Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Biochemistry & Molecular Biophysics

First Advisor

Paul A. Janmey

Abstract

Proper functionality of biological membranes depends on the regulation of lipid composition and localization. Spatial localization of molecules within the lipid bilayer depends on both steric effects due to their acyl chains and attractive or repulsive interactions between lipid head groups, such as those mediated by the electrostatic charge of the lipid. Most eukaryotic lipids are zwitterionic or have a charge of -1 at physiological pH, but some lipids such as phosphatidylinositol bisphosphate (PtdInsP2) bear a net charge of -4. The ability of these highly charged lipids to interact with monovalent and divalent cations affects their spatial organization and temporal distribution on the cytoplasmic side of membranes. In turn, these lipids act as important effectors of apoptosis, inflammation, motility, and proliferation through their interactions with proteins at the membrane interface and transmembrane ion channels. We hypothesize that in some settings, the isomers of PtdInsP2 - PtdIns(3,5)P2 and PtdIns(4,5)P2 - act by changing the physical-chemical properties of the membrane rather than by specific biochemical binding to proteins. We also predict that PtdIns(3,5)P2 and PtdIns(4,5)P2 alter the mechanical of properties in distinct ways due to the larger size and altered charge distribution in the head group of PtdIns(3,5)P2. We used multiscale computational techniques, ranging from quantum-level electronic structure calculations to all-atom molecular dynamics simulations of bilayers to characterize the biological role of PtdInsP2. Our results demonstrate that the different roles of PtdIns(4,5)P2 and PtdIns(3,5)P2 in vivo are not simply determined by their localization, but also due to intrinsic factors different between them such as molecular size, propensity to bind cellular divalent cations, and the partial dehydration of those ions which may affect the ability of PtdIns(3,5)P2 and PtdIns(4,5)P2 to form phosphoinositide-rich clusters in vitro and in vivo.

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