Computational investigation of the effects of lipid composition and membrane curvature on membrane mechanics and membrane-protein interactions

• Main Author: Kumar, Jatin
• Other Authors: Huang Changjin
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2024
• Subjects: Engineering
• Online Access: https://hdl.handle.net/10356/173388
• Institution: Nanyang Technological University

As a ubiquitous structure in biological cells, biological membranes are essential for cellular homeostasis and many other important cellular functions. The basic structure of biological membranes primarily consists of a continuous double layer of lipid molecules with integral proteins that span the membrane and/or peripheral proteins that loosely attach to one side of the membrane. Although the double layer structure is well characterized, the biophysical properties of lipid membranes can be complicated by both their high heterogeneity in lipid composition and the high membrane curvature that commonly exists in various subcellular components. Examples of highly curved membranes includes the filopodium membranes extended beyond the leading edge of lamellipodia in migrating cells, small intracellular and extracellular vesicles that are responsible for material transport and intercellular communication, respectively, the envelope of enveloped viruses (e.g., HIV virus and coronaviruses, etc.), etc. How the heterogeneity in lipid composition and membrane curvature modulates the biophysical properties of the membrane and consequently the interaction of the membrane with other cellular entities (e.g., membrane proteins, ions, etc.) remains largely elusive so far. In this PhD work, we studied the effects of lipid composition and membrane curvature on membrane biophysical properties and its interaction with other cellular entities using molecular dynamics (MD) simulations. First of all, the effect of the lipid tail characteristics on the biophysical properties of binary lipid membranes was studied using all-atom MD simulations. Our simulations reveal that the hydrophobic length matching among different lipids drives the biophysical properties of binary membranes to deviate from the predictions based on the linear rule of mixtures. We further investigated the effect of membrane curvature on the dynamics of a symmetrically shaped transmembrane protein Aquaporin 0 (AQP0) using coarse-grained MD simulations. In this work, our simulations identify the asymmetry of the pressure profile across the membrane thickness direction as one of the key factors in controlling protein dynamics in membranes of different curvatures. Finally, we studied the effect of membrane curvature on its interaction with a viral non-structural protein 1 (nsP1) complex using both atomic and coarse-grained MD simulations and uncovered its enhanced binding towards curved membranes. Our improved understanding of the effects of lipid composition and membrane curvature on its biophysical properties and protein-membrane interaction not only provides mechanistic insights into many biological processes that involve biological membranes, but also paves the way for the design of more effective drug delivery platforms, antiviral peptides, etc.