Date of Graduation

5-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Materials Science & Engineering (PhD)

Degree Level

Graduate

Department

Materials Science & Engineering

Advisor/Mentor

Moradi, Mahmoud

Committee Member

Qian, Xianghong

Second Committee Member

Wang, Yong

Third Committee Member

Chen, Jingyi

Fourth Committee Member

Ware, Morgan E.

Keywords

cholesterol; drug delivery design; therapeutic applications

Abstract

Cholesterol is crucial in modulating the behavior and characteristics of biological membranes, liposomes, and proteoliposomes, for instance in drug delivery applications. Cholesterol regulates membrane stability by influencing lipid density, phase separation, and protein-membrane interactions. In planar bilayers, cholesterol enhances membrane thickness, reduces permeability, and promotes lipid ordering, adding rigidity and fluidity. Cholesterol also modulates membrane curvature in curved bilayers and vesicles, stabilizing low-curvature regions. In this work, all-atom molecular dynamics (MD) simulations were employed to examine how varying cholesterol concentrations influence the structure and dynamics of membranes, focusing on planar and curved geometries. Bilayers with cholesterol molar ratios of 0%, 10%, 20%, 30%, 40%, and 50% were simulated, analyzing parameters such as area per lipid (APL), membrane thickness, leaflet interdigitation, and segmental order parameters (SCD). Increasing cholesterol concentration in planar bilayers decreased APL, while increasing membrane thickness and lipid ordering, consistent with cholesterol condensing effect. In curved bilayers, cholesterol induced an expansion effect, particularly in the inner leaflet, with APL increasing as cholesterol concentration rose. SCD profiles indicated that cholesterol enhanced tail ordering up to 40%, after which the effect plateaued, suggesting structural saturation or packing frustration. These findings emphasize the need to consider curvature in liposomal drug delivery design. Additionally, the impact of cholesteryl hemisuccinate (CHS) on the conformational dynamics of mGluR2 involved in neurotransmitter signaling, was studied. CHS concentrations modulated mGluR2 structural stability and conformational behavior, particularly in transmembrane helices, affecting receptor dynamics in both active and inactive states. Optimal CHS concentrations stabilized mGluR2, balancing rigidity and flexibility, with implications for receptor-targeted drug design. This study provides molecular insights into cholesterol role in regulating membrane behavior, lipid-protein interactions, and GPCR function, facilitating the rational design of liposomal systems for therapeutic applications.

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