Charachterizing Structure and Dynamics of Calcium-Induced Clusters of Phosphatidylserine in Mixed Lipid Bilayers

Abstract

The cellular membrane plays a key role in the regulation and activation of peripheral membrane proteins. For instance, the enzymatic activity of several coagulation factors and signaling proteins is regulated by their specific binding to negatively charged regions of the cellular membrane that are rich in anionic lipids such as phosphatidylserine (PS). The lipid composition of the membrane and the ionic content of the immediate solution significantly modify structural properties of the bilayer surface. In particular, calcium-induced clustering of PS lipids has been suggested to modulate membrane-protein interactions. We employ our novel highly mobile membrane mimetic (HMMM) model combined with molecular dynamics simulations to investigate structural and dynamic properties determining these interactions. The HMMM model, while preserving full representation of the lipid head groups that are required for detailed characterization of specific interactions, provides 1-2 orders of magnitude speed up in lipid mobility. Extended simulations with HMMM systems including anionic (POPS), zwitterionic phosphatydilcholine (POPC), or POPS/POPC binary mixtures provide a detailed view of structural changes that occur due to lipid-lipid and lipid-ion interactions, specifically those that drive PS clustering. Simulations revealed a diverse set of PC-PS-Ca2+ microdomains of consistent geometry. In particular, we observed 2PC:2PS:Ca2+:water and 2PS:Ca2+:3water stoichiometries. Ca2+ ions interact with phosphate groups of PC and PS as well as with the carboxy groups of PS. Interestingly, unimolecular chelation of Ca2+ by the same PS head group is often observed within the clusters. In contrast to monovalent Na+, the presence of divalent Ca2+ shows its long-lived coordination with lipid head groups that modulates their orientation and leads to formation of PS clusters. Prior to the development of the HMMM method these observations were out of reach of atomistic simulations.