ERC FUNDED PROJECTS

The paradigm of the structure-function relationship in proteins is outdated. Biological macromolecules and supramolecular assemblies are highly dynamic objects. Evidence that their motions are of utmost importance to their functions is regularly identified. The understanding of the physical chemistry of biological processes at an atomic level has to rely not only on the description of structure but also on the characterization of molecular motions. The investigation of protein motions will be undertaken with a very innovative methodological approach in nuclear magnetic resonance relaxation. In order to widen the ranges of frequencies at which local motions in proteins are probed, we will first use and develop new techniques for a prototype shuttle system for the measurement of relaxation at low fields on a high-field NMR spectrometer. Second, we will develop a novel system: a set of low-field NMR spectrometers designed as accessories for high-field spectrometers. Used in conjunction with the shuttle, this system will offer (i) the sensitivity and resolution (i.e. atomic level information) of a high-field spectrometer (ii) the access to low fields of a relaxometer and (iii) the ability to measure a wide variety of relaxation rates with high accuracy. This system will benefit from the latest technology in homogeneous permanent magnet development to allow a control of spin systems identical to that of a high-resolution probe. This new apparatus will open the way to the use of NMR relaxation at low fields for the refinement of protein motions at an atomic scale. Applications of this novel approach will focus on the bright side of protein dynamics: (i) the largely unexplored dynamics of intrinsically disordered proteins, and (ii) domain motions in large proteins. In both cases, we will investigate a series of diverse protein systems with implications in development, cancer and immunity.

1 462 080 €

Start date: 2012-01-01, End date: 2017-12-31

This project investigates the two-way relationship between spatio-temporal genome organization and coordinated gene regulation, through an approach at the interface between physics, computer science and biology. In the nucleus, preferred positions are observed from chromosomes to single genes, in relation to normal and pathological cellular states. Evidence indicates a complex spatio-temporal coupling between co-regulated genes: e.g. certain genes cluster spatially when responding to similar factors and transcriptional noise patterns suggest domain-wide mechanisms. Yet, no individual experiment allows probing transcriptional coordination in 4 dimensions (FISH, live locus tracking, Hi-C...). Interpreting such data also critically requires theory (stochastic processes, statistical physics…). A lack of appropriate experimental/analytical approaches is impairing our understanding of the 4D genome. Our proposal combines cutting-edge single-molecule imaging, signal-theory data analysis and physical modeling to study how genes coordinate in space and time in a single nucleus. Our objectives are to understand (a) competition/recycling of shared resources between genes within subnuclear compartments, (b) how enhancers communicate with genes domain-wide, and (c) the role of local conformational dynamics and supercoiling in gene co-regulation. Our organizing hypothesis is that, by acting on their microenvironment, genes shape their co-expression with other genes. Building upon my expertise, we will use dual-color MS2/PP7 RNA labeling to visualize for the first time transcription and motion of pairs of hormone-responsive genes in real time. With our innovative signal analysis tools, we will extract spatio-temporal signatures of underlying processes, which we will investigate with stochastic modeling and validate through experimental perturbations. We expect to uncover how the functional organization of the linear genome relates to its physical properties and dynamics in 4D.

1 499 750 €

Start date: 2018-04-01, End date: 2023-03-31

What is responsible for the emergence of homochirality, the almost exclusive use of one enantiomer over its mirror image? And what led to the evolution of life’s homochiral biopolymers, DNA/RNA, proteins and lipids, where all the constituent monomers exhibit the same handedness? Based on in-situ observations and laboratory studies, we propose that this handedness occurs when chiral biomolecules are synthesized asymmetrically through interaction with circularly polarized photons in interstellar space. The ultimate goal of this project will be to demonstrate how the diverse set of heterogeneous enantioenriched molecules, available from meteoritic impact, assembles into homochiral pre-biopolymers, by simulating the evolutionary stages on early Earth. My recent research has shown that the central chiral unit of RNA, ribose, forms readily under simulated comet conditions and this has provided valuable new insights into the accessibility of precursors of genetic material in interstellar environments. The significance of this project arises due to the current lack of experimental demonstration that amino acids, sugars and lipids can simultaneously and asymmetrically be synthesized by a universal physical selection process. A synergistic methodology will be developed to build a unified theory for the origin of all chiral biological building blocks and their assembly into homochiral supramolecular entities. For the first time, advanced analyses of astrophysical-relevant samples, asymmetric photochemistry triggered by circularly polarized synchrotron and laser sources, and chiral amplification due to polymerization processes will be combined. Intermediates and autocatalytic reaction kinetics will be monitored and supported by quantum calculations to understand the underlying processes. A unified theory on the asymmetric formation and self-assembly of life’s biopolymers is groundbreaking and will impact the whole conceptual foundation of the origin of life.

1 500 000 €

Start date: 2019-04-01, End date: 2024-03-31

The emergence of life is one of the most fascinating and yet largely unsolved questions in the natural sciences, and thus a significant challenge for scientists from many disciplines. There is growing evidence that ribonucleic acid (RNA) polymers, which are capable of genetic information storage and self-catalysis, were involved in the early forms of life. But despite recent progress, RNA synthesis without biological machineries is very challenging. The current project aims at understanding how to synthesize RNA in abiotic conditions. I will solve problems associated with three critical aspects of RNA formation that I will rationalize at a molecular level: (i) accumulation of precursors, (ii) formation of a chemical bond between RNA monomers, and (iii) tolerance for alternative backbone sugars or linkages. Because I will study problems ranging from the formation of chemical bonds up to the stability of large biopolymers, I propose an original computational multi-scale approach combining techniques that range from quantum calculations to large-scale all-atom simulations, employed together with efficient enhanced-sampling algorithms, forcefield improvement, cutting-edge analysis methods and model development. My objectives are the following: 1 • To explain why the poorly-understood thermally-driven process of thermophoresis can contribute to the accumulation of dilute precursors. 2 • To understand why linking RNA monomers with phosphoester bonds is so difficult, to understand the molecular mechanism of possible catalysts and to suggest key improvements. 3 • To rationalize the molecular basis for RNA tolerance for alternative backbone sugars or linkages that have probably been incorporated in abiotic conditions. This unique in-silico laboratory setup should significantly impact our comprehension of life’s origin by overcoming major obstacles to RNA abiotic formation, and in addition will reveal significant orthogonal outcomes for (bio)technological applications.

1 497 031 €

Start date: 2018-02-01, End date: 2023-01-31