Abstract
We report all-atom molecular dynamics simulations of asymmetric bilayers containing phosphoinositides in the presence of monovalent and divalent cations. We have characterized the molecular mechanism by which these divalent cations interact with phosphoinositides. Ca2+ desolvates more readily, consistent with single-molecule calculations, and forms a network of ionic-like bonds that serve as a ‘molecular glue’ that allows a single ion to coordinate with up to three phosphatidylinositol-(4,5)-bisphosphate (PI(4, 5)P2) lipids. The phosphatidylinositol-(3,5)-bisphosphate isomer shows no such effect and neither does PI(4, 5)P2 in the presence of Mg2+. The resulting network of Ca2+-mediated lipid-lipid bonds grows to span the entire simulation space and therefore has implications for the lateral distribution of phosophoinositides in the bilayer. We observe context-specific differences in lipid diffusion rates, lipid surface densities and bilayer structure. The molecular-scale delineation of ion-lipid arrangements reported here provides insight into similar nanocluster formation induced by peripheral proteins to regulate the formation of functional signalling complexes on the membrane.
Highlights
We report all-atom molecular dynamics simulations of asymmetric bilayers containing phosphoinositides in the presence of monovalent and divalent cations
The interface between the intracellular and extracellular environment, defined by the boundary of the cell’s plasma membrane, is the location of bidirectional outside-in and inside-out signalling responses. Such signalling pathways often involve a class of rare phospholipids known as polyphosphoinositides (PPIs) which can act as the starting point for second messengers and serve directly in transmitting signals
PPIs with two phosphate groups connected to the inositol ring—we focus on phosphatidylinositol-(4,5)-bisphosphate (PI(4, 5)P2) and phosphatidylinositol-(3,5)-bisphosphate (PI(3, 5)P2) in this study—can range from − 3e to − 5e depending on pH and the counterions present, whereas most mammalian lipids are neutral, zwitterionic, or carry a charge of − 1e, see figure 1 [3]
Summary
We report all-atom molecular dynamics simulations of asymmetric bilayers containing phosphoinositides in the presence of monovalent and divalent cations. PPIs with two phosphate groups connected to the inositol ring—we focus on phosphatidylinositol-(4,5)-bisphosphate (PI(4, 5)P2) and phosphatidylinositol-(3,5)-bisphosphate (PI(3, 5)P2) in this study—can range from − 3e to − 5e depending on pH and the counterions present, whereas most mammalian lipids are neutral, zwitterionic, or carry a charge of − 1e, see figure 1 [3] Despite their low abundance in terms of the overall numbers, numerous cellular processes, including cytoskeletal assembly, are controlled by the level and spatial localization of PPIs on the cell membrane [4]. The detection and visualization of PPIs in vivo has far relied on indirect perception through labelled proteins or chemical modification of PPIs with bulky dyes Owing to these limitations, one of the unresolved issues in understanding how phosphoinositides regulate cytoskeletal assembly and membrane curvature is how these scarce lipids affect the activity of many proteins [18]. The authors noted that they do not yet have a molecular model to explain the mechanism by which multivalent metal ions promote clustering [27]
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