Abstract
Pleckstrin homology (PH) domains are lipid-binding modules present in peripheral membrane proteins which interact with phosphatidyl-inositol phosphates (PIPs) in cell membranes. We use multiscale molecular dynamics simulations to characterize the localization and anomalous dynamics of the DAPP1 PH domain on the surface of a PIP-containing lipid bilayer. Both translational and rotational diffusion of the PH domain on the lipid membrane surface exhibit transient subdiffusion, with an exponent α ≈ 0.5 for times of less than 10 ns. In addition to a PIP3 molecule at the canonical binding site of the PH domain, we observe additional PIP molecules in contact with the protein. Fluctuations in the number of PIPs associated with the PH domain exhibit 1/f noise. We suggest that the anomalous diffusion and long-term correlated interaction of the PH domain with the membrane may contribute to an enhanced probability of encounter with target complexes on cell membrane surfaces.
Highlights
Association of peripheral proteins with target lipids and/or proteins in cell membranes is essential for many trafficking and signaling events
We show that the Pleckstrin homology (PH)/phosphatidyl-inositol phosphates (PIPs) complex obtained from our simulations is in good agreement with the PH/inositol phosphate (InsP) complex obtained by X-ray crystallography
The progress of this can be measured by the distance between the center of mass (COM) of the DAPP1 PH domain and the lipid membranes [Fig. 1C]
Summary
Association of peripheral proteins with target lipids and/or proteins in cell membranes is essential for many trafficking and signaling events. Recent studies have shown that MD simulations can be used to investigate the molecular mechanism of association of peripheral proteins with membranes[10,12,13,14,15] This in silico approach provides insights into the molecular details of the localization, penetration and diffusion of peripheral proteins on a membrane. Because the temporal and spatial patterns of localization of peripheral proteins on membranes are central to their biochemical activity, the diffusional behavior of bound PH domains may be expected to be linked to their functional roles in the cell This makes it important to more fully understand the diffusional behavior of peripheral proteins bound to membranes, both from a biophysical and from a functional perspective
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
