Deciphering Complex Energy Landscape at Atomic Resolution of Human HSP90 using NMR and AI-Enhanced tools.
HSP90 is a human chaperone involved in the folding of a wide variety of client proteins, including many oncogenic proteins. This complex molecular machinery is known to undergo massive conformational rearrangements throughout its functional cycle. X-ray crystallography and cryoEM have provided high-resolution snapshot structures of this human machinery in complex with cochaperones and client proteins, but have failed to provide the kinetic and time-resolved information needed for a full understanding of its mechanism. We plan to use NMR experiments combined with a new AI-enhanced analysis tool to obtain a detailed picture of the energy landscape of this important drug target. This project will provide structural information on the different excited states of HSP90 and the conformational dynamics between these states. In collaboration with the pharmaceutical industry, we will exploit this new approach to reveal how ligands can modulate the energy landscape and population of different functional states. This information will be particularly useful for the design of new drugs capable of blocking the HSP90 chaperone in a single state, an important step towards the development of more specific and effective drugs.
Study of emerging materials for Threshold Switching Selector for MRAM technology
The objective of this thesis is to explore novel Threshold Switching Selector (TSS) materials for emerging MRAM (Magnetic Random-Access Memory) technologies. A selector serves as a simple two-terminal device, behaving like a switch or a diode that turns on above a certain voltage and stays off otherwise. When combined to a memory element, it prevents sneak current in non-selected memory cells, enabling denser memories. In addition, TSS aims at replacing the selection transistor and at reducing the number of vias to connect with the CMOS, thus saving power and surface area.
To achieve TSS compatible with MRAM, it is critical to develop new selectors materials that match the characteristics of magnetic tunnel junction (MTJ). For example, Ovonic threshold switch (OTS) used with phase change PC-RAM (in production) has a threshold voltage larger than 2V. This voltage is too high for MTJs that must be operated below 1V to avoid degrading the MgO tunnel barrier.
Spintronics-based non-volatile FPGA development for space applications
In microelectronics, we can distinguish between two types of integrated circuit. ASICs (Application Specific Integrated Circuits) dedicated to only one application and FPGAs (Field Programmable Gate Arrays) dedicated to digital electronics, on which we focus in this thesis. The main advantage of FPGAs is that they can be reprogrammed. These circuits are made up of several elementary logic cells, interconnected via a programmable interconnect system. This makes them particularly sensitive to radiation, since a fault in the memory permanently alters the operation of the FPGA. Traditional FPGAs are based on SRAM or Flash memories. The aim of this thesis is to evaluate the use of MRAM as a configuration and interconnect memory for FPGAs, and in particular as a means of improving/simplifying the implementation of standard hardening techniques for space applications, while reducing cost thanks to its density. The work will involve inserting multi-level magnetic components known as magnetic tunnel junctions, and assessing their value. To do this, we'll be using several simulation tools to inject particles present in space at different points in the circuit, and compare the results with a conventional version. In this way, it will be possible to measure the effectiveness of such a hardening process based on magnetic technology.
Topological-superconductor group IV nanomaterials
We are currently embracing the second quantum revolution, where major breakthroughs in solid-state technologies have been achieved by engineering materials with different electrical conductivities (metals, insulators, semiconductors (SEMI)), eventually reaching infinite conductivity in cooled superconductors (SC). This flourishing ecosystem has been enriched by the recent discovery of a new class of materials with remarkable electronic properties - topological (TOP) materials(1) - that is now driving both the theoretical and experimental work in condensed matter physics. Significant advances in understanding fundamental material properties, devising new fabrication processes, and discovering novel material systems are required to fully harvest the potential of solid-state quantum devices. Superconducting spin qubits, gate-tunable spin qubits, and topological qubits systems are commonly fabricated by combining multiple materials with fundamentally different properties - heterogeneous integration - in hybrid SC/SEMI and SC/TOP junctions. This is a significant challenge in material science since any structural defects and roughness at the interface between two materials would compromise the ability to detect and manipulate quantum states. The properties of these hybrid junctions are affected by the interface purity within the heterostructure, where the presence of oxides, impurities, or structural defects is a detrimental source of noise and dissipation in these material systems.(2)
The goal of this PhD thesis is to develop a scalable material platform where quantum properties can be engineered simply by tailoring the crystal structure of a single atomic element – Tin (Sn) – and achieve interfaces with the highest quality. Topological insulator/topological semimetal phases can be tailored in diamond cubic a-Sn by controlling strain,(3) while body-centered tetragonal ß-Sn behaves as a superconductor at temperatures below 4 K.(4) Currently, a controlled switch between a/ß-Sn phases is out of reach using a conventional thin film geometry.
The PhD student will establish the growth of one-dimensional (1D) Sn nanowires (NWs) on a Silicon wafer using a molecular beam epitaxy (MBE) system. NWs offer the ideal system to control the crystalline phase of a material without nucleating structural defects.(5) In this thesis, this crystal-phase engineering paradigm will be developed for group IV NWs to achieve a precise control over the growth of a-Sn and ß-Sn phases (i.e. TOP and SC phases). This protocol will then enable the growth of defect-free a/ß-Sn NWs with atomically-sharp interfaces and with the highest structural quality. This nanostructured material will provide a truly homogeneous integration of multiple states of matter in solid-state quantum devices, paving the way to explore the fundamental processes in topological quantum computation,(6) spintronics,(7) and quantum photonics.(8)
The student will investigate the structural properties (scanning electron microscopy, atomic force microscopy, transmission electron microscopy, X-ray diffraction, atom probe tomography) and optical properties (Raman) of the a/ß-Sn NWs using a variety of characterization techniques available at CEA. To demonstrate the presence of TOP or SC phases in these nanomaterials, the student will fabricate a NW field-effect transistor (FET) (single NW transfer to a SiO2/Si substrate, electron beam lithography, metals and oxides deposition). Next, magnetotransport measurements at cryogenic temperatures (1 K or less) will be performed to demonstrate the TOP behavior in a-Sn and SC state in ß-Sn. This thesis will train the student with a diverse skillset ranging from materials growth, structural and optoelectronic characterization, device fabrication, and quantum transport measurements.
(1) P. Liu et al., Nat. Rev. Mater. 4, 479–496 (2019).
(2) N. P. de Leon et al., Science 372, 1–20 (2021).
(3) A. Barfuss et al., Phys Rev Lett. 111, 157205 (2013).
(4) Y. Zhang et al., Sci Rep. 6, 32963 (2016).
(5) S. Assali et al., Nano Letters. 15 (12) (2015).
(6) A. Stern, N. H. Lindner, Science. 339, 1179-1184 (2013).
(7) J. Ding et al., Advanced Materials. 33, 2005909 (2021).
(8) E. D. Walsh et al., Science. 372, 409-412 (2021).
Contribution of artificial intelligence (AI) to understand the modes of action of microRNAs, application to cancer
MicroRNAs have demonstrated importance in a large number of carcinogenesis processes ranging from initiation, propagation and the appearance of metastases. They raise many hopes as therapeutic treatment targets. However, the drug candidate MRX34 (which mimics a microRNA) proved to be a failure in patients because it was too toxic. It is therefore urgent to better understand the mode of action of microRNAs in order to design new therapeutic strategies.
The thesis project proposes to use two cutting-edge technologies for this: microRNA/mRNA co-sequencing data, at the single cell level, and artificial intelligence techniques (AI, including neural networks and XGBoost ). It will benefit from the contribution of two other projects, which end in 2025 (an overlap of a few months with the CFR thesis): a thesis financed by Pfizer-INSERM, and a multi-team project financed by the cancer plan. These two projects have already enabled rigorous statistical analysis of co-sequencing data at the single cell level, which will be used during the PhD work. A collaboration, already initiated, is planned with Gipsa-Lab, Grenoble, specialist in machine learning / AI.
Molecular dynamics and disorder in the viral replication machinery of SARS CoV 2
The nucleoprotein (N) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential for genome replication, encapsidating the viral genome and regulating gene transcription. The central disordered domain is essential to the function of this highly dynamic protein, containing a number of important mutations that are responsible for enhanced viral fitness, and comprising a region that is hyperphosphorylated during the viral cycle. NMR spectroscopy is the tool of choice for studying the conformational behaviour of intrinsically disordered proteins, an abundant class of proteins that are functional in their disordered form. They represent 40% of the proteome and are too dynamic to be studied by crystallography or electron microscopy. The host lab has developed a large number of unique NMR-based tools to help understand the function of this class of proteins at atomic resolution. We will use NMR, paramagnetic NMR, small angle scattering, single molecule FRET and electron microscopy, in combination with molecular dynamics simulation, to describe the interactions of N with viral partner proteins and viral RNA. Post-translational modification, in particular phosphorylation, is thought to play an important functional role, that remains poorly understood, we will investigate the impact of phosphorylation on conformational dynamics and relate this to modifications in function. The results will be correlated with light end electron microscopy, carried out in collaboration.
[FeFe]-hydrogenase active site assembly machinery
To tackle the climate crisis, humanity urgently needs renewable and decarbonized energy sources. A promising solution lies in harnessing dihydrogen (H2), and enzymes known as [FeFe] hydrogenases can play a vital role in its production. These enzymes catalyze the reversible oxidation of dihydrogen, employing an active site called the "H-cluster," a complex organometallic structure. The intricate biosynthesis of this cluster involves three maturation proteins: HydG, HydE, and HydF. Despite recent progress, a full understanding of this process remains elusive due to the complexity of the chemical reactions involved. Our goal is to conduct a structural study combined with step-by-step reaction monitoring using spectroscopy. This approach aims to identify and characterize various reaction intermediates of one key enzyme in the process. This collaborative project involves two leading CEA teams specializing in the study of oxygen-sensitive metalloproteins. The doctoral student will benefit from an ideal scientific and technical environment to achieve this objective, crucially important for advancing hydrogen economy development.
Localization and dynamics of key nucleoid-associated proteins during stress-induced bacterial nucleoid remodeling.
Nucleoid remodeling, and in particular, nucleoid compaction, is a common stress response mechanism in bacteria that allows bacteria to rapidly respond to sudden changes in their environment. Using advanced optical microscopy approaches, we recently followed the changes in nucleoid shape and volume induced by exposure to intense UV-C light in the radiation resistant bacterium, Deinococcus radiodurans. This two-step process involves a rapid initial nucleoid condensation step followed by a slower decompaction phase to restore normal nucleoid morphology, before cell growth and division can resume. Nucleoid associated proteins (NAP) are known to be key players in this process, although the details of their implication remain largely elusive. We have started to shed light on the central role of the major NAP, the histone-like HU protein, in this process. The proposed PhD project will extend this work to the study of 5 additional NAPs involved in stress-induced nucleoid remodeling. The PhD student will perform biochemical studies to follow the abundance of these key factors, live cell imaging to map their distribution and single-particle tracking to determine their dynamics. This work will contribute to a better understanding of the fundamental processes that govern bacterial genome organisation and how they are affected by UV radiation and DNA damage.
characterization of acyltransferases in two oleaginous marine algae
The project aims to study the plastidial lipid metabolism of two microalgae using the CRISPR-Cas9 system. This project is in the context of increasing atmospheric CO2 and climate change. Photosynthetic microalgae can capture CO2 and convert it into lipids, which is useful for various industrial applications. However, stramenopile microalgae have a unique cellular structure, making it challenging to apply knowledge from simpler models. Therefore, we need a better understanding of lipid synthesis in these microalgae to enhance their ability to sequester CO2 and produce lipids for biotechnological applications. Our research focuses on the biosynthesis pathway of plastidial galactoglycerolipids, the dominant lipids in photosynthetic organisms, in two model microalgae, Phaeodactylum tricornutum and Microchloropsis gaditana. These lipids consist of a glycerol backbone, fatty acids (FAs), and galactose residues. FAs are produced in the plastids, then modified in other parts of the cell to form long-chain polyunsaturated FAs, such as eicosapentaenoic acid (EPA). The transport pathway of EPA to the plastid is still poorly understood. Then, EPA is esterified onto glycerol-3-phosphate (G3P) through enzymes called acyltransferases (AT). This study is one of the key research areas of our team. The synthesis of galactoglycerolipids in stramenopiles involves several steps, including esterifying an FA onto G3P, forming phosphatidic acid, converting it to diacylglycerol, and adding galactose residues to form the final lipids. In summary, our research aims to understand how these microalgae produce important lipids for CO2 capture and industrial applications. This research is relevant for combating climate change and reducing our dependence on fossil fuels.
Theoretical studies of orbitronic and spin-orbit phenomena in heterostructures comprising van der Waals materials, metals and oxides
The proposed PhD thesis aims at finding the best-unexplored combinations of transition metals, oxides and 2D materials (transition metal dichalcogenides, 2D magnets, graphene…) to help optimizing and providing scientific underpinnings of next generation energy efficient spintronic storage and memory devices based on emerging fields of spin-orbitronics and orbitronics. The latter is a fascinating new field of research that exploits orbital currents and their interaction with spin currents mediated by spin-orbit coupling.
Namely, using first principles calculations combined with tight-binding approach and linear response theory, we will screen the potential of aforementioned heterostructures not only for spin-orbit phenomena such as Dzyaloshinskii-Moriya interaction (DMI), perpendicular magnetic anisotropy (PMA) and spin-charge interconversion based on Rashba and Rashba-Edelstein effects (REE), but also focus on Orbital Rashba Edelstein Effect (OREE). Furthermore, the mechanisms of control of these phenomena via external stimuli (strain, external electric and magnetic fields) will be investigated as well. These studies will help finding optimal material combination to tune DMI, PMA and spin-charge interconversion efficiency to help optimizing spintronic devices making thereby a significant contribution to the development of sustainable microelectronics.
The PhD will be based on a multiscale approach including ab initio, tight-binding and atomistic approaches thus highly motivated candidate with a good background in solid state physics, condensed matter theory and numerical simulations is required. He/she will perform his/her calculations on Spintec computational cluster nodes using first-principles packages based on density functional theory (DFT) combined with other simulation codes/tools. Results obtained will be carefully analyzed with the possibility of publication in international scientific journals. Strong collaboration with labs in France (CEA/LETI, UMPhy CNRS/Thales, Aix-Marseille Univ…) and abroad (ICN2-Barcelona, PGI Forschungszentrum Jülich, Osaka University) are previewed.