Biology subjects

Khodadadi, E.

Publications and source records attributed to Khodadadi, E..

5 recordsLinked to original sources

bioRxiv2026

Cholesterol-Dependent Structure and Dynamics of Curved Lipid Vesicles Revealed by Dry MARTINI Simulations

Cholesterol is a key regulator of membrane structure and dynamics, yet its effects on large curved vesicles under implicit-solvent coarse-grained conditions remain incompletely understood. Equilibrating large Dry MARTINI vesicles is challenging because transient membrane deformations can arise during the early stages of equilibration. Here, we developed a leaflet-specific restrained-equilibration protocol that preserves vesicle geometry while allowing local lipid relaxation. All restraints were removed before production simulations, and all reported results were obtained from unbiased trajectories. Using this protocol together with the Dry MARTINI force field and the TS2CG membrane builder, we simulated [~]50 nm DOPC vesicles containing 0-40 mol% cholesterol in three independent 20 {micro}s production simulations for each membrane composition. Increasing cholesterol concentration produced a consistent structural reorganization of the membrane, characterized by increased membrane thickness and lipid-tail ordering, and decreased species-specific Voronoi area per lipid, lipid-tail interdigitation, solvent-accessible surface area, and vesicle shape anisotropy. Cholesterol flip-flop increased progressively with cholesterol concentration, whereas DOPC flip-flop exhibited a reproducible non-monotonic dependence with a maximum near 20 mol% cholesterol. Comparison with our previous explicit-solvent MARTINI simulations showed that the major cholesterol-dependent structural trends were preserved across both solvent representations, whereas species-specific lipid packing, lipid-tail interdigitation, and the absolute magnitude of lipid flip-flop remained sensitive to the solvent representation. Overall, Dry MAR-TINI combined with the restrained-equilibration protocol provides an efficient framework for studying large curved cholesterol-containing vesicles.

bioengineering↗

bioRxiv2026

Interplay Between Cholesterol Concentration and Membrane Curvature in Liposomes Revealed by Molecular Dynamics Simulations

Liposomes are widely used as model membranes and nanoscale drug delivery systems, where cholesterol plays a key role in regulating bilayer structure and dynamics. However, how cholesterol concentration influences the structure and dynamics of liposome and how this influence is dependent on membrane curvature are not fully understood at the molecular level. In this work, coarse-grained molecular dynamics simulations using the MARTINI force field were employed to examine the concentration-dependent behavior of cholesterol in planar and curved membranes composed of cholesterol and unsaturated phospholipids, namely DOPC. More specifically, a planar lipid bilayer and an approximately 50-nm liposome were simulated to represent two extreme limits of small and large curvature, respectively. Increasing cholesterol concentration led to thicker membranes and reduced solvent exposure, consistent with cholesterols condensing effect. Membrane curvature enhanced interleaflet coupling and increased tail interdigitation relative to planar systems. Notably, DOPC flip-flop rate in spherical bilayers exhibited a non-monotonic dependence on cholesterol content, reflecting a balance between curvature-induced packing stress and cholesterol-driven ordering. These findings provide molecular-level insight into how cholesterol and curvature together shape the structure and dynamics of unsaturated lipid bilayers.

biophysics↗

bioRxiv2026

An Investigation of the Conformational Dynamics of ABC Exporter PCAT1 using Microsecond-Level MD Simulations

Peptidase-containing ATP-binding cassette transporters (PCATs) couple ATP hydrolysis with proteolytic processing and export of cargo peptides across cellular membranes. Despite their importance in bacterial secretion systems, the molecular determinants governing nucleotide binding and stabilization in PCAT transporters remain incompletely understood. In particular, recent experimental observations suggest that PCAT1 may display altered nucleotide preferences compared with canonical ABC transporters. Here, we employed microsecond-scale all-atom molecular dynamics simulations combined with free energy perturbation (FEP) calculations to characterize nucleotide binding, protein stability, and conformational dynamics of PCAT1 across multiple biochemical conditions. Simulations were performed for inward-facing (IF) and outward-facing (OF) conformations in the presence or absence of Mg2+ and substrate peptides. Structural analyses reveal that substrate and Mg2+ jointly stabilize the IF conformation, reducing global structural fluctuations and enhancing nucleotide retention in the binding pockets. In contrast, systems lacking Mg2+ exhibit increased nucleotide mobility and partial dissociation events. Thermodynamic analysis using FEP calculations further demonstrates that ATP binding is strongly stabilized in the IF state, particularly in the presence of Mg2+, whereas nucleotide stability is reduced when Mg2+ coordination is absent. To identify the molecular origins of nucleotide stabilization, we introduce a residue-level free energy decomposition approach that quantifies the contribution of individual residues to nucleotide binding energetics. This analysis reveals that the Walker A residue Lys525 provides the dominant stabilizing interaction with ATP, while neighboring residues within the Walker A motif contribute additional stabilization. In contrast, acidic residues of the Walker B motif primarily participate in catalytic organization rather than direct nucleotide stabilization. Together, these results provide a comprehensive molecular description of nucleotide stabilization and conformational regulation in PCAT1. The combined structural and energetic analyses support a model in which Mg2+ coordination and substrate binding cooperatively stabilize the inward-facing state and organize the nucleotide-binding site for productive ATP hydrolysis. More broadly, this work demonstrates how residue-level free energy analysis can reveal the energetic architecture of nucleotide recognition in ABC transporters.

biophysics↗

bioRxiv2025

Molecular Insights into Cholesterol Concentration Effects on Planar and Curved Lipid Bilayers for Liposomal Drug Delivery

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 {degrees}A2 to 40 {degrees}A2, accompanied by increased membrane thickness and lipid ordering, consistent with cholesterols classical condensing effect. In contrast, curved bilayers exhibited a cholesterol-induced expansion effect, particularly in the inner leaflet, where APL increased from approximately 60 {degrees}A2 to 90 {degrees}A2 with 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 cholesterols 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.

biophysics↗

bioRxiv2025

Lipid-Mediated Modulation of mGluR2 Embedded in Micelle and Bilayer Environments: Insights from Molecular Dynamics

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 mGluR2s structural stability and conformational behavior, with a marked impact observed within transmembrane helices TM1, TM2, and TM3, which constitute the core of the receptors transmembrane domain. In micelle environments, mGluR2 displayed unique conformational dynamics influenced by CHS, underscoring the receptors 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 mGluR2s 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.

biophysics↗