Using Molecular Dynamics Simulations and Statistical Modeling to Explore Membrane Structure and Membrane-Protein Interactions

Abstract

The structure of cellular membranes gives rise to important biological phenomena, and understanding the (de)mixing behavior of multicomponent lipid bilayers is an important step toward unraveling the nature of spatial composition heterogeneities in cellular membranes and their role in biological function. In this dissertation we focus on the spatial organization and compositional heterogeneity of model membrane systems and their interaction with small, biologically relevant peptides. I employed both coarse-grained and atomistic molecular dynamics simulations to study the composition phase diagram of a quaternary mixture of phospholipids and cholesterol, as well as to sample the configurational space of peptide-membrane interactions. I investigate the mechanisms controlling membrane spatial heterogeneity and membrane protein interaction. This work yields important new insight into both the structural properties of lipid bilayer systems with spatial and compositional heterogeneity at vastly different length scales, which has prompted numerous publications in the field seeking for a plausible mechanism. This work will also provide perspectives on configurations of the PAP248-286 peptide upon interacting with membranes, which, despite its importance for human health, has not received as much attention from the research community as other amyloid-forming peptides. In this wide-open field such simulations will have significant scientific impact.