisphenol A (BPA), and components of adverse outcome pathways (AOPs).Methods: The proposed approach combines a text mining (TM) procedure and integrative systems biology to comprehensively analyze the scientific literature to enrich AOPs related to environmental stressors. First, to identify relevant associations between BPS and different AOP components, a list of abstracts was screened using the developed text-mining tool AOP-helpFinder, which calculates scores based on the graph theory to prioritize the findings. Then, to fill gaps between BPS, biological events, and adverse outcomes (AOs), a systems biology approach was used to integrate information from the AOP-Wiki and ToxCast databases, followed by manual curation of the relevant publications.Results: Links between BPS and 48 AOP key events (KEs) were identified and scored via 31 references. The main outcomes were related to reproductive health, endocrine disruption, impairments of metabolism, and obesity. We then explicitly analyzed co-mention of the terms BPS and obesity by data integration and manual curation of the full text of the publications. Several molecular and cellular pathways were identified, which allowed the proposal of a biological explanation for the association between BPS and obesity.Conclusions: By analyzing dispersed information from the literature and databases, our novel approach can identify links between stressors and AOP KEs. The findings associating BPS and obesity illustrate the use of computational tools in predictive toxicology and highlight the relevance of the approach to decision makers assessing substituents to toxic chemicals. https://doi.org/10.1289/EHP420