The molecular study of lipid membrane curvature generation and sustainment mechanisms using all-atom and ultra-coarse-grained simulations.

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Abstract / Project Summary Diverse cellular functions require lipid membrane remodeling. This remodeling can be due to something as simple as a protein changing conformation to as complex as cell division. Regardless of the purpose, the remodeling energetics are determined by delicate, atomic-level lipid-lipid, protein-lipid, and / or protein-protein interactions that lead to macroscopic membrane shape changes and underline diseases involving local lipid concentration, cellular toxin / virus entry, and how the cell maintains its integrity. This proposal seeks to quantify the physical origins of biologically important membrane remodeling processes and propose important lipid-lipid / protein-lipid interaction motifs using molecular dynamics (MD) and ultra-coarse-grained (UCG) simulations. MD simulations inherently describe delicate protein / lipid interactions albeit on limited time- and length-scales. Some problems cannot be efficiently studied using all-atom MD, and in these cases, the systems will be drastically simplified to access larger time- and length-scale dynamics data. This simplification method is called UCGing herein, and is a physics-based method of extracting dynamics data from all-atom simulations to inform the physics of the UCG model (e.g., a lipid membrane is represented as a fluctuating mesh and proteins are reduced to simple geometric shapes). UCGing acts as a logical bridge between all-atom simulations and experimental techniques that typically access longer time- and length-scales than all-atom MD. This proposal aims to study diverse situations where lipid membrane remodeling is critical and not fully understood: i) interactions between special lipids called gangliosides as well as their strong interactions with cholera toxin; ii) the lipid-lipid and protein-lipid interactions that stabilize large cellular “dimples” called caveolae; and iii) the strong protein-protein interactions that “scaffold” some of the most highly curved lipid membranes in the human body. This work supports the NIGMS mission of understanding fundamental biological structures and processes at the A° ngstrom- to nanometer-scale by describing molecular and energetic detail of important biological events. In addition to studying these biologically meaningful systems, this fellowship will be centered around training. Training will include building and honing scientific, ethical, and personal knowledge that will produce a more mature and readied independent researcher.