Computational Lipidomics and the Lipid Organization of Cell Envelopes

Abstract

The detailed lipid organization of cellular membranes remains elusive. A typical plasma membrane contains hundreds of different lipid species that are actively regulated by the cell. Currently over 30,000 biologically relevant lipids have been identified and specific organisms often synthesize thousands of different lipid types. This is far greater diversity than is needed to maintain bilayer barrier properties and to solvate membrane proteins. Why organisms go through the costly progress of creating and maintaining such a large diversity of lipids is one of the big open questions in biology. What is the individual role of these lipids, and how do they interact and organize in the membrane plane?To start to address these questions we optimized and developed the Martini coarse-grained force field lipidome. We systematically explore over a hundred different lipid types using the Martini model. Bulk properties of each individual lipid type (e.g. bilayer thickness, area per lipid, diffusion, order parameter and area compressibility) were analyzed and overall trends compared to experimental values. Using pre-existing Martini lipids and the newly characterized ones, idealized plasma membranes containing dozens of different lipid types asymmetrically distributed between the membrane leaflets were constructed and simulated on the multi microsecond time scale. In terms of lipid composition these are by an order of magnitude the most complex simulations to date. These large-scale simulations provide a high-resolution view on the lipid organization of plasma membranes at an unprecedented level of complexity and allow us to analyze a variety of plasma membrane physicochemical properties, including: lipid-lipid interactions, bilayer bulk material properties, domain formation and coupling between the bilayer leaflets. Overall, the plasma membranes show global non-ideal mixing of different lipid species at different spatiotemporal scales.