Date of Award
Open Access Dissertation
Mark J. Uline
Protein localization on biological membranes is motivated by either highly selective recognition of specific target membrane components or nonspecific attraction to general physical properties of the membrane, such as charge, lipid heterogeneity, and curvature. Here we discuss the interaction between lipidated proteins and lipid bilayer membranes from a comprehensive examination of how features of the membrane and its lipid constituents, including lipid composition, headgroup size, degree of tail saturation, tail length (bilayer thickness), and membrane geometry, affect the adsorption ability of the proteins. Of key importance is the strong interconnection among these compositional and morphological elements of the membrane in mediating the adsorption behavior of lipidated proteins. As a model protein, we use the dual lipidated (palmitoyl and farnesyl) anchoring motif of the signaling GTPase, N-Ras (tN-Ras). We find marked augmentation in tN-Ras adsorption with increasing degree of membrane curvature — a trend that is tightly regulated by the bilayer characteristics mentioned above. Experimental results from collaborative research laboratories are fully reproduced by our molecular-level mean-field theoretical model of the systems under study.
Of note, the theory suggests an explicit dependence of the selective adsorption behavior of tN-Ras, with respect to membrane composition and curvature, on the unique lateral pressure profile through the width of a given bilayer. We propose the membrane’s heterogeneous distribution of lateral pressure to be an important mechanism that governs the membrane-protein interaction. Another primary contribution of this work is the revelation that changes in the local Gaussian curvature of the bilayer, independent of mean curvature, motivates a substantial response in the lateral pressure profile through the bilayer’s width, and thus the adsorption trends of the tN-Ras protein. The Gaussian curvature has traditionally been a quantity neglected in theoretical studies involving membrane curvature, stemming from the approximation of the lipid bilayer as an infinitely thin, two-dimensional sheet. The results herein have demonstrated that the structural heterogeneity that exists at the atomic scale through the membrane’s core provokes macroscopic consequences that determine biological function. Thus, an over-arching theme of this work is a message conveying that the width of the bilayer is an essential dimension to be considered in the physics of membrane shape transitions.
Kennard, S. C.(2022). Molecular Theoretical Model for Lipid Bilayers: Adsorption of Lipidated Proteins on Lipid Bilayers as a Function of Bilayer Composition and Curvature. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/6941