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Computational Perspective to Dynamical Protein-Lipid Complexes under Crowded Conditions

Final Report Summary - CROWDED-PRO-LIPIDS (Computational Perspective to Dynamical Protein-Lipid Complexes under Crowded Conditions)

One of the great challenges is to understand how cellular functions emerge in cell membrane systems. Unlocking this mystery is key to a vast majority of human diseases. In this project, we used a variety of theoretical and molecular simulation techniques to gain insight into the dynamical interplay between lipids, proteins, and carbohydrates, paying particular attention to crowded conditions. The aim was to pave the way for understanding the dynamics of lipid-protein-glycan complexes and their resulting functions.

The topic is exceptionally important since membrane-associated proteins constitute roughly 30% of all proteins in cells, thus they are responsible for a major fraction of cellular functions such as cell adhesion, immune response, and signaling between the cells’ internal and external environments. It has been realized earlier that lipids play an important role in modulating membrane protein function, but the nanoscale mechanisms underlying this have remained unclear. The understanding in this respect has been even more limited under protein crowding, though many of the membranes in cells are highly rich in proteins.

In studies where the project focused on membrane proteins interacting with lipids, it was clarified how certain specific glycolipids as well as glycosylation modulate the conformation and hence visibility/function of membrane receptors, in particular the epidermal growth factor receptor. The project also resolved in a pioneering study how cholesterol modulates and stabilizes the conformation and dynamics of G-protein coupled receptors such as the beta-2-adrenergic receptor in an allosteric manner. As to membrane dynamics, and in particular lateral diffusion controlling the formation of functional lipid-protein assemblies, the project clarified the role of protein crowding on lateral diffusion and found it to be exceptionally significant in slowing down the diffusion and giving rise to anomalous diffusion that plays a role in protein oligomerization. Under protein crowding, the research showed that the famous Saffman-Delbrück relation breaks down and is replaced by another physical law describing the dependence of protein diffusion on protein size. Overall, the strong anomalous diffusion observed under protein crowding turned out to be an exceptionally fascinating dynamic process whose potential biological relevance is currently being exploring.

Another situation where protein crowding and lipid-protein interactions contribute at the same time concerns lipoproteins known as carriers of cholesterol. In this context, the project clarified, for instance, how lipid oxidation affects lipoprotein properties such as the enzymatic activity at the surface of the lipoproteins. It was also clarified how synthetic nanoparticles such as fullerene interfere with interactions taking place in lipoproteins. Given that lipoproteins are involved in emergence of diseases such as atherosclerosis, the project also resolved molecular processes that could reduce the risk to get such diseases. For instance, it was determined how anacetrapib – a drug interacting with the cholesteryl ester transfer protein (CETP) – can foster the impairment of CETP function and hence increase the amount of “good” cholesterol and lower the concentration of “bad” cholesterol in circulation.

In the project, an arsenal of theoretical and molecular simulation techniques was used to shed light on nanoscale processes that underlie the function of membrane-associated proteins. Together with experimental collaborators, the ERC project team did several breakthroughs by showing how lipids can modulate protein function, in particular under protein crowding.