Prajna Dhar

Molecular Engineering and Interfacial Nanomedicine Lab
Department of Chemical and Petroleum Engineering
University of Kansas



Lipid-protein Interactions

Lipid-protein interactions in biological assembly and function: Lipid-protein interactions influence a wide variety of cellular processes (e.g., signal transduction, intracellular transport, antimicrobial defense, and energy conversion in cells). Using model lipid systems, our lab focuses on obtaining a molecular understanding of several disease pathways.

  1. Exploring how lipid-protein interactions help us to breathe: Understanding interactions between lung surfactant proteins, phospholipids and cholesterol that together minimize the work of breathing will impact the design of novel lung surfactants that can be used to treat respiratory diseases in both neonates, infants and adults (the mechanism of lung surfactant dysfunction and respiratory distress are different in these different groups). Using a combination of physicochemical tools, including fluorescence microscopy and atomic force microscopy, we study the effect of different lipids and proteins on the line tension between domains in model lung surfactatants. In addition, we study how domain morphology can be related to its ability to undergo reversible collapse. The figure below shows how a native protein SP-B and a synthetic mimic Mini-B control the formation of reversible folds in a model phospholipid mixture.

    Collapse morphology in model lung surfactant mixture



  2. Understanding lipid-protein interactions in neurodegenerative diseases: recent experimental evidence indicates that in vivo, lipid membranes may serve as two-dimensional templates that induce aggregation of soluble protein monomers into higher order structures, ultimately resulting in the deposition of highly organized fibrillar structures such as amyloid plaques and neurofibrillary tangles. These structures form a common pathology of degenerative disorders affecting the central nervous system (e.g., Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease) and a variety of peripheral tissues (e.g., type II diabetes, liver cirrhosis and degenerative eye diseases). While the interaction between the protein molecules forming early aggregates become difficult to access, particularly for intrinsically disordered proteins (IDPs), largely due to lack of experimental techniques to study such changes, in systems that lack structural order. As a result, detailed knowledge of the organizing principles, particularly the role of the lipid membranes as two-dimensional templates governing the early stages of this directed assembly process, is currently limited. In collaboration with Professor T. Christopher Gamblin’s group at the University of Kansas, we are working to develop an understanding of the initial steps in interface mediated directed self-assembly of IDPs with relevance to various neurodegenerative diseases.



    Preliminary research in our lab also shows that both air-water interface and solid-liquid interfaces can induce oligomer formation in nanomolar concentrations of otherwise soluble Tau protein, even in the absence of any inducer molecules or lipid membranes. This suggests that not only lipid-membranes, but any interface could potentially direct the self-assembly of these intrinsically disordered proteins, simply by reducing a three-dimensional search to a two-dimensional search, that also minimizes the energy barrier for self-assembly. These observations underscore the need to gain fundamental knowledge regarding the possible physical laws governing interface mediated self-assembly of soluble proteins to prevent unwanted interface-induced protein aggregation with deleterious results.