Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Cell Biology

Language

English (en)

Date of Award

January 2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Nathan Baker

Abstract

My thesis work focuses on understanding the role of biological membranes in cellular processes. I am particularly interested in how small molecules perturb membrane structure and regulate membrane function. Membranes are primarily responsible for segregating different compartments of biological cells from each other. However, they have other roles as well, including influencing signal transduction in the cell, both through associated membrane proteins and directly through alterations in membrane organization. In order to understand how small molecules change membranes, I use molecular dynamics simulations of small simplified membranes to examine, at an atomic-level detail, how the addition of small molecules to the membrane can perturb its structure and physical properties and alter membrane function. I focus on a group of small molecules called oxysterols, oxygenated derivatives of cholesterol. They are present in small concentrations in mammalian cells and have been shown to be involved in multiple regulatory pathways involving control of cellular cholesterol levels. The mechanisms through which they transduce signals is not yet well understood. While several oxysterol-binding proteins have been identified, some pathways in which these molecules act appear to be protein-independent. Using molecular dynamics simulations of oxysterols in membranes, I have shown that 1) oxysterols arrange themselves within membranes very differently than cholesterol, 2) the presence of oxysterols causes changes in cholesterol organization within the membrane, and 3) the effects of oxysterols on membranes are highly dependent on the phospholipid composition of the membrane. These simulations have provided atomic detail of how oxysterols can change membrane properties, and provided potential mechanisms of oxysterol signaling that can be further investigated using experimental approaches.

DOI

https://doi.org/10.7936/K7W37TBD

Comments

Permanent URL: http://dx.doi.org/10.7936/K7W37TBD

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