Project description
Simulating macromolecular crowding within cells
Crowding of macromolecules within cells is believed to impact the function of proteins by modulating their stability and dynamics. However, studying this phenomenon at the experimental level in cells has proved very challenging. The EU-funded CROWDY project proposes to simulate macromolecular crowding through an intricate framework that takes into account the complex nature of the proteins and their presence in different cellular environments. Moreover, scientists will investigate the effects of crowding near cell membranes. Collectively, the project will increase our understanding of protein function in vivo in diseases such as amyotrophic lateral sclerosis.
Objective
In living cells, proteins operate in an extremely crowded environment, which has a substantial impact on their structural and dynamical properties. Taking into account the effects of macromolecular crowding is thus imperative for a full understanding of protein function in vivo. However, despite a growing interest in the characterization of in-cell crowding, its net effect remains only partially understood as experimental studies addressing such phenomena in the cytoplasm are very challenging. In this project, we aim to examine the effect of macromolecular crowding on protein mobility and stability at the microscopic resolution. To this end, we will deploy a novel multi-scale simulation approach developed in the host laboratory. This multi-scale framework combines a detailed description of proteins with an efficient lattice-based model of solvent hydrodynamics. In the course of the project, we will consider systems of progressive complexity, ranging from crowded binary protein suspensions through a model of a bacterial cytoplasm and a lipid vesicle forming a biological nanoreactor. Our computational studies will be performed in close contact with two top-level experimental groups active in the field. We will pay particular attention to the behavior of superoxide dismutase 1, a protein involved in amyotrophic lateral sclerosis. Our multi-scale molecular simulations will shed light on how protein dynamics and stability are locally affected by the heterogeneity of the cellular environment. Moreover, we will investigate how crowding is modulated by the presence of membrane surfaces. The simulations will allow us to clarify the origins of crowding effects at an atomistic level, which will provide a vital support for the microscopic interpretation of experimental data. Thus, our project will offer unprecedented insights into the structure and dynamics of the crowded environment inside living cells.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF-EF-ST - Standard EFCoordinator
75794 Paris
France