CROWDY · Toward the microscopic simulations of cell-like environments.
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-05-01 → 2021-04-30
- EU contribution
- €196,708
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Toward the microscopic simulations of cell-like environments.
The interior of a living cell is a highly crowded place—in fact, up to 40 % of the entire volume is filled by proteins and other biomolecules. This means that a protein immersed in such a densely packed environment constantly bounces into other molecules and transiently binds to them before moving to other interaction partners. The interactions with the crowded intracellular environment may affect various properties of proteins, such as their ability to move and the stability of their native conformations, that is, the three-dimensional structures that allow proteins to carry out their functions. Therefore, to understand how these vital molecules work inside cells, it is important to accurately describe the intracellular environment and its impacts on protein mobility and stability. While it is often difficult to obtain experimental information on molecular interactions taking place in the extremely crowded and heterogeneous conditions, such microscopic details can be captured using computer simulations. However, the large spread of time- and length scales that are involved in such crowded systems poses a serious challenge to existing simulation techniques. In this project, we implemented a multi-scale simulation scheme combining coarse-grained simulations (using the lattice Boltzmann molecular dynamics technique) with detailed atomistic simulations to investigate the diffusion and stability of proteins under conditions mimicking those existing in cells. This scheme allowed us to explore protein motions in large crowded systems and, subsequently, zoom in to investigate atomistic details of protein conformations and intermolecular interactions, including interactions with lipid membranes. The results revealed how crowding shapes protein stability and diffusion at different temperatures. Moreover, they provided microscopic insights into changes that occur in the cellular interior when a cell dies due to a high temperature.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union