(M1530-06-34) Molecular Dynamics Study Using Coarse-Grained Simulation with Martini Force Field for Structural Stability and Formation of Docetaxel Loaded DOPC and DPPC Lipid Vesicle

Purpose: DOPC (1,2-Dioleoyl-sn-glycero-3-phosphocholine) and DPPC (Dipalmitoyl phosphatidyl choline) phospholipids loaded with Docetaxel were used for the simulation of liposome formation using Schrodinger Materials Science suite 2023-24. The relevance of liposome formation and structural stability with each phospholipid type were evaluated using the coarse grain martini force field. Coarse-grained (CG) models enable longer simulations of larger systems such as lipids by reducing the number of degrees of freedom compared to all-atom models that would help determine the lipid vesicle formation and structural stability. The stability of these structures depends on their phospholipid composition, which significantly impacts the efficacy of disease treatment and drug delivery. Thus, molecular dynamics simulation details valuable insights into exploring the structure and functionality for the lipids in formulation and development of liposomes.

Methods: The coarse grain structures of DOPC and DPPC phospholipids were imported as a coarse-grained state from Materials Science 2023-4 and docetaxel was prepared using the coarse grain sketcher and assigned the coarse-grained force field (1). Simulation boxes were defined with 901 lipids, 60311 molecules of water, 6031 molecules of anti-freeze water, and 5 molecules of drug molecules (2). The simulation time for each liposome was 3000 ns with temperature 300 k, NPT ensemble class, and the time second was set at 10 fs.

Results: The CG simulation of systems showed that the system prepared with DOPC lipids formed a vesicle while that of DPPC lipids formed a nano disc like bilayer structure (Figure 1). At the onset of the simulation, DOPC and DPPC phospholipids were dispersed randomly and heterogeneously among water molecules. Over time, their hydrophobic interactions with the lipid chain cause them to cluster together, resulting in phospholipid molecules aligning side by side. The trajectories were analyzed for the diffusion coefficient, gyration radius (Rg), cluster analysis, Root mean square deviation (RMSD), and Radial distribution function (RDF) to understand the structural stability of the vesicular system (Figure 2). RMSD parameters for DOPC and DPPC lipids attain equilibrium around 1 nanosecond, after which it reaches a constant value to ensure stable structural formation. The number of clusters decreased within the system from 40 to 10 for DOPC and DPPC and further decreased to 1 as the increase in phospholipid collisions resulted in the formation of merged clusters to make the final lipid vesicles. Aggregation to form a single large cluster of lipid vesicle was 1000 ns for the DOPC while for DPPC, it was determined as 700 ns. The Rg indicated that the DOPC and DPPC liposomes remained compressed throughout the simulation duration. The initial values of Rg were approximately above 100 for both DOPC and DPPC which was reduced to less than 60 at the end of simulation. The relative decrease in the Rg confirms the formation of both the elliptical and closed vesicular and nanodisc models with both lipids. The gyration radius of the DOPC and DPPC was not observed with a sharp drop that suggested, there was no significant structural transformation on the self-assembly of lipids. The mean square displacement (MSD) represents the average squared distance a particle travels over time. The diffusion coefficient was determined from the slope of the linear region of the MSD-versus-time curve. The values for the diffusion coefficient range were 7.538 x10-11 m²s^-1 and 9.6905 x10-11 m²s^-1 respectively for both DOPC and DPPC depending on the time scale and the applied force field. The RDF parameter verified that the DOPC and DPPC phospholipids exhibit equilibrium and that the 3000 ns time scale is appropriate for forming and equilibrating the vesicle and nano disc model with both lipids. The attainment of equilibrium in the lipid system is demonstrated by the formation of stable lipid bilayers, indicating sufficient stability by the end of the simulation.

Conclusion: Nanosecond analysis, along with the formation analysis including diffusion coefficient, RDF, gyration radius, cluster analysis, and RMSD demonstrated the formation of a stable self-assembled liposome structure from the two types of phospholipids DOPC and DPPC using Martini Coarse Grained simulation.

References: Paolo Decuzzi et al. Biomolecules. 2022 Oct 13; 23(11): 4678 - 4686. (2) Javadi, H. & Darvishi et al. Sci Rep 2020 Feb 04; 10, 1837.

Snapshots of trajectory of simulated system containing DOPC lipid or DPPC lipid

Trajectory analysis of simulated systems containing DOPC lipid or DPPC lipid