Cardiomyocyte sarcolemma modelling and lipid-protein interactions.

Abstract

The cardiomyocyte sarcolemma is a crucial cellular organelle in heart function. The vital components of the sarcolemma are membrane proteins that generate and control the cardiac action potential, responsible for cardiomyocyte contractibility and heart rhythm. Their malfunction can be caused by congenital mutations and side effects of antiarrhythmic therapies and can lead to life-threatening conditions related to heart failure. Other main components are represented by several lipid types, which not only provide the matrix for membrane proteins but also play active roles in regulating protein function. Shifts in membrane physiology through changes in the lipidomic profile or lipid-protein interactions can also cause cardiac disorders. Our goal is to characterize specific lipid-protein interactions in the sarcolemma by studying lipid redistribution around proteins and identifying lipid binding sites that can potentially regulate protein function. We combined lipidomic, cryo-electron microscopy and X-ray crystallography studies to build computational models of the cardiomyocyte sarcolemma. The membrane models consist of 16 lipid species, which differ in headgroup type, levels of acyl tail unsaturation and length. We embedded a selected membrane protein (cardiac ion channel, transporter or receptor) in a lipid bilayer and performed molecular dynamics simulations with the Martini coarse-grained models. We simulated each system with a corresponding membrane protein for 120 μs and analyzed lipid-protein interactions in terms of lipid redistribution around the proteins via computing lipid depletion-enrichment index, lipid density, and predicting lipid binding sites.Our results reproduce experimental findings of the interactions between lipids and the Kir2.2 potassium channel. We propose potential lipid binding sites for other proteins, highlighting similarities and differences in lipid redistribution and interaction with the cardiomyocyte proteins. Such findings unveil new possible lipid-protein interactions in the cardiomyocyte sarcolemma and provide an understanding of their relevance in heart function.