Multiscale Simulations of Membrane Recognition by Lipid Kinases

Abstract

Peripheral membrane proteins associate with lipids in the plasma membrane in many important cell signalling processes. Type I phosphatidylinositol phosphate kinase A (PIP5K1A) is one such example, which phosphorylates the head group of the lipid phosphatidylinositol 4-phosphate (PI4P) to generate phosphatidylinositol (4,5)-bisphosphate (PIP2). The dynamic interactions of peripheral proteins with their target membranes is difficult to capture on experimentally. A recent crystal structure at 3.3 Å resolution enables the further investigation of the structure and dynamics of PIP5K1A and its interactions with lipids in the plasma membrane. Here we use coarse-grained (CG) and atomistic (AT) MD simulations of the PIP5K1A protein kinase to investigate the nature of monomer and dimer binding to the plasma membrane and their effects on lipid clustering. The AT simulations suggest that whilst dimerisation of the kinase results in an increase in the area of the binding surface, the monomers may not bind concurrently. This in turn suggests that an allosteric mechanism for stabilisation of the productive binding conformation is more likely. We have also used simulations to investigate the relationship between conformational dynamics of the activation loop and interactions with lipids in the cell membrane. Furthermore, large-scale CG simulations (1 million particles) reveal how lipid composition and membrane curvature relate to the interactions of an ensemble of 25 kinases with a model membrane. PIP kinases are implicated in many cancers as a result of their influence on cell processes. Studies in mice and human tissue samples suggest that inhibition of PIP5K1A is a potential target for treatment. Simulations of the interactions of PIP5K1A with realistic models of cell membranes will aid design of drugs targeted at these and other related lipid kinases.