Anomalous Dynamics of Pleckstrin Homology Domains on Lipid Membrane Surfaces

Abstract

Association and diffusion of peripheral proteins to the cell membrane during many signaling and trafficking events in the cell occurs via lipid-binding modules e.g. pleckstrin homology (PH) domains. PH domains are a highly structurally conserved family of proteins which is believed to associate with various phosphatidyl inositol phosphates (PIPs) molecules in the plasma membrane thus initiating multiple signaling cascades. Despite the available structural and functional data for a variety of different PH domains the diffusive and interacting dynamics of these proteins with the lipid membrane and in particular with PIP molecules has been veiled. Using a coarse-grained molecular dynamics simulation approach, we investigate the localization and dynamic of different PH domains on a lipid bilayer surface of complex phospholipid composition. Our results demonstrate that the different PH domains associate with the PIP molecules in the membrane via a highly positively charged loop in good agreement with available experimental data. We also show that translational and rotational diffusion of PH domains on the lipid membrane surface exhibit transient sub-diffusion. Moreover, we find that fluctuations of the number of PIPs binding with the PH domains exhibit 1/f noise. Constructing a dichotomous process for the number of the PIPs, we find that the process can be regarded as a correlated renewal process where residence times are correlated.