Protein Crowding in Lipid Bilayers Gives Rise to Non-Gaussian Anomalous Lateral Diffusion of Phospholipids and Proteins

Cell membranes comprised largely of lipids and proteins are exceptionally crowded and typically contain 50–100 lipids per protein. However, the role of protein crowding on lateral membrane dynamics has received very little attention, which is quite surprising given that numerous studies have recently identified crowding to play an important role in multiple biological phenomena such as protein stability, signaling, and gene transcription. Furthermore, since lateral protein and lipid diffusion are the key processes driving a number of dynamical processes in cell membranes, the importance of understanding the role of crowding in lateral membrane dynamics is crucial. Here, we show that the theoretical paradigms established and validated for protein-poor membranes no longer hold true in protein-rich membranes.

Biomembranes are exceptionally crowded with proteins with typical protein-to-lipid ratios being around 1∶50−1∶100. Protein crowding has a decisive role in lateral membrane dynamics as shown by recent experimental and computational studies that have reported anomalous lateral diffusion of phospholipids and membrane proteins in crowded lipid membranes. Based on extensive simulations and stochastic modeling of the simulated trajectories, we here investigate in detail how increasing crowding by membrane proteins reshapes the stochastic characteristics of the anomalous lateral diffusion in lipid membranes. We observe that correlated Gaussian processes of the fractional Langevin equation type, identified as the stochastic mechanism behind lipid motion in noncrowded bilayer, no longer adequately describe the lipid and protein motion in crowded but otherwise identical membranes. It turns out that protein crowding gives rise to a multifractal, non-Gaussian, and spatiotemporally heterogeneous anomalous lateral diffusion on time scales from nanoseconds to, at least, tens of microseconds. Our investigation strongly suggests that the macromolecular complexity and spatiotemporal membrane heterogeneity in cellular membranes play critical roles in determining the stochastic nature of the lateral diffusion and, consequently, the associated dynamic phenomena within membranes. Clarifying the exact stochastic mechanism for various kinds of biological membranes is an important step towards a quantitative understanding of numerous intramembrane dynamic phenomena.

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