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Abstract Liposomal carriers provide a flexible and effective strategy for delivering therapeutics across a broad spectrum of diseases. Cholesterol is frequently included in these systems to improve membrane rigidity and limit permeability. Despite its widespread use, the optimal cholesterol-to-lipid proportion for achieving stable and efficient liposome performance remains to be fully determined. In this work, we apply all-atom molecular dynamics simulations to explore how different cholesterol concentrations influence the structural and dynamic characteristics of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) bilayers, considering both planar and curved membrane geometries. Bilayers with cholesterol molar ratios of 0%, 10%, 20%, 30%, 40%, and 50% were simulated, and key biophysical parameters including area per lipid (APL), membrane thickness, leaflet interdigitation, and deuterium order parameters (SCD) were analyzed. In planar bilayers, increasing cholesterol concentration led to a progressive decrease in APL from approximately 60^°A²to 40^°A², accompanied by increased membrane thickness and lipid ordering, consistent with cholesterol’s classical condensing effect. In contrast, curved bilayers exhibited a cholesterol-induced expansion effect, particularly in the inner leaflet, where APL increased from approximately 60^°A²to 90^°A²with rising cholesterol levels. SCD profiles showed that cholesterol enhanced tail ordering up to 40% concentration, beyond which the effect plateaued or slightly declined, suggesting structural saturation or packing frustration. Membrane thickness displayed a monotonic increase in planar bilayers but followed a nonlinear trend in curved systems due to curvature-induced stress. These findings highlight that cholesterol’s influence on membrane properties is highly dependent on bilayer geometry and asymmetry. While planar bilayers exhibit predictable responses, curved systems reveal nonclassical behaviors that challenge traditional models of cholesterol-lipid interactions. This work provides molecular-level insights and establishes a computational framework for the rational design of liposomal systems, emphasizing the need to account for curvature and asymmetry in membrane engineering. 

Abstract Metabotropic glutamate receptor 2 (mGluR2), a subclass C member of the G protein-coupled receptor (GPCR) superfamily, is essential for regulating neurotransmitter signaling and facilitating synaptic adaptability in the central nervous system. This receptor, like other GPCRs, is highly sensitive to its surrounding lipid environment, where specific lipid compositions can influence its stability, conformational dynamics, and function. In particular, cholesteryl hemisuccinate (CHS) plays a critical role in stabilizing mGluR2 and modulating its structural states within cellular membranes and micellar environments. However, the molecular basis for this lipid-mediated modulation remains largely unexplored. To investigate the effects of CHS and lipid composition on mGluR2, we employed all-atom molecular dynamics simulations of mGluR2 embedded in both detergent micelles (BLMNG and CHS) and a POPC lipid bilayer containing 0%, 10%, and 25% CHS. These simulations were conducted for both active and inactive states of the receptor. Our findings reveal that CHS concentration modulates mGluR2’s structural stability and conformational behavior, with a marked impact observed within transmembrane helices TM1, TM2, and TM3, which constitute the core of the receptor’s transmembrane domain. In micelle environments, mGluR2 displayed unique conformational dynamics influenced by CHS, underscoring the receptor’s sensitivity to its lipid surroundings. Notably, a CHS concentration of 10% elicited more pronounced conformational changes than either cholesterol-depleted (0%) or cholesterol-enriched (25%) systems, indicating an optimal CHS range for maintaining structural stability. Our study provides atomistic insights into how lipid composition and CHS concentration impact mGluR2’s conformational landscape in distinct micelle and bilayer environments. These findings advance our understanding of lipid-mediated modulation in GPCR function, highlighting potential avenues for receptor-targeted drug design, particularly in cases where lipid interactions play a significant role in therapeutic efficacy.