Systematic simulation of the interactions of pleckstrin homology domains with membranes.

Pleckstrin homology (PH) domains can recruit proteins to membranes by recognition of phosphatidylinositol phosphate (PIP) lipids. Several family members are linked to diseases including cancer. We report the systematic simulation of the interactions of 100 mammalian PH domains with PIP-containing membranes. The observed PIP interaction hotspots recapitulate crystallographic binding sites and reveal a number of insights: (i) The β1 and β2 strands and their connecting loop constitute the primary PIP interaction site but are typically supplemented by interactions at the β3-β4 and β5-β6 loops; (ii) we reveal exceptional cases such as the Exoc8 PH domain; (iii) PH domains adopt different membrane-bound orientations and induce clustering of anionic lipids; and (iv) beyond family-level insights, our dataset sheds new light on individual PH domains, e.g., by providing molecular detail of secondary PIP binding sites. This work provides a global view of PH domain/membrane association involving multivalent association with anionic lipids.