CORDIS - Resultados de investigaciones de la UE

Non-Equilibrium Protein Assembly: from Building Blocks to Biological Machines

Periodic Reporting for period 3 - NEPA (Non-Equilibrium Protein Assembly: from Building Blocks to Biological Machines)

Período documentado: 2022-01-01 hasta 2023-06-30

All living organisms are constructed of proteins that spontaneously combine into nanoscale structures called assemblies. Such assemblies enable life – they give shape and support to cells, connect cells into tissues and organs, and form nanomachines that drive cell division, cell transport, healing, and motility. To produce work, protein assemblies consume energy. How energy inputs drive protein self-organisation, and create “living-like” structures from inanimate molecules, is currently poorly understood.

Better understanding of the fundamental principles of how life emerges at molecular scales could enable us to reprogram assembly phenomena in living organisms when needed, and can guide the design of functional biomimetic assemblies and bio-inspired nano-machines.

Protein assembly includes many interconnected effects that are difficult—or even impossible—to separate from one another in experiment. Luckily, proteins and protein assemblies still must obey the laws of physics and the principles of chemistry. The goal of my grant is to develop computer models, rooted in physics and chemistry, to discover the physical principles of energy-driven protein assemblies in the cell. I focused on the representative examples of the three main ways in which energy is supplied to protein assemblies in the cell: through chemical gradients, chemical reactions of energy-rich molecules, and mechanical forces. The predictions of my models are tested in experiments and used to explain experimental observations, in a close collaboration with experimental colleagues, to deliver an in-depth understanding of the molecular mechanisms that control the emergence of function in energy-driven protein assemblies.
The team consisting of postdoctoral scientists, PhD students, and myself, funded by this ERC project, have made substantial progress on the topic. We developed a model for how mechanosensitive protein channels, cell membranes, and proteins self-organise under chemical gradients, and have made predictions on the implications of these processes on the regulation of cell volume, the development of cellular compartments, and cell reshaping. We have developed a model for self-organisation of membrane proteins under mechanical forces, in collaboration with experimental partners, and for extracellular matrix protein assembly under mechanical forces. We have invested substantial efforts into understanding how active elastic ESCRT-III filaments, driven by consumption of energy rich molecules, perform work to reshape and divide cells across evolution, which was published in a series of papers with our experimental collaborators. On the methodological side, we have developed a new framework for studying macromolecular self-organisation by i) coupling evolutionary algorithms with molecular simulations, and ii) by coupling the assembly processes to energy consumption. Finally, we have studied general properties of protein assembly out of equilibrium.

The PI and the group have presented the above results at over 70 international meetings and institute/departmental visits across Europe and the US.
We established a new framework that couples minimal coarse-grained models for protein assembly to i) gradients in osmolytes, ii) external mechanical forces, and iii) dynamic formation and breakage of supramolecular bonds to mimic the consumption of energy-rich molecules. In addition, a new computational framework that couples evolutionary algorithms and molecular dynamics simulations has been established.

Using a combination of the above new methods, we have proposed physical mechanisms for how active elastic ESCRT-III filaments reshape cells in cell trafficking and cell division across evolution, and our predictions have been compared to and tested in experiments. We have proposed the physical mechanisms for collective self-organisation of mechanosensitive channels and their implications to cell volume sensing. We have identified a mechanism for passive transport of macromolecules in mechanical gradients. We have identified a new physical mechanism for the control of the size of protein assemblies, and used it to explain experimental data. We have developed a model for self-assembly in non-thermal fluctuating environments.
Non-equilibrium protein assembly