Characterizing Lipid-Protein Interactions and Cellular Membrane Properties Using Computational Methods

Abstract

Biological membranes are dynamic structures composed of lipids and proteins, acting as selective barriers in living cells. Modern research has transformed our understanding of these systems from passive barriers to active participants in cellular processes, with lipid-protein interactions emerging as critical regulators of membrane properties and cellular signaling pathways. Molecular dynamics simulations offer powerful tools for studying these complex systems at the molecular level. During my PhD, I leveraged Martini coarse-grained models for large-scale simulations of biomembranes over extended timescales. First, we characterized lipid distribution patterns around structurally diverse membrane embeddings in asymmetric bilayers, revealing how lipid distribution is influenced by protein geometry and surface properties. Building on these insights, we developed a comprehensive cardiomyocyte sarcolemma model with ten vital membrane proteins each embedded in physiologically relevant lipid compositions. We identified unique lipid signatures around each protein, stable interactions between anionic lipids and protein domains, while also mapping novel cholesterol and diacylglycerol distribution patterns. Next, we incorporated endocannabinoids into our membrane models to investigate their effects on Kir2.1 potassium channels. Combining computational and experimental methods, we demonstrated that endocannabinoids alter channel conductance by modifying membrane physical properties rather than through direct binding. Finally, we examined how different lipid environments affect the yeast transcription factor Mga2. The results showed that Mga2 senses lipid packing and responds to edelfosine, a lysoPC analog. Deep learning predicted Mga2 conformations solely from lipid distributions, highlighting lipid fingerprints' predictive power. These findings advance membrane biology understanding and suggest new avenues for drug discovery and therapies targeting membrane processes.