Diffusion of Lipids and Proteins in Complex Membranes

Integral membrane proteins are tiny factories with big responsibilities in signaling and transport. These proteins are constantly looking for oligomerization partners and favorable lipid environments to perform their functions that are critical for our health. The search processes are driven by thermally-agitated lateral diffusion. Cellular membranes are crowded and highly heterogeneous entities. Their structure is assumed to couple to the dynamics of molecules within the membrane, rendering diffusion therein complex too. Clarifying this connection can help us to grasp how cells regulate dynamic processes by locally varying their membrane properties, and how this further affects protein function. Unfortunately, despite persistent experimental work, our understanding of this structure–dynamics–function coupling remains poor.

In this Thesis, we present our findings on how protein crowding and lipid packing affect the lateral dynamics of lipids and proteins in membranes and monolayers. We have employed molecular dynamics simulations using both atomistic and coarsegrained models to resolve how the rate and nature of diffusion are affected by these two factors. We also advanced the related methodology, which turned out to be beneficial for studying lipid membranes that are crowded with proteins.

We find that crowding and packing slow down lipid and protein diffusion and extend the anomalous diffusion regime. We demonstrate that models used to predict diffusion coefficients of lipids and proteins struggle in such conditions. Finally, we observe that protein crowding effects non-Gaussian diffusion that does not follow the diffusion mechanism observed for protein-free bilayers, nor any other known mechanism.

Our observations help us understand the dynamics in crowded membranes, and hence shed light on the kinetics of numerous membrane-mediated phenomena. The findings suggest that normal diffusion is likely absent in the membranes of living cells, where the motion of each lipid and protein is heavily affected by its heterogeneous surroundings. The results also pave the way towards understanding central processes in the utterly complex plasma membranes of living cells. Here, the possible future applications lie in pharmaceuticals that affect protein function by disturbing the formation of functional protein–protein or protein–lipid units by perturbing the dynamic properties of the membranes and monolayers.