(4kg) Molecular Insights into Lipid-Protein Interactions and Lipid Composition Impacts on Ion Channel Protein in Bilayer Membrane

The interactions between lipid bilayer membrane and membrane proteins are essential in multiple biochemical processes and applications, such as ion transport, signal transduction, biosensors, and drug delivery. Among important classes of membrane proteins, voltage-gated ion channels (VGIC) have been shown to be highly sensitive to membrane properties and a variety of lipids. They are regulated not only through the electromechanical potential across the membrane, but also through the lipid composition of the membranes that contain the channels. However, the molecular details of lipid-protein interactions and the mechanisms on how various lipids modulate the channel functions remain elusive. Hence, in this study, we examine the interactions and influences of different lipids on the voltage-gated sodium channel – a critical VGIC in cellular homeostasis and signaling – and their lipid-dependent gating. The channel is embedded in 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) lipid bilayer membrane with other lipid components, including anionic phospholipid (phosphatidic acid - POPA) and non-phospholipid (cholesterol - CHOL). The systems are investigated using multiscale in silico approach, combining molecular dynamics simulation and continuum modeling. As a result, molecular simulations reveal the distribution and aggregation of lipids around the channel protein, while continuum model elucidates the difference in electromechanical energy and open probability of the channel caused by these different lipids. Our model predicts that the anionic lipids aggregate around positively charged residues and affect channel gating via direct electrostatic interactions; meanwhile, cholesterols aggregate near aromatic residues and restrict channel opening through membrane stiffening. Overall, the study aids in the mechanistic understanding of lipid impacts on membrane ion channel proteins, and provide a reference for further studies on mutual lipid-protein interactions in more complex membrane systems for various biomedical, mechanical, and chemical applications.

*We gratefully acknowledge financial support from the New Jersey Institute of Technology and the National Science Foundation, United States through Grants No. CMMI-2237530 and CBET- 2327899.

Research Interests

My research interests lie at the intersection of multiscale modeling and simulation, the mechanics of biological and material systems, and complex biophysical/ biochemical processes spanning across several spatiotemporal scales. I am captivated by the sophistication of biological/biomolecular and nanoscale structures (including the lipid bilayer membranes, lipid/protein complexes, cellular assemblies, soft materials, nanomaterials such as nanoparticles and nanocomposites), the interaction between nanostructures and biological systems, as well as their intricate behaviors such as membrane dynamics, physiological processes, mechanical deformation, structural stability, fluctuation, poration, electromechanical coupling, and lipid-protein or protein-protein interactions. I am passionate about and dedicated to unraveling the mechanistic underpinnings of their properties across various time and length scales. By employing multiscale framework, such as combining molecular dynamics and continuum modeling, I seek to bridge the gap between molecular events, nanoscopic interactions, and macroscopic phenomena in these systems for various applications in engineering, mechanical, biomedical, and chemical fields.